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Qian M, Guan M, Wang L, Hu N. Tacrolimus and diabetic rodent models. Pharmacol Rep 2025; 77:333-354. [PMID: 39836342 DOI: 10.1007/s43440-024-00693-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 12/19/2024] [Accepted: 12/29/2024] [Indexed: 01/22/2025]
Abstract
Tacrolimus (TAC) is an immunosuppressant widely utilized in organ transplantation. One of its primary adverse effects is glucose metabolism disorder, which significantly increases the risk of diabetes. Investigating the molecular mechanisms underlying TAC-induced diabetes is essential for developing effective prevention and treatment strategies for these adverse effects. In addition, TAC can induce cost-effective, non-obese animal models of diabetes, where the metabolic parameter changes closely resemble those observed during the onset and progression of type 2 diabetes (T2DM), post-transplantation diabetes mellitus (PTDM), and associated complications. This review, based on articles indexed in PubMed up to August 19, 2024, identified 48 studies focusing on TAC-induced diabetic rodent models and 22 studies exploring the effects of TAC on diabetic or obese rodent models. These studies were systematically summarized based on TAC dosage, route of administration, duration of administration, and glucose metabolism indices used for evaluation. Additionally, the impact of TAC dose reduction or discontinuation on glucose metabolism was assessed, along with pharmacological agents that modulate TAC-induced diabetes, including anti-diabetic medications, anti-inflammatory and antioxidant compounds, biologics, and antibiotics. Key signaling pathways implicated in TAC-induced diabetes include CaN/NFAT, PI3K/AKT/mTOR, and TGF-β/Smad, all of which impair islet β-cell function, thereby contributing to diabetes development. This review provides a concise summary of the characteristics of relevant murine models, offering valuable guidance for selecting appropriate and economical animal models for future research.
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Affiliation(s)
- Minyan Qian
- Department of Pharmacy, The First People's Hospital of Changzhou/The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215127, Jiangsu, China
| | - Mengmeng Guan
- Department of Pharmacy, The First People's Hospital of Changzhou/The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215127, Jiangsu, China
| | - Liying Wang
- Department of Pharmacy, The First People's Hospital of Changzhou/The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Nan Hu
- Department of Pharmacy, The First People's Hospital of Changzhou/The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
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Altabas V, Bulum T. Current Challenges in Pancreas and Islet Transplantation: A Scoping Review. Biomedicines 2024; 12:2853. [PMID: 39767759 PMCID: PMC11673013 DOI: 10.3390/biomedicines12122853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/07/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Type 1 diabetes mellitus is an autoimmune condition characterized by the destruction of pancreatic β-cells, necessitating insulin therapy to prevent life-threatening complications such as diabetic ketoacidosis. Despite advancements in glucose monitoring and pharmacological treatments, managing this disease remains challenging, often leading to long-term complications and psychological burdens, including diabetes distress. Advanced treatment options, such as whole-pancreas transplantation and islet transplantation, aim to restore insulin production and improve glucose control in selected patients with diabetes. The risk of transplant rejection necessitates immunosuppressive therapy, which increases susceptibility to infections and other adverse effects. Additionally, surgical complications, including infection and bleeding, are significant concerns, particularly for whole-pancreas transplantation. Recently, stem cell-derived therapies for type 1 diabetes have emerged as a promising alternative, offering potential solutions to overcome the limitations of formerly established transplantation methods. The purpose of this scoping review was to: (1) summarize the current evidence on achieved insulin independence following various transplantation methods of insulin-producing cells in patients with type 1 diabetes; (2) compare insulin independence rates among whole-pancreas transplantation, islet cell transplantation, and stem cell transplantation; and (3) identify limitations, challenges and potential future directions associated with these techniques. We systematically searched three databases (PubMed, Scopus, and Web of Science) from inception to November 2024, focusing on English-language, peer-reviewed clinical studies. The search terms used were 'transplantation' AND 'type 1 diabetes' AND 'insulin independence'. Studies were included if they reported on achieved insulin independence, involved more than 10 patients with type 1 diabetes, and had a mean follow-up period of at least one year. Reviewers screened citations and extracted data on transplant type, study population size, follow-up duration, and insulin independence rates. We identified 1380 papers, and after removing duplicates, 705 papers remained for title and abstract screening. A total of 139 English-language papers were retrieved for full-text review, of which 48 studies were included in this review. The findings of this scoping review indicate a growing body of literature on transplantation therapy for type 1 diabetes. However, significant limitations and challenges, like insufficient rates of achieved insulin independence, risks related to immunosuppression, malignant diseases, and ethical issues remain with each of the established techniques, highlighting the need for innovative approaches such as stem cell-derived islet transplantation to promote β-cell regeneration and protection.
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Affiliation(s)
- Velimir Altabas
- Department of Endocrinology, Diabetes and Metabolic Diseases Mladen Sekso, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Tomislav Bulum
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, 10000 Zagreb, Croatia
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Chetboun M, Masset C, Maanaoui M, Defrance F, Gmyr V, Raverdy V, Hubert T, Bonner C, Supiot L, Kerleau C, Blancho G, Branchereau J, Karam G, Chelghaf I, Houzet A, Giral M, Garandeau C, Dantal J, Le Mapihan K, Jannin A, Hazzan M, Caiazzo R, Kerr-Conte J, Vantyghem MC, Cantarovich D, Pattou F. Primary Graft Function and 5 Year Insulin Independence After Pancreas and Islet Transplantation for Type 1 Diabetes: A Retrospective Parallel Cohort Study. Transpl Int 2023; 36:11950. [PMID: 38213551 PMCID: PMC10783428 DOI: 10.3389/ti.2023.11950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 12/08/2023] [Indexed: 01/13/2024]
Abstract
In islet transplantation (ITx), primary graft function (PGF) or beta cell function measured early after last infusion is closely associated with long term clinical outcomes. We investigated the association between PGF and 5 year insulin independence rate in ITx and pancreas transplantation (PTx) recipients. This retrospective multicenter study included type 1 diabetes patients who underwent ITx in Lille and PTx in Nantes from 2000 to 2022. PGF was assessed using the validated Beta2-score and compared to normoglycemic control subjects. Subsequently, the 5 year insulin independence rates, as predicted by a validated PGF-based model, were compared to the actual rates observed in ITx and PTx patients. The study enrolled 39 ITx (23 ITA, 16 IAK), 209 PTx recipients (23 PTA, 14 PAK, 172 SPK), and 56 normoglycemic controls. Mean[SD] PGF was lower after ITx (ITA 22.3[5.2], IAK 24.8[6.4], than after PTx (PTA 38.9[15.3], PAK 36.8[9.0], SPK 38.7[10.5]), and lower than mean beta-cell function measured in normoglycemic control: 36.6[4.3]. The insulin independence rates observed at 5 years after PTA and PAK aligned with PGF predictions, and was higher after SPK. Our results indicate a similar relation between PGF and 5 year insulin independence in ITx and solitary PTx, shedding new light on long-term transplantation outcomes.
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Affiliation(s)
- Mikael Chetboun
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of General, Endocrine and Metabolic Surgery, Lille, France
| | - Christophe Masset
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Mehdi Maanaoui
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of Nephrology, Lille, France
| | - Frédérique Defrance
- CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Lille, France
| | - Valéry Gmyr
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Violeta Raverdy
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of General, Endocrine and Metabolic Surgery, Lille, France
| | - Thomas Hubert
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Caroline Bonner
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Lisa Supiot
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Clarisse Kerleau
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - Gilles Blancho
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Julien Branchereau
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Georges Karam
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Ismaël Chelghaf
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - Aurélie Houzet
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - Magali Giral
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Claire Garandeau
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - Jacques Dantal
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Kristell Le Mapihan
- CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Lille, France
| | - Arnaud Jannin
- CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Lille, France
| | - Marc Hazzan
- CHU Lille, Department of Nephrology, Lille, France
| | - Robert Caiazzo
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of General, Endocrine and Metabolic Surgery, Lille, France
| | - Julie Kerr-Conte
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Marie-Christine Vantyghem
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Lille, France
| | - Diego Cantarovich
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - François Pattou
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of General, Endocrine and Metabolic Surgery, Lille, France
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So WY, Liao Y, Liu WN, Rutter GA, Han W. Paired box 6 gene delivery preserves beta cells and improves islet transplantation efficacy. EMBO Mol Med 2023; 15:e17928. [PMID: 37933577 DOI: 10.15252/emmm.202317928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 10/09/2023] [Accepted: 10/13/2023] [Indexed: 11/08/2023] Open
Abstract
Loss of pancreatic beta cells is the central feature of all forms of diabetes. Current therapies fail to halt the declined beta cell mass. Thus, strategies to preserve beta cells are imperatively needed. In this study, we identified paired box 6 (PAX6) as a critical regulator of beta cell survival. Under diabetic conditions, the human beta cell line EndoC-βH1, db/db mouse and human islets displayed dampened insulin and incretin signalings and reduced beta cell survival, which were alleviated by PAX6 overexpression. Adeno-associated virus (AAV)-mediated PAX6 overexpression in beta cells of streptozotocin-induced diabetic mice and db/db mice led to a sustained maintenance of glucose homeostasis. AAV-PAX6 transduction in human islets reduced islet graft loss and improved glycemic control after transplantation into immunodeficient diabetic mice. Our study highlights a previously unappreciated role for PAX6 in beta cell survival and raises the possibility that ex vivo PAX6 gene transfer into islets prior to transplantation might enhance islet graft function and transplantation outcome.
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Affiliation(s)
- Wing Yan So
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Yilie Liao
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, 528400, China
- Center for Neurometabolism and Regenerative Medicine, Bioland Laboratories, Guangzhou, Guangdong, 510530, China
| | - Wai Nam Liu
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Guy A Rutter
- Centre de Recherche du CHUM, Faculté de Médicine, Université de Montréal, Montréal, QC, Canada
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
- Lee Kong Chian Imperial Medical School, Nanyang Technological University, Singapore, Singapore
| | - Weiping Han
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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Lemos JRN, Poggioli R, Ambut J, Bozkurt NC, Alvarez AM, Padilla N, Vendrame F, Ricordi C, Baidal DA, Alejandro R. Impact of GAD65 and IA2 autoantibodies on islet allograft survival. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2023; 4:1269758. [PMID: 38028981 PMCID: PMC10679328 DOI: 10.3389/fcdhc.2023.1269758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 10/02/2023] [Indexed: 12/01/2023]
Abstract
Introduction Islet transplantation (ITx) shows promise in treating T1D, but the role of islet autoantibodies on graft survival has not been clearly elucidated. We aimed to analyze the effect of GAD65 and IA2 autoantibody status on graft survival and attainment of insulin independence in subjects with T1D who underwent ITx. Method We conducted a retrospective cohort study on 47 ITx recipients from 2000 to 2018. Islet infusion was performed via intrahepatic portal (n=44) or onto the omentum via laparoscopic approach (n=3). Immunosuppression involved anti-IL2 receptor antibody, anti-TNF, and dual combinations of sirolimus, tacrolimus, or mycophenolate mofetil (Edmonton-like) in 38 subjects (80.9%). T-cell depletion induction with Edmonton-like maintenance was used in 9 subjects (19%). GAD65 and IA2 autoantibodies were assessed pre-transplant and post-transplant (monthly) until graft failure, and categorized as persistently negative, persistently positive, or seroconverters. Graft survival was analyzed using U-Mann-Whitney test, and Quade's nonparametric ANCOVA adjusted for confounders. Kaplan-Meier and Log-Rank tests were employed to analyze attainment of insulin independence. P value <0.05 indicated statistical significance. Results ITx recipients with persistent autoantibody negativity (n = 21) showed longer graft function (98 [61 - 182] months) than those with persistent autoantibody positivity (n = 18; 38 [13 - 163] months), even after adjusting for immunosuppressive induction protocol (P = 0.027). Seroconverters (n=8) had a median graft survival time of 73 (7.7 - 167) months, which did not significantly differ from the other 2 groups. Subjects with persistently single antibody positivity to GAD65 (n = 8) had shorter graft survival compared to negative islet autoantibody (GAD65/IA2) subjects (n = 21; P = 0.016). Time of graft survival did not differ in subjects with single antibody positivity to IA2. The proportion of insulin independence attainment was similar irrespective of autoantibody status. Conclusion The persistence of islet autoantibodies, as markers of islet autoimmunity, may represent an underappreciated contributing factor to the failure of transplanted β cells. Whether induction with T-cell depletion may lead to improved graft survival, independent of islet autoantibody status, could not be evaluated in our cohort. Larger prospective studies are needed to further address the role of islet autoantibody status on islet graft survival.
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Affiliation(s)
- Joana R. N. Lemos
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Raffaella Poggioli
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Jonathan Ambut
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Nujen C. Bozkurt
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Ana M. Alvarez
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Nathalia Padilla
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Francesco Vendrame
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Camillo Ricordi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Cellular Transplantation, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - David A. Baidal
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Rodolfo Alejandro
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
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Chetboun M, Drumez E, Ballou C, Maanaoui M, Payne E, Barton F, Kerr-Conte J, Vantyghem MC, Piemonti L, Rickels MR, Labreuche J, Pattou F. Association between primary graft function and 5-year outcomes of islet allogeneic transplantation in type 1 diabetes: a retrospective, multicentre, observational cohort study in 1210 patients from the Collaborative Islet Transplant Registry. Lancet Diabetes Endocrinol 2023; 11:391-401. [PMID: 37105208 PMCID: PMC10388704 DOI: 10.1016/s2213-8587(23)00082-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 03/04/2023] [Accepted: 03/06/2023] [Indexed: 04/29/2023]
Abstract
BACKGROUND Allogeneic islet transplantation is a validated therapy in type 1 diabetes; however, there is decline of transplanted islet graft function over time and the mechanisms underlying this decline are unclear. We evaluated the distinct association between primary graft function (PGF) and 5-year islet transplantation outcomes. METHODS In this retrospective, multicentre, observational cohort study, we enrolled all patients from the Collaborative Islet Transplant Registry who received islet transplantation alone (ITA recipients) or islet-after-kidney transplantation (IAK recipients) between Jan 19, 1999, and July 17, 2020, with a calculable PGF (exposure of interest), measured 28 days after last islet infusion with a validated composite index of islet graft function (BETA-2 score). The primary outcome was cumulative incidence of unsuccessful islet transplantation, defined as an HbA1c of 7·0% (53 mmol/mol) or higher, or severe hypoglycaemia (ie, requiring third-party intervention to correct), or a fasting C-peptide concentration of less than 0·2 ng/mL. Secondary outcomes were graft exhaustion (fasting C-peptide <0·3 ng/mL); inadequate glucose control (HbA1c ≥7·0% [53 mmol/mol] or severe hypoglycaemia); and requirement for exogenous insulin therapy (≥14 consecutive days). Associations between PGF and islet transplantation outcomes were explored with a competing risk analysis adjusted for all covariates suspected or known to affect outcomes. A predictive model based on PGF was built and internally validated by using bootstraps resampling method. FINDINGS In 39 centres worldwide, we enrolled 1210 patients with a calculable PGF (of those without missing data, mean age 47 years [SD 10], 712 [59·5%] were female, and 865 (97·9%) were White), who received a median of 10·8 thousand islet-equivalents per kg of bodyweight (IQR 7·4-13·5). 986 (82·4%) were ITA recipients and 211 (17·6%) were IAK recipients. Of 1210 patients, 452 (37·4%) received a single islet infusion and 758 (62·6%) received multiple islet infusions. Mean PGF was 14·3 (SD 8·8). The 5-year cumulative incidence of unsuccessful islet transplantation was 70·7% (95% CI 67·2-73·9), and was inversely and linearly related to PGF, with an adjusted subhazard ratio (sHR) of 0·77 (95% CI 0·72-0·82) per 5-unit increase of BETA-2 score (p<0·0001). Secondary endpoints were similarly related to PGF. The model-adjusted median C-statistic values of PGF for predicting 5-year cumulative incidences of unsuccessful islet transplantation, graft exhaustion, inadequate glucose control, and exogenous insulin therapy were 0·70 (range 0·69-0·71), 0·76 (0·74-0·77), 0·65 (0·64-0·66), and 0·72 (0·71-0·73), respectively. INTERPRETATION This global multicentre study reports a linear and independent association between PGF and 5-year clinical outcomes of islet transplantation. The main study limitations are its retrospective design and the absence of analysis of complications. FUNDING Public Health Service Research, National Institutes of Health, Juvenile Diabetes Research Foundation International, Agence National de la Recherche, Fondation de l'Avenir, and Fonds de Dotation Line Renaud-Loulou Gasté.
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Affiliation(s)
- Mikaël Chetboun
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France; CHU Lille, Department of General and Endocrine Surgery, Lille, France
| | - Elodie Drumez
- CHU Lille, ULR 2694 Évaluation des technologies de santé et des pratiques médicales (METRICS), Lille, France
| | - Cassandra Ballou
- Collaborative Islet Transplant Registry, The EMMES Company, Rockville, MD, USA
| | - Mehdi Maanaoui
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France; CHU Lille, Department of Nephrology, Lille, France
| | - Elizabeth Payne
- Collaborative Islet Transplant Registry, The EMMES Company, Rockville, MD, USA
| | - Franca Barton
- Collaborative Islet Transplant Registry, The EMMES Company, Rockville, MD, USA
| | - Julie Kerr-Conte
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France
| | - Marie-Christine Vantyghem
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France; CHU Lille, Department of Endocrinology, Diabetology, and Metabolism, Lille, France
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS, Ospedale San Raffaele, 20132 Milan, Italy
| | - Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Julien Labreuche
- CHU Lille, ULR 2694 Évaluation des technologies de santé et des pratiques médicales (METRICS), Lille, France
| | - François Pattou
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France; CHU Lille, Department of General and Endocrine Surgery, Lille, France.
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Extracellular Vesicles: The Future of Diagnosis in Solid Organ Transplantation? Int J Mol Sci 2023; 24:ijms24065102. [PMID: 36982182 PMCID: PMC10048932 DOI: 10.3390/ijms24065102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/10/2023] Open
Abstract
Solid organ transplantation (SOT) is a life-saving treatment for end-stage organ failure, but it comes with several challenges, the most important of which is the existing gap between the need for transplants and organ availability. One of the main concerns in this regard is the lack of accurate non-invasive biomarkers to monitor the status of a transplanted organ. Extracellular vesicles (EVs) have recently emerged as a promising source of biomarkers for various diseases. In the context of SOT, EVs have been shown to be involved in the communication between donor and recipient cells and may carry valuable information about the function of an allograft. This has led to an increasing interest in exploring the use of EVs for the preoperative assessment of organs, early postoperative monitoring of graft function, or the diagnosis of rejection, infection, ischemia-reperfusion injury, or drug toxicity. In this review, we summarize recent evidence on the use of EVs as biomarkers for these conditions and discuss their applicability in the clinical setting.
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8
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Loretelli C, Pastore I, Lunati ME, Abdelsalam A, Usuelli V, Assi E, Fiorina E, Loreggian L, Balasubramanian HB, Xie Y, Yang J, El Essawy B, Montefusco L, D'Addio F, Ben Nasr M, Fiorina P. eATP and autoimmune diabetes. Pharmacol Res 2023; 190:106709. [PMID: 36842542 DOI: 10.1016/j.phrs.2023.106709] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 02/26/2023]
Abstract
PURPOSE OF REVIEW The purine nucleotide adenosine triphosphate (ATP) is released into extracellular spaces as extracellular ATP (eATP) as a consequence of cell injury or death and activates the purinergic receptors. Once released, eATP may facilitate T-lymphocyte activation and differentiation. The purpose of this review is to elucidate the role of ATP-mediated signaling in the immunological events related to type 1 diabetes (T1D). RECENT FINDINGS T lymphocytes mediate immune response during the onset of T1D and promote pancreatic islet or whole pancreas rejection in transplantation. Recent data suggest a potential role for eATP in early steps of T1D onset and of allograft rejection. In different preclinical experimental models and clinical trials, several drugs targeting purinergic signaling have been employed to abrogate lymphocyte activation and differentiation, thus representing an achievable treatment to prevent/revert T1D or to induce long-term islet allograft function. SUMMARY In preclinical and clinical settings, eATP-signaling inhibition induces immune tolerance in autoimmune disease and in allotransplantation. In this view, the purinergic system may represent a novel therapeutic target for auto- and allo-immunity.
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Affiliation(s)
- Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Ahmed Abdelsalam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Emma Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Lara Loreggian
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Hari Baskar Balasubramanian
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Yanan Xie
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Yang
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Basset El Essawy
- Medicine, Al-Azhar University, Cairo, Egypt; Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Boston, MA, USA
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy; Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy; Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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9
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Lemos JRN, Baidal DA, Poggioli R, Fuenmayor V, Chavez C, Alvarez A, Ricordi C, Alejandro R. HLA-B Matching Prolongs Allograft Survival in Islet Cell Transplantation. Cell Transplant 2023; 32:9636897231166529. [PMID: 37526141 PMCID: PMC10395153 DOI: 10.1177/09636897231166529] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 03/08/2023] [Accepted: 03/14/2023] [Indexed: 08/02/2023] Open
Abstract
Islet cell transplantation (ITx) is an effective therapeutic approach for selected patients with type 1 diabetes with hypoglycemia unawareness and severe hypoglycemia events. In organ transplantation, human leukocyte antigen (HLA) mismatching between donor and recipient negatively impacts transplant outcomes. We aimed to determine whether HLA matching has an impact on islet allograft survival. Forty-eight patients were followed up after islet transplantation at our institution from 2000 to 2020 in a retrospective cohort. Patients underwent intrahepatic ITx or laparoscopic omental approach. Immunosuppression was dependent upon the protocol. We analyzed HLA data restricted to A, B, and DR loci on allograft survival using survival and subsequent multivariable analyses. Patients were aged 42.8 ± 8.4 years, and 64.3% were female. Diabetes duration was 28.6 ± 11.6 years. Patients matching all three HLA loci presented longer graft survival (P = 0.030). Patients with ≥1 HLA-B matching had longer graft survival compared with zero matching (P = 0.025). The number of HLA-B matching was positively associated with time of graft survival (Spearman's rho = 0.590; P = 0.034). Analyses adjusted for confounders showed that ≥1 matching for HLA-B decreased the risk of allograft failure (P = 0.009). Our data suggest that HLA-B matching between recipients and donors improved islet allograft survival. Matching all three HLA loci (A, B, and DR) was also associated with prolonged islet allograft survival. Prospective studies and a larger sample size are warranted to validate our findings.
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Affiliation(s)
- Joana R. N. Lemos
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - David A. Baidal
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Raffaella Poggioli
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Virginia Fuenmayor
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Carmen Chavez
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Ana Alvarez
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Camillo Ricordi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL, USA
- Division of Cellular Transplantation, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Rodolfo Alejandro
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL, USA
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10
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The challenge of HLA donor specific antibodies in the management of pancreatic islet transplantation: an illustrative case-series. Sci Rep 2022; 12:12463. [PMID: 35864198 PMCID: PMC9304358 DOI: 10.1038/s41598-022-16782-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/15/2022] [Indexed: 11/26/2022] Open
Abstract
Islet transplantation is a unique paradigm in organ transplantation, since multiple donors are required to achieve complete insulin-independence. Preformed or de novo Donor Specific Antibodies (DSA) may target one or several donor islets, which adds complexity to the analysis of their impact. Adult patients with type 1 diabetes transplanted with pancreatic islets between 2005 and 2018 were included in a single-center observational study. Thirty-two recipients with available sera tested by solid-phase assays for anti-HLA antibodies during their whole follow-up were analyzed. Twenty-five recipients were islet-transplantation-alone recipients, and 7 islet-after-kidney recipients. Seven recipients presented with DSA at any time during follow-up (two with preformed DSA only, one with preformed and de novo DSA, 4 with de novo DSA only). Only islet-transplantation-alone recipients presented with de novo DSA. Three clinical trajectories were identified according to: 1/the presence of preformed DSA, 2/early de novo DSA or 3/late de novo DSA. Only late de novo DSA were associated with unfavorable outcomes, depicted by a decrease of the β-score. Islet transplantation with preformed DSA, even with high MFI values, is associated with favorable outcomes in our experience. On the contrary, de novo DSA, and especially late de novo DSA, may be associated with allograft loss.
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11
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Lam A, Oram RA, Forbes S, Olateju T, Malcolm AJ, Imes S, Shapiro AMJ, Senior PA. Estimation of Early Graft Function Using the BETA-2 Score Following Clinical Islet Transplantation. Transpl Int 2022; 35:10335. [PMID: 35874309 PMCID: PMC9301872 DOI: 10.3389/ti.2022.10335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022]
Abstract
Little is known about how early islet graft function evolves in the clinical setting. The BETA-2 score is a validated index of islet function that can be calculated from a single blood sample and lends itself to frequent monitoring of graft function. In this study, we characterized early graft function by calculating weekly BETA-2 score in recipients who achieved insulin independence after single transplant (group 1, n = 8) compared to recipients who required a second transplant before achieving insulin independence (group 2, n = 7). We also determined whether graft function 1-week post-transplant was associated with insulin independence in individuals who received initial transplant between 2000–2017 (n = 125). Our results show that graft function increased rapidly reaching a plateau 4–6 weeks post-transplant. The BETA-2 score was higher in group 1 compared to group 2 as early as 1-week post-transplant (15 + 3 vs. 9 + 2, p = 0.001). In an unselected cohort, BETA-2 at 1-week post-transplant was associated with graft survival as defined by insulin independence during median follow up of 12 months (range 2–119 months) with greater survival among those with BETA-2 score >10 (p < 0.001, log-rank test). These findings suggest that primary graft function is established within 4–6 weeks post-transplant and graft function at 1-week post-transplant predicts long-term transplant outcomes.
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Affiliation(s)
- Anna Lam
- Clinical Islet Transplant Program, Department of Medicine, University of Alberta and Alberta Health Services, Edmonton, AB, Canada
- *Correspondence: Anna Lam,
| | - Richard A. Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
| | - Shareen Forbes
- BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Tolu Olateju
- Clinical Islet Transplant Program, Department of Medicine, University of Alberta and Alberta Health Services, Edmonton, AB, Canada
| | - Andrew J. Malcolm
- Clinical Islet Transplant Program, Department of Medicine, University of Alberta and Alberta Health Services, Edmonton, AB, Canada
| | - Sharleen Imes
- Clinical Islet Transplant Program, Department of Medicine, University of Alberta and Alberta Health Services, Edmonton, AB, Canada
| | - A. M. James Shapiro
- Clinical Islet Transplant Program, Department of Medicine, University of Alberta and Alberta Health Services, Edmonton, AB, Canada
| | - Peter A. Senior
- Clinical Islet Transplant Program, Department of Medicine, University of Alberta and Alberta Health Services, Edmonton, AB, Canada
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12
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Walker S, Appari M, Forbes S. Considerations and challenges of islet transplantation and future therapies on the horizon. Am J Physiol Endocrinol Metab 2022; 322:E109-E117. [PMID: 34927459 DOI: 10.1152/ajpendo.00310.2021] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Islet transplantation is a treatment for selected adults with type 1 diabetes and severe hypoglycemia. Islets from two or more donor pancreases, a scarce resource, are usually required to impact glycemic control, but the treatment falls short of a cure. Islets are avascular when transplanted into the hypoxic liver environment and subjected to inflammatory insults, immune attack, and toxicity from systemic immunosuppression. The Collaborative Islet Transplant Registry, with outcome data on over 1,000 islet transplant recipients, has demonstrated that larger islet numbers transplanted and older age of recipients are associated with better outcomes. Induction with T-cell depleting agents and the TNF-α inhibitor etanercept and maintenance systemic immunosuppression with mTOR inhibitors in combination with calcineurin inhibitors also appear advantageous, but concerns remain over immunosuppressive toxicity. We discuss strategies and therapeutics that address specific challenges of islet transplantation, many of which are at the preclinical stage of development. On the horizon are adjuvant cell therapies with mesenchymal stromal cells and regulatory T cells that have been used in preclinical models and in humans in other contexts; such a strategy may enable reductions in immunosuppression in the early peri-transplant period when the islets are vulnerable to apoptosis. Human embryonic stem cell-derived islets are in early-phase clinical trials and hold the promise of an inexhaustible supply of insulin-producing cells; effective encapsulation of such cells or, silencing of the human leukocyte antigen (HLA) complex would eliminate the need for immunosuppression, enabling this therapy to be used in all those with type 1 diabetes.
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Affiliation(s)
- Sophie Walker
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Mahesh Appari
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Shareen Forbes
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
- Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
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13
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Forbes S, Flatt AJ, Bennett D, Crookston R, Pimkova M, Birtles L, Pernet A, Wood RC, Burling K, Barker P, Counter C, Lumb A, Choudhary P, Rutter M, Rosenthal M, Sutherland A, Casey J, Johnson P, Shaw JAM. The impact of islet mass, number of transplants, and time between transplants on graft function in a national islet transplant program. Am J Transplant 2022; 22:154-164. [PMID: 34355503 PMCID: PMC9292186 DOI: 10.1111/ajt.16785] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/07/2021] [Accepted: 07/26/2021] [Indexed: 01/25/2023]
Abstract
The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3-8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291-15 417] vs. 6442 [5156-7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta -0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.
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Affiliation(s)
- Shareen Forbes
- BHF Centre for Cardiovascular SciencesQueen's Medical Research InstituteUniversity of EdinburghEdinburghUK
- Transplant UnitRoyal Infirmary of EdinburghEdinburghUK
| | - Anneliese J. Flatt
- Translational and Clinical Research InstituteNewcastle UniversityNewcastle upon TyneUK
- Institute of TransplantationFreeman HospitalNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Denise Bennett
- Institute of TransplantationFreeman HospitalNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Robert Crookston
- Nuffield Department of SurgeryUniversity of OxfordJohn Radcliffe HospitalOxfordUK
| | - Mirka Pimkova
- Institute of Immunity and TransplantationRoyal Free HospitalLondonUK
| | - Linda Birtles
- Diabetes, Endocrinology and Metabolism CentreManchester University NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
| | - Andrew Pernet
- Department of DiabetesSchool of Life Course SciencesKing's College LondonUK
| | - Ruth C. Wood
- Newcastle Clinical Trials UnitNewcastle UniversityNewcastle upon TyneUK
| | - Keith Burling
- Core Biochemical Assay LaboratoryNIHR Cambridge Biomedical Research CentreCambridgeUK
| | - Peter Barker
- Core Biochemical Assay LaboratoryNIHR Cambridge Biomedical Research CentreCambridgeUK
| | - Claire Counter
- NHS Blood and Transplant, Statistics and Clinical ResearchBristolUK
| | - Alistair Lumb
- Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK
- NIHR Oxford Biomedical Research CentreOxfordUK
| | - Pratik Choudhary
- Department of DiabetesSchool of Life Course SciencesKing's College LondonUK
| | - Martin K. Rutter
- Diabetes, Endocrinology and Metabolism CentreManchester University NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
- Division of Diabetes, Endocrinology and GastroenterologySchool of Medical SciencesFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Miranda Rosenthal
- Institute of Immunity and TransplantationRoyal Free HospitalLondonUK
| | | | - John Casey
- Transplant UnitRoyal Infirmary of EdinburghEdinburghUK
| | - Paul Johnson
- Nuffield Department of SurgeryUniversity of OxfordJohn Radcliffe HospitalOxfordUK
| | - James A. M. Shaw
- Translational and Clinical Research InstituteNewcastle UniversityNewcastle upon TyneUK
- Institute of TransplantationFreeman HospitalNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
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14
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Rios P, Baidal D, Lemos J, Camhi SS, Infante M, Padilla N, Gil AMA, Fuenmayor V, Ambut J, Qasmi FA, Mantero AM, Cayetano SM, Ruiz P, Ricordi C, Alejandro R. Long-term Persistence of Allosensitization After Islet Allograft Failure. Transplantation 2021; 105:2490-2498. [PMID: 33481552 PMCID: PMC8289921 DOI: 10.1097/tp.0000000000003635] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown. METHODS We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured yearly for the duration of graft function within 1 y after graft failure at enrollment and yearly thereafter. RESULTS In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 y postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow-up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7-15 y. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88%-98%) and DSA positivity persisted for 15 y in 75% (3/4) of subjects. CONCLUSIONS Allosensitization was minimal while subjects remained on immunosuppression, but after discontinuation of immunosuppressive therapy, the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 y. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting list times for identification of a suitable donor in the case of requiring a subsequent transplant.
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Affiliation(s)
- Paola Rios
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - David Baidal
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Joana Lemos
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Stephanie S. Camhi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Marco Infante
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Nathalia Padilla
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Ana M. Alvarez Gil
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Virginia Fuenmayor
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Jonathan Ambut
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Fatima A. Qasmi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Alejandro M. Mantero
- Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL
| | - Shari Messinger Cayetano
- Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL
| | - Phillip Ruiz
- Department of Surgery and Pathology, University of Miami Miller School of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Camillo Ricordi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
- Division of Cellular Transplantation, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL
| | - Rodolfo Alejandro
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
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15
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Krentz NAJ, Shea LD, Huising MO, Shaw JAM. Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering. Lancet Diabetes Endocrinol 2021; 9:708-724. [PMID: 34480875 PMCID: PMC10881068 DOI: 10.1016/s2213-8587(21)00170-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/17/2021] [Accepted: 06/08/2021] [Indexed: 02/09/2023]
Abstract
Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies.
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Affiliation(s)
- Nicole A J Krentz
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Lonnie D Shea
- Departments of Biomedical Engineering, Chemical Engineering, and Surgery, College of Engineering and School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA, USA; Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, CA, USA
| | - James A M Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
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16
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Sabbah S, Liew A, Brooks AM, Kundu R, Reading JL, Flatt A, Counter C, Choudhary P, Forbes S, Rosenthal MJ, Rutter MK, Cairns S, Johnson P, Casey J, Peakman M, Shaw JA, Tree TIM. Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function. Am J Transplant 2021; 21:1027-1038. [PMID: 32865886 DOI: 10.1111/ajt.16285] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 07/15/2020] [Accepted: 08/10/2020] [Indexed: 01/25/2023]
Abstract
Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.
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Affiliation(s)
- Shereen Sabbah
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, UK.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - Aaron Liew
- Newcastle University Translational and Clinical Research Institute, Newcastle, UK
| | - Augustin M Brooks
- Newcastle University Translational and Clinical Research Institute, Newcastle, UK
| | - Rhiannon Kundu
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, UK.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - James L Reading
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, UK.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - Anneliese Flatt
- Newcastle University Translational and Clinical Research Institute, Newcastle, UK
| | - Claire Counter
- Organ Donation and Transplantation, NHS Blood and Transplant, Bristol, UK
| | - Pratik Choudhary
- Diabetes Research Group, Guy's, King's and St. Thomas' School of Medicine, King's College London, London, UK
| | - Shareen Forbes
- Edinburgh Transplant Centre and Endocrinology Unit, University of Edinburgh, Edinburgh, UK
| | | | - Martin K Rutter
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, School of Medical Sciences, University of Manchester, Manchester, UK.,Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Stephanie Cairns
- Clinical Immunology Department, Scottish National Blood Transfusion Service, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Paul Johnson
- Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - John Casey
- Edinburgh Transplant Centre and Endocrinology Unit, University of Edinburgh, Edinburgh, UK
| | - Mark Peakman
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, UK.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - James A Shaw
- Newcastle University Translational and Clinical Research Institute, Newcastle, UK.,Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Timothy I M Tree
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, UK.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
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17
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Tenenbaum M, Plaisance V, Boutry R, Pawlowski V, Jacovetti C, Sanchez-Parra C, Ezanno H, Bourry J, Beeler N, Pasquetti G, Gmyr V, Dalle S, Kerr-Conte J, Pattou F, Hirai SI, Regazzi R, Bonnefond A, Froguel P, Abderrahmani A. The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta-cell proliferation during postnatal development. Cell Mol Life Sci 2021; 78:287-298. [PMID: 32189007 PMCID: PMC11072213 DOI: 10.1007/s00018-020-03499-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 03/04/2020] [Indexed: 12/13/2022]
Abstract
Unveiling the key pathways underlying postnatal beta-cell proliferation can be instrumental to decipher the mechanisms of beta-cell mass plasticity to increased physiological demand of insulin during weight gain and pregnancy. Using transcriptome and global Serine Threonine Kinase activity (STK) analyses of islets from newborn (10 days old) and adult rats, we found that highly proliferative neonatal rat islet cells display a substantially elevated activity of the mitogen activated protein 3 kinase 12, also called dual leucine zipper-bearing kinase (Dlk). As a key upstream component of the c-Jun amino terminal kinase (Jnk) pathway, Dlk overexpression was associated with increased Jnk3 activity and was mainly localized in the beta-cell cytoplasm. We provide the evidence that Dlk associates with and activates Jnk3, and that this cascade stimulates the expression of Ccnd1 and Ccnd2, two essential cyclins controlling postnatal beta-cell replication. Silencing of Dlk or of Jnk3 in neonatal islet cells dramatically hampered primary beta-cell replication and the expression of the two cyclins. Moreover, the expression of Dlk, Jnk3, Ccnd1 and Ccnd2 was induced in high replicative islet beta cells from ob/ob mice during weight gain, and from pregnant female rats. In human islets from non-diabetic obese individuals, DLK expression was also cytoplasmic and the rise of the mRNA level was associated with an increase of JNK3, CCND1 and CCND2 mRNA levels, when compared to islets from lean and obese patients with diabetes. In conclusion, we find that activation of Jnk3 signalling by Dlk could be a key mechanism for adapting islet beta-cell mass during postnatal development and weight gain.
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Affiliation(s)
- Mathie Tenenbaum
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France.
| | - Valérie Plaisance
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
- Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France
| | - Raphael Boutry
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
| | - Valérie Pawlowski
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
- Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France
| | - Cécile Jacovetti
- Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland
| | - Clara Sanchez-Parra
- Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland
| | - Hélène Ezanno
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
| | - Julien Bourry
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
| | - Nicole Beeler
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
| | - Gianni Pasquetti
- Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France
| | - Valery Gmyr
- Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France
| | - Stéphane Dalle
- Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U1191, Montpellier University, Montpellier, France
| | - Julie Kerr-Conte
- Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France
| | - François Pattou
- Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France
| | - Syu-Ichi Hirai
- Départment of Biology, Wakayama University, Wakayama, Japan
| | - Romano Regazzi
- Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland
| | - Amélie Bonnefond
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
- Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK
| | - Philippe Froguel
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France
- Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK
| | - Amar Abderrahmani
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France.
- Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France.
- Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK.
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18
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Yang Z, Li X, Zhang C, Sun N, Guo T, Lin J, Li F, Zhang J. Amniotic Membrane Extract Protects Islets From Serum-Deprivation Induced Impairments and Improves Islet Transplantation Outcome. Front Endocrinol (Lausanne) 2020; 11:587450. [PMID: 33363516 PMCID: PMC7753361 DOI: 10.3389/fendo.2020.587450] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/04/2020] [Indexed: 11/25/2022] Open
Abstract
Islet culture prior to transplantation is a standard practice in many transplantation centers. Nevertheless, the abundant islet mass loss and function impairment during this serum-deprivation culture period restrain the success of islet transplantation. In the present study, we used a natural biomaterial derived product, amniotic membrane extract (AME), as medium supplementation of islet pretransplant cultivation to investigate its protective effect on islet survival and function and its underlying mechanisms, as well as the engraftment outcome of islets following AME treatment. Results showed that AME supplementation improved islet viability and function, and decreased islet apoptosis and islet loss during serum-deprived culture. This was associated with the increased phosphorylation of PI3K/Akt and MAPK/ERK signaling pathway. Moreover, transplantation of serum-deprivation stressed islets that were pre-treated with AME into diabetic mice revealed better blood glucose control and improved islet graft survival. In conclusion, AME could improve islet survival and function in vivo and in vitro, and was at least partially through increasing phosphorylation of PI3K/Akt and MAPK/ERK signaling pathway.
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Affiliation(s)
| | | | | | | | | | | | | | - Jialin Zhang
- Department of Hepatobiliary Surgery, The First Hospital of China Medical University, Shenyang, China
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19
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Flatt AJS, Bennett D, Counter C, Brown AL, White SA, Shaw JAM. β-Cell and renal transplantation options for diabetes. Diabet Med 2020; 37:580-592. [PMID: 31705689 DOI: 10.1111/dme.14177] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/07/2019] [Indexed: 12/16/2022]
Abstract
Despite major advances in structured education, insulin delivery and glucose monitoring, diabetes self-management remains an unremitting challenge. Insulin therapy is inextricably linked to risk of dangerous hypoglycaemia and sustained hyperglycaemia remains a leading cause of renal failure. This review sets out to demystify transplantation for diabetes multidisciplinary teams, facilitating consideration and incorporation within holistic overall person-centred management. Deceased and living donor kidney, whole pancreas and isolated islet transplant procedures, indications and potential benefits are described, in addition to outcomes within the integrated UK transplant programme.
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Affiliation(s)
- A J S Flatt
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK
| | - D Bennett
- Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK
| | - C Counter
- Statistics and Clinical Studies, NHS Blood and Transplant, Bristol, UK
| | - A L Brown
- Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK
| | - S A White
- Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK
| | - J A M Shaw
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK
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20
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Maffi P, Lundgren T, Tufveson G, Rafael E, Shaw JAM, Liew A, Saudek F, Witkowski P, Golab K, Bertuzzi F, Gustafsson B, Daffonchio L, Ruffini PA, Piemonti L. Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes. Diabetes Care 2020; 43:710-718. [PMID: 32019854 PMCID: PMC7876579 DOI: 10.2337/dc19-1480] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 12/11/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients. RESEARCH DESIGN AND METHODS A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control. RESULTS The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression. CONCLUSIONS In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.
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Affiliation(s)
- Paola Maffi
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Torbjörn Lundgren
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska, Sweden
| | | | | | - James A M Shaw
- Institute of Cellular Medicine, Newcastle University, and Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, U.K
| | - Aaron Liew
- Institute of Cellular Medicine, Newcastle University, and Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, U.K
| | - Frantisek Saudek
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Piotr Witkowski
- Transplantation Institute, University of Chicago Medicine, Chicago, IL
| | - Karolina Golab
- Transplantation Institute, University of Chicago Medicine, Chicago, IL
| | | | | | - Luisa Daffonchio
- Research and Development Department, Dompé farmaceutici S.p.A., Milan, Italy
| | | | - Lorenzo Piemonti
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
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21
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A Feasible Method for Quantifying Living Pancreatic Human Islets in Murine Livers Posttransplantation by Confocal Laser Scanning Microscopy. Transplantation 2020; 104:e144-e150. [PMID: 32080160 DOI: 10.1097/tp.0000000000003191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Current histological methods cannot accurately determine the survival rate of human pancreatic islets following portal vein infusion. This is due, in part, to the low number of infused islets relative to the whole liver. In this study, we assessed the ability of confocal laser scanning microscopy (CLSM) to track human islets posttransplantation. METHODS Immunodeficient mice were transplanted with human islets. Following engraftment, animals were euthanized, livers procured, and human islet β cells immunofluorescently labeled with an insulin-specific antibody and evaluated by CLSM. A calibration curve comparing the area of insulin + hepatic islet β cells to the number of human islets collected was developed. Levels of human C-peptide were measured in transplant recipients to determine islet function. RESULTS The short-term survival rate of islet transplants was defined as y = 0.0422x + 2.7008, in which x is human islet number and y is liver islet β cell area. Employing CLSM, human islets were detected in immunofluorescent labeled murine liver tissue sections posttransplantation. The β cell-relative area of human islets in 500 islet equivalent (IEQ) specimens was 20.21 ± 1.16 mm and in 1000 IEQ specimens 39.4 ± 2.23 mm posttransplantation. Human islet posttransplant survival rates were 82.9 ± 5.50% (500 IEQ group) and 86.9 ± 5.28% (1000 IEQ group). CONCLUSIONS These data indicate that CLSM can be employed to quantify and characterize pancreatic human islets after transplantation to murine livers.
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22
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Schaschkow A, Sigrist S, Mura C, Barthes J, Vrana NE, Czuba E, Lemaire F, Neidl R, Dissaux C, Lejay A, Lavalle P, Bruant-Rodier C, Bouzakri K, Pinget M, Maillard E. Glycaemic control in diabetic rats treated with islet transplantation using plasma combined with hydroxypropylmethyl cellulose hydrogel. Acta Biomater 2020; 102:259-272. [PMID: 31811957 DOI: 10.1016/j.actbio.2019.11.047] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/15/2019] [Accepted: 11/22/2019] [Indexed: 12/18/2022]
Abstract
Islet transplantation is one of the most efficient cell therapies used in clinics and could treat a large proportion of patients with diabetes. However, it is limited by the high requirement of pancreas necessary to provide the sufficient surviving islet mass in the hepatic tissue and restore normoglycaemia. Reduction in organ procurement requirements could be achieved by extrahepatic transplantation using a biomaterial that enhances islet survival and function. We report a plasma-supplemented hydroxypropyl methylcellulose (HPMC) hydrogel, engineered specifically using a newly developed technique for intra-omental islet infusion, known as hOMING (h-Omental Matrix Islet filliNG). The HPMC hydrogel delivered islets with better performance than that of the classical intrahepatic infusion. After the validation of the HPMC suitability for islets in vivo and in vitro, plasma supplementation modified the rheological properties of HPMC without affecting its applicability with hOMING. The biomaterial association was proven to be more efficient both in vitro and in vivo, with better islet viability and function than that of the current clinical intrahepatic delivery technique. Indeed, when the islet mass was decreased by 25% or 35%, glycaemia control was observed in the group of plasma-supplemented hydrogels, whereas no regulation was observed in the hepatic group. Plasma gelation, observed immediately post infusion, decreased anoïkis and promoted vascularisation. To conclude, the threshold mass for islet transplantation could be decreased using HPMC-Plasma combined with the hOMING technique. The simplicity of the hOMING technique and the already validated use of its components could facilitate its transfer to clinics. STATEMENT OF SIGNIFICANCE: One of the major limitations for the broad deployment of current cell therapy for brittle type 1 diabetes is the islets' destruction during the transplantation process. Retrieved from their natural environment, the islets are grafted into a foreign tissue, which triggers massive cell loss. It is mandatory to provide the islets with an 3D environment specifically designed for promoting isletimplantation to improve cell therapy outcomes. For this aim, we combined HPMC and plasma. HPMC provides suitable rheological properties to the plasma to be injectable and be maintained in the omentum. Afterwards, the plasma polymerises around the graft in vivo, thereby allowing their optimal integration into their transplantation site. As a result, the islet mass required to obtain glycaemic control was reduced by 35%.
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23
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Vantyghem MC, Chetboun M, Gmyr V, Jannin A, Espiard S, Le Mapihan K, Raverdy V, Delalleau N, Machuron F, Hubert T, Frimat M, Van Belle E, Hazzan M, Pigny P, Noel C, Caiazzo R, Kerr-Conte J, Pattou F. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study. Diabetes Care 2019; 42:2042-2049. [PMID: 31615852 DOI: 10.2337/dc19-0401] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 08/03/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft. RESEARCH DESIGN AND METHODS We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43-92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function. RESULTS The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22-57) and 28% (13-45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62-92) and 78% (57-89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence. CONCLUSIONS Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.
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Affiliation(s)
- Marie-Christine Vantyghem
- University of Lille, U1190-EGID, Lille, France .,Department of Endocrinology, Diabetology, and Metabolism, Centre Hospitalier Universitaire de Lille, Lille, France.,Inserm, U1190, Lille, France
| | - Mikael Chetboun
- University of Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France.,Department of General and Endocrine Surgery, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Valéry Gmyr
- University of Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - Arnaud Jannin
- Department of Endocrinology, Diabetology, and Metabolism, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Stéphanie Espiard
- Department of Endocrinology, Diabetology, and Metabolism, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Kristell Le Mapihan
- Department of Endocrinology, Diabetology, and Metabolism, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Violeta Raverdy
- University of Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - Nathalie Delalleau
- University of Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - François Machuron
- Department of Methodology, Biostatistics, and Data Management, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Thomas Hubert
- University of Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - Marie Frimat
- Department of Nephrology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Eric Van Belle
- Department of Cardiology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Marc Hazzan
- Department of Nephrology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Pascal Pigny
- Department of Biochemistry and Hormonology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Christian Noel
- Department of Nephrology, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Robert Caiazzo
- University of Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France.,Department of General and Endocrine Surgery, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Julie Kerr-Conte
- University of Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - François Pattou
- University of Lille, U1190-EGID, Lille, France .,Inserm, U1190, Lille, France.,Department of General and Endocrine Surgery, Centre Hospitalier Universitaire de Lille, Lille, France
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24
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Vantyghem MC, de Koning EJP, Pattou F, Rickels MR. Advances in β-cell replacement therapy for the treatment of type 1 diabetes. Lancet 2019; 394:1274-1285. [PMID: 31533905 PMCID: PMC6951435 DOI: 10.1016/s0140-6736(19)31334-0] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/28/2019] [Accepted: 05/31/2019] [Indexed: 12/17/2022]
Abstract
The main goal of treatment for type 1 diabetes is to control glycaemia with insulin therapy to reduce disease complications. For some patients, technological approaches to insulin delivery are inadequate, and allogeneic islet transplantation is a safe alternative for those patients who have had severe hypoglycaemia complicated by impaired hypoglycaemia awareness or glycaemic lability, or who already receive immunosuppressive drugs for a kidney transplant. Since 2000, intrahepatic islet transplantation has proven efficacious in alleviating the burden of labile diabetes and preventing complications related to diabetes, whether or not a previous kidney transplant is present. Age, body-mass index, renal status, and cardiopulmonary status affect the choice between pancreas or islet transplantation. Access to transplantation is limited by the number of deceased donors and the necessity of immunosuppression. Future approaches might include alternative sources of islets (eg, xenogeneic tissue or human stem cells), extrahepatic sites of implantation (eg, omental, subcutaneous, or intramuscular), and induction of immune tolerance or encapsulation of islets.
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Affiliation(s)
- Marie-Christine Vantyghem
- University of Lille, European Genomic Institute for Diabetes, Lille, France; Department of Endocrinology, Diabetology and Metabolism, Centre Hospitalier Universitaire de Lille, Lille, France; Inserm, Translational Research for Diabetes, Lille, France.
| | - Eelco J P de Koning
- Department of Medicine, Leiden University Medical Center, Leiden, Netherlands; Hubrecht Institute of the Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, Netherlands
| | - François Pattou
- University of Lille, European Genomic Institute for Diabetes, Lille, France; Department of General and Endocrine Surgery Centre, Centre Hospitalier Universitaire de Lille, Lille, France; Inserm, Translational Research for Diabetes, Lille, France
| | - Michael R Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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25
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Abstract
PURPOSE OF REVIEW In patients with type 1 diabetes with extreme glycemic variability, the restoration of pancreas endocrine function is potentially and completely achieved with islets of Langerhans (tissue derived from whole organ) or pancreas (whole organ) transplantation. The aim of our review is to report on the latest studies and to highlight the benefits and risks of the two procedures, providing clearer, more selective, evidence-based clinical indications that also consider the impact on the degenerative complications of diabetes as a potential benefit. RECENT FINDINGS Clinical experience in this field has been dynamic over the last three decades, and has been characterized by the development of more standardized protocols and a clearer definition of clinical outcome. On the contrary, the recommendations thus far are not well delineated and tend to overlap, and the past ADA position statement for pancreas transplant alone has also been applied to islet transplant alone, without differentiation. Both outcome-driven and non-outcome-driven criteria are considered in the conclusions, in an attempt to streamline indications for islet-alone or pancreas-alone transplantation.
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Affiliation(s)
- Paola Maffi
- Diabetes Research Institute - Internal Medicine and Transplant Unit, IRCCS Scientific Institute Ospedale San Raffaele, Milan, Italy.
| | - Antonio Secchi
- Internal Medicine and Transplant Unit, Vita-Salute San Raffaele University, Milan, Italy
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26
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Defining Outcomes for β-cell Replacement Therapy in the Treatment of Diabetes: A Consensus Report on the Igls Criteria From the IPITA/EPITA Opinion Leaders Workshop. Transplantation 2019. [PMID: 29528967 DOI: 10.1097/tp.0000000000002158] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
β-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of β-cell replacement therapy. There was consensus that β-cell replacement therapy could be considered as a treatment for β-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c) and the occurrence of severe hypoglycemia. Optimal β-cell graft function is defined by near-normal glycemic control (HbA1c ≤6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good β-cell graft function requires HbA1c less than 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal β-cell graft function is defined by failure to achieve HbA1c less than 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed β-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good function are considered successful clinical outcomes.
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Evaluation of [ 68Ga]DO3A-VS-Cys 40-Exendin-4 as a PET Probe for Imaging Human Transplanted Islets in the Liver. Sci Rep 2019; 9:5705. [PMID: 30952975 PMCID: PMC6450933 DOI: 10.1038/s41598-019-42172-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 03/22/2019] [Indexed: 11/15/2022] Open
Abstract
[68Ga]DO3A-VS-Cys40-Exendin-4, a glucagon-like peptide 1 receptor agonist, was evaluated as a potential PET tracer for the quantitation of human islets transplanted to the liver. The short-lived PET radionuclide 68Ga, available on a regular basis from a 68Ge/68Ga generator, is an attractive choice. Human C-peptide was measured to evaluate human islet function post-transplantation and prior to microPET imaging. [68Ga]DO3A-VS-Cys40-Exendin-4 was radiosynthesized and evaluated for PET imaging of transplanted human islets in the liver of healthy NOD/SCID mice. The biodistribution of the tracer was evaluated to determine the uptake into various organs, and qPCR of liver samples was conducted to confirm engrafted islet numbers after PET imaging. Measurement of human C-peptide indicated that higher engrafted islet mass resulted in higher human C-peptide levels in post-transplantation. The microPET imaging yielded high resolution images of liver-engrafted islets and also showed significant retention in mouse livers at 8 weeks post-transplantation. Biodistribution studies in mice revealed that liver uptake of [68Ga]DO3A-VS-Cys40-Exendin-4 was approximately 6-fold higher in mice that received 1000 islet equivalent (IEQ) than in non-transplanted mice. qPCR analysis of insulin expression suggested that islet engraftment numbers were close to 1000 IEQ transplanted. In conclusion, human islets transplanted into the livers of mice exhibited significant uptake of [68Ga]DO3A-VS-Cys40-Exendin-4 compared to the livers of untreated mice; and imaging of the mice using PET showed the human islets clearly with high contrast against liver tissue, enabling accurate quantitation of islet mass. Further validation of [68Ga]DO3A-VS-Cys40-Exendin-4 as an islet imaging probe for future clinical application is ongoing.
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28
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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29
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Rickels MR, Stock PG, de Koning EJP, Piemonti L, Pratschke J, Alejandro R, Bellin MD, Berney T, Choudhary P, Johnson PR, Kandaswamy R, Kay TWH, Keymeulen B, Kudva YC, Latres E, Langer RM, Lehmann R, Ludwig B, Markmann JF, Marinac M, Odorico JS, Pattou F, Senior PA, Shaw JAM, Vantyghem MC, White S. Defining outcomes for β-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transpl Int 2018; 31:343-352. [PMID: 29453879 DOI: 10.1111/tri.13138] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 01/09/2018] [Accepted: 02/12/2018] [Indexed: 12/12/2022]
Abstract
β-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas & Islet Transplant Association (IPITA) and European Pancreas & Islet Transplantation Association (EPITA) held a workshop to develop consensus for an IPITA/EPITA Statement on the definition of function and failure of current and future forms of β-cell replacement therapy. There was consensus that β-cell replacement therapy could be considered as a treatment for β-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c ) and the occurrence of severe hypoglycemia. Optimal β-cell graft function is defined by near-normal glycemic control [HbA1c ≤ 6.5% (48 mmol/mol)] without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good β-cell graft function requires HbA1c < 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal β-cell graft function is defined by failure to achieve HbA1c < 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed β-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good functional outcomes are considered successful clinical outcomes.
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Affiliation(s)
- Michael R Rickels
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Peter G Stock
- Department of Surgery, Division of Transplantation, University of California at San Francisco, San Francisco, CA, USA
| | - Eelco J P de Koning
- Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Lorenzo Piemonti
- Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy
| | | | - Rodolfo Alejandro
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Melena D Bellin
- Department of Pediatrics, Division of Endocrinology, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, USA
| | - Thierry Berney
- Department of Surgery, Division of Transplantation and Visceral Surgery, Geneva University Hospital, Geneva, Switzerland
| | | | - Paul R Johnson
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Raja Kandaswamy
- Department of Surgery, Division of Transplantation, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, USA
| | - Thomas W H Kay
- Department of Medicine, St. Vincent's Hospital, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Vic., Australia
| | - Bart Keymeulen
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Yogish C Kudva
- Department of Internal Medicine, Division of Endocrinology, Diabetes, Metabolism & Nutrition, Mayo Clinic, Rochester, MN, USA
| | | | | | - Roger Lehmann
- Department of Endocrinology and Diabetology, University Hospital Zurich, Zurich, Switzerland
| | - Barbara Ludwig
- Department of Medicine III, Division of Endocrinology and Diabetes, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - James F Markmann
- Department of Surgery, Division of Transplantation, Massachusetts General Hospital, Boston, MA, USA
| | | | - Jon S Odorico
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - François Pattou
- Department of General and Endocrine Surgery, Centre Hospitalier Universitaire de Lille, Inserm, Université de Lille, Lille, France
| | - Peter A Senior
- Department of Medicine, Division of Endocrinology & Metabolism, University of Alberta, Edmonton, AB, Canada
| | - James A M Shaw
- Institute of Transplantation, The Freeman Hospital, Newcastle University, Newcastle upon Tyne, UK
| | - Marie-Christine Vantyghem
- Department of Endocrinology, Diabetology and Metabolism, Centre Hospitalier Universitaire de Lille, Inserm, Université de Lille, Lille, France
| | - Steven White
- Institute of Transplantation, The Freeman Hospital, Newcastle University, Newcastle upon Tyne, UK
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Abstract
β cell replacement with either pancreas or islet transplantation has progressed immensely over the last decades with current 1- and 5-year insulin independence rates of approximately 85% and 50%, respectively. Recent advances are largely attributed to improvements in immunosuppressive regimen, donor selection, and surgical technique. However, both strategies are compromised by a scarce donor source. Xenotransplantation offers a potential solution by providing a theoretically unlimited supply of islets, but clinical application has been limited by concerns for a potent immune response against xenogeneic tissue. β cell clusters derived from embryonic or induced pluripotent stem cells represent another promising unlimited source of insulin producing cells, but clinical application is pending further advances in the function of the β cell like clusters. Exciting developments and rapid progress in all areas of β cell replacement prompted a lively debate by members of the young investigator committee of the International Pancreas and Islet Transplant Association at the 15th International Pancreas and Islet Transplant Association Congress in Melbourne and at the 26th international congress of The Transplant Society in Hong Kong. This international group of young investigators debated which modality of β cell replacement would predominate the landscape in 10 years, and their arguments are summarized here.
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31
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Holdcraft RW, Dumpala PR, Smith BH, Gazda LS. A model for determining an effective in vivo dose of transplanted islets based on in vitro insulin secretion. Xenotransplantation 2018; 25:e12443. [PMID: 30054944 DOI: 10.1111/xen.12443] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 04/20/2018] [Accepted: 06/11/2018] [Indexed: 11/29/2022]
Abstract
BACKGROUND Allogeneic islet transplantation for the treatment of type 1 diabetes often requires multiple implant procedures, from as many as several human pancreas donors, to achieve lasting clinical benefit. Given the limited availability of human pancreases for islet isolation, porcine islets have long been considered a potential option for clinical use. Agarose-encapsulated porcine islets (macrobeads) permit long-term culture and thus a thorough evaluation of microbiological safety and daily insulin secretory capacity, prior to implantation. The goal of this study was the development of a method for determining an effective dose of encapsulated islets based on their measured in vitro insulin secretion in a preclinical model of type 1 diabetes. METHODS Spontaneously diabetic BioBreeding diabetes-prone rats were implanted with osmotic insulin pumps in combination with continuous glucose monitoring to establish the daily insulin dose required to achieve continuous euglycaemia in individual animals. Rats were then implanted with a 1×, 2× or 3× dose (defined as the ratio of macrobead in vitro insulin secretion per 24 hours to the recipient animal's total daily insulin requirement) of porcine islet macrobeads, in the absence of immunosuppression. In vivo macrobead function was assessed by recipient non-fasted morning blood glucose values, continuous glucose monitoring and the presence of peritoneal porcine C-peptide. At the end of the study, the implanted macrobeads were removed and returned to in vitro culture for the evaluation of insulin secretion. RESULTS Diabetic rats receiving a 2× macrobead implant exhibited significantly improved blood glucose regulation compared to that of rats receiving a 1× dose during a 30-day pilot study. In a 3-month follow-up study, 2× and 3× macrobead doses initially controlled blood glucose levels equally well, although several animals receiving a 3× dose maintained euglycaemia throughout the study, compared to none of the 2× animals. The presence of porcine C-peptide in rat peritoneal fluid 3 months post-implant and the recurrence of hyperglycaemia following macrobead removal, along with the finding of persistent in vitro insulin secretion from retrieved macrobeads, confirmed long-term graft function. CONCLUSIONS Increasing dosages of islet macrobeads transplanted into diabetic rats, based on multiples of in vitro insulin secretion matched to the recipient's exogenous insulin requirements, correlated with improved blood glucose regulation and increased duration of graft function. These results demonstrate the usefulness of a standardized model for the evaluation of the functional effectiveness of islets intended for transplantation, in this case using intraperitoneally implanted agarose macrobeads, in diabetic rats. The results suggest that some features of this islet-dosing methodology may be applicable, and indeed necessary, to clinical allogeneic and xenogeneic islet transplantation.
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Affiliation(s)
| | | | - Barry H Smith
- The Rogosin Institute, New York, New York.,NewYork Presbyterian - Weill Cornell Medical Center, New York, New York
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32
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Forbes S, Lam A, Koh A, Imes S, Dinyari P, Malcolm AJ, Shapiro AMJ, Senior PA. Comparison of metabolic responses to the mixed meal tolerance test vs the oral glucose tolerance test after successful clinical islet transplantation. Clin Transplant 2018; 32:e13301. [PMID: 29851179 DOI: 10.1111/ctr.13301] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2018] [Indexed: 01/02/2023]
Abstract
Following islet transplantation, mixed meal tolerance tests (MMTs) are routinely utilized to assess graft function, but how the 90-minute MMTT glucose value relates to a 120-minute glucose concentration of ≥11.1 mmol/L used to diagnose diabetes following a standardized 75 g-OGTT, is not known. We examined this relationship further. Thirteen subjects with Type 1 diabetes and stable transplant grafts, not on exogenous insulin with HbA1c < 7% (53 mmol/mol), were studied on 17 occasions with paired OGTTs and MMTTs. Receiver operating characteristic (ROC) curves were constructed to derive the 90-minute MMTT glucose threshold associated with a 120-minute glucose concentration following a 75 g-OGTT (OGTT120 ) ≥11.1 mmol/L and their diagnostic accuracy. Studies with OGTT120 ≥11.1 mmol/L (n = 5) had diminished C-peptide: glucose, greater integrated glucose and diminished insulin: glucose area under the curve (AUC) ratios (0-120 minutes) and disposition indices; all P < .05, contrasting with MMTTs where no difference in the 90-minute glucose concentrations, C-peptide:glucose, integrated glucose, C-peptide and C-peptide: glucose AUCs (0-90 minutes) was seen; all P > .05. A 90-minute MMTT glucose concentration ≥8.0 mmol/L demonstrated a sensitivity and specificity of ≥80% for the diagnosis of OGTT120 ≥11.1 mmol/L; area under ROC curve (mean ± SEM) 73 ± 13%. A 90-minute MMTT glucose ≥8.0 mmol/L, identifies islet transplant recipients who may require closer monitoring for graft dysfunction.
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Affiliation(s)
- Shareen Forbes
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Scotland, UK.,Department of Medicine, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada
| | - Anna Lam
- Department of Medicine, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada
| | - Angela Koh
- Department of Medicine, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada
| | - Sharleen Imes
- Department of Medicine, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada.,Department of Surgery, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada
| | - Parastoo Dinyari
- Department of Surgery, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada
| | - Andrew J Malcolm
- Department of Surgery, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada
| | - A M James Shapiro
- Department of Surgery, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada
| | - Peter A Senior
- Department of Medicine, Clinical Islet Transplant Programme, University of Alberta, Edmonton, AB, Canada
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Rattananinsruang P, Dechsukhum C, Leeanansaksiri W. Establishment of Insulin-Producing Cells From Human Embryonic Stem Cells Underhypoxic Condition for Cell Based Therapy. Front Cell Dev Biol 2018; 6:49. [PMID: 29868580 PMCID: PMC5962719 DOI: 10.3389/fcell.2018.00049] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 04/16/2018] [Indexed: 12/27/2022] Open
Abstract
Diabetes mellitus (DM) is a group of diseases characterized by abnormally high levels of glucose in the blood stream. In developing a potential therapy for diabetic patients, pancreatic cells transplantation has drawn great attention. However, the hinder of cell transplantation for diabetes treatment is insufficient sources of insulin-producing cells. Therefore, new cell based therapy need to be developed. In this regard, human embryonic stem cells (hESCs) may serve as good candidates for this based on their capability of differentiation into various cell types. In this study, we designed a new differentiation protocol that can generate hESC-derived insulin-producing cells (hES-DIPCs) in a hypoxic condition. We also emphasized on the induction of definitive endoderm during embryoid bodies (EBs) formation. After induction of hESCs differentiation into insulin-producing cells (IPCs), the cells obtained from the cultures exhibited pancreas-related genes such as Pdx1, Ngn3, Nkx6.1, GLUT2, and insulin. These cells also showed positive for DTZ-stained cellular clusters and contained ability of insulin secretion in a glucose-dependent manner. After achievement to generated functional hES-DIPCs in vitro, some of the hES-DIPCs were then encapsulated named encapsulated hES-DIPCs. The data showed that the encapsulated cells could possess the function of insulin secretion in a time-dependent manner. The hES-DIPCs and encapsulated hES-DIPCs were then separately transplanted into STZ-induced diabetic mice. The findings showed the significant blood glucose levels regulation capacity and declination of IL-1β concentration in all transplanted mice. These results indicated that both hES-DIPCs and encapsulated hES-DIPCs contained the ability to sustain hyperglycemia condition as well as decrease inflammatory cytokine level in vivo. The findings of this study may apply for generation of a large number of hES-DIPCs in vitro. In addition, the implication of this work is therapeutic value in type I diabetes treatment in the future. The application for type II diabetes treatment remain to be investigated.
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Affiliation(s)
- Piyaporn Rattananinsruang
- School of Preclinic, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Chavaboon Dechsukhum
- School of Pathology, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Wilairat Leeanansaksiri
- School of Preclinic, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, Thailand
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Nijhoff MF, Dubbeld J, van Erkel AR, van der Boog PJM, Rabelink TJ, Engelse MA, de Koning EJP. Islet alloautotransplantation: Allogeneic pancreas transplantation followed by transplant pancreatectomy and islet transplantation. Am J Transplant 2018; 18:1016-1019. [PMID: 29160954 DOI: 10.1111/ajt.14593] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/22/2017] [Accepted: 11/02/2017] [Indexed: 01/25/2023]
Abstract
Simultaneous pancreas-kidney (SPK) transplantation is an important treatment option for patients with type 1 diabetes (T1D) and end-stage renal disease (ESRD). Due to complications, in up to 10% of patients, allograft pancreatectomy is necessary shortly after transplantation. Usually the donor pancreas is discarded. Here, we report on a novel procedure to rescue endocrine tissue after allograft pancreatectomy. A 39-year-old woman with T1D and ESRD who had undergone SPK transplantation required emergency allograft pancreatectomy due to bleeding at the vascular anastomosis. Islets were isolated from the removed pancreas allograft, and almost 480 000 islet equivalents were infused into the portal vein. The patient recovered fully. After 3 months, near-normal mixed meal test (fasting glucose 7.0 mmol/L, 2-hour glucose 7.5 mmol/L, maximal stimulated C-peptide 3.25 nmol/L, without insulin use in the preceding 36 hours) was achieved. Glycated hemoglobin while taking a low dose of long-acting insulin was 32.7 mmol/mol hemoglobin (5.3%). When a donor pancreas is lost after transplantation, rescue β cell therapy by islet alloautotransplantation enables optimal use of scarce donor pancreata to optimize glycemic control without additional HLA alloantigen exposure.
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Affiliation(s)
- M F Nijhoff
- Department of Medicine, Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands.,Division of Endocrinology and Metabolism, Leiden University Medical Centre, Leiden, the Netherlands
| | - J Dubbeld
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - A R van Erkel
- Department of Radiology, Leiden University Medical Centre, Leiden, the Netherlands
| | - P J M van der Boog
- Department of Medicine, Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - T J Rabelink
- Department of Medicine, Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - M A Engelse
- Department of Medicine, Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands
| | - E J P de Koning
- Department of Medicine, Division of Nephrology and Transplantation, Leiden University Medical Centre, Leiden, the Netherlands.,Division of Endocrinology and Metabolism, Leiden University Medical Centre, Leiden, the Netherlands
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35
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Benomar K, Chetboun M, Espiard S, Jannin A, Le Mapihan K, Gmyr V, Caiazzo R, Torres F, Raverdy V, Bonner C, D'Herbomez M, Pigny P, Noel C, Kerr-Conte J, Pattou F, Vantyghem MC. Purity of islet preparations and 5-year metabolic outcome of allogenic islet transplantation. Am J Transplant 2018; 18:945-951. [PMID: 28941330 DOI: 10.1111/ajt.14514] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 08/23/2017] [Accepted: 09/04/2017] [Indexed: 01/25/2023]
Abstract
In allogenic islet transplantation (IT), high purity of islet preparations and low contamination by nonislet cells are generally favored. The aim of the present study was to analyze the relation between the purity of transplanted preparations and graft function during 5 years post-IT. Twenty-four patients with type 1 diabetes, followed for 5 years after IT, were enrolled. Metabolic parameters and daily insulin requirements were compared between patients who received islet preparations with a mean purity <50% (LOW purity) or ≥50% (HIGH purity). We also analyzed blood levels of carbohydrate antigen 19-9 (CA 19-9)-a biomarker of pancreatic ductal cells-and glucagon, before and after IT. At 5 years, mean hemoglobin A1c (HbA1c levels) (P = .01) and daily insulin requirements (P = .03) were lower in the LOW purity group. Insulin independence was more frequent in the LOW purity group (P < .05). CA19-9 and glucagon levels increased post-IT (P < .0001) and were inversely correlated with the degree of purity. Overall, our results suggest that nonislet cells have a beneficial effect on long-term islet graft function, possibly through ductal-to-endocrine cell differentiation. ClinicalTrial.gov NCT00446264 and NCT01123187.
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Affiliation(s)
- K Benomar
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France.,UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
| | - M Chetboun
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - S Espiard
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France
| | - A Jannin
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France
| | - K Le Mapihan
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France
| | - V Gmyr
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
| | - R Caiazzo
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - F Torres
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - V Raverdy
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - C Bonner
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
| | - M D'Herbomez
- Department of Biology, CHRU Lille, Lille, France
| | - P Pigny
- Department of Biology, CHRU Lille, Lille, France
| | - C Noel
- Department of Nephrology and Transplantation, CHRU Lille, Lille, France
| | - J Kerr-Conte
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
| | - F Pattou
- UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France.,Department of Endocrine Surgery, CHRU Lille, Lille, France
| | - M C Vantyghem
- Department of Endocrinology and Metabolism, CHRU Lille, Lille, France.,UMR 1190, Translational Research in Diabetes INSERM, Lille, France.,EGID (European Genomic Institute for Diabetes), Univ Lille, Lille, France
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36
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Zhu H, Li W, Liu Z, Li W, Chen N, Lu L, Zhang W, Wang Z, Wang B, Pan K, Zhang X, Chen G. Selection of Implantation Sites for Transplantation of Encapsulated Pancreatic Islets. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:191-214. [PMID: 29048258 DOI: 10.1089/ten.teb.2017.0311] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic islet transplantation has been validated as a valuable therapy for type 1 diabetes mellitus patients with exhausted insulin treatment. However, this therapy remains limited by the shortage of donor and the requirement of lifelong immunosuppression. Islet encapsulation, as an available bioartificial pancreas (BAP), represents a promising approach to enable protecting islet grafts without or with minimal immunosuppression and possibly expanding the donor pool. To develop a clinically implantable BAP, some key aspects need to be taken into account: encapsulation material, capsule design, and implant site. Among them, the implant site exerts an important influence on the engraftment, stability, and biocompatibility of implanted BAP. Currently, an optimal site for encapsulated islet transplantation may include sufficient capacity to host large graft volumes, portal drainage, ease of access using safe and reproducible procedure, adequate blood/oxygen supply, minimal immune/inflammatory reaction, pliable for noninvasive imaging and biopsy, and potential of local microenvironment manipulation or bioengineering. Varying degrees of success have been confirmed with the utilization of liver or extrahepatic sites in an experimental or preclinical setting. However, the ideal implant site remains to be further engineered or selected for the widespread application of encapsulated islet transplantation.
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Affiliation(s)
- Haitao Zhu
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China .,2 Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University , Xi'an, China
| | - Wenjing Li
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Zhongwei Liu
- 3 Department of Cardiology, Shaanxi Provincial People's Hospital , Xi'an, China
| | - Wenliang Li
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Niuniu Chen
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Linlin Lu
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Wei Zhang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Zhen Wang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Bo Wang
- 2 Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University , Xi'an, China .,4 Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University , Xi'an, China
| | - Kaili Pan
- 5 Department of Pediatrics (No. 2 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Xiaoge Zhang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Guoqiang Chen
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
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Age and Early Graft Function Relate With Risk-Benefit Ratio of Allogenic Islet Transplantation Under Antithymocyte Globulin-Mycophenolate Mofetil-Tacrolimus Immune Suppression. Transplantation 2017; 101:2218-2227. [DOI: 10.1097/tp.0000000000001543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Islet Transplantation Provides Superior Glycemic Control With Less Hypoglycemia Compared With Continuous Subcutaneous Insulin Infusion or Multiple Daily Insulin Injections. Transplantation 2017; 101:1268-1275. [PMID: 27490410 DOI: 10.1097/tp.0000000000001381] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND The aim was to compare efficacy of multiple daily injections (MDI), continuous subcutaneous insulin infusion (CSII) and islet transplantation to reduce hypoglycemia and glycemic variability in type 1 diabetes subjects with severe hypoglycemia. METHODS This was a within-subject, paired comparison of MDI and CSII and CSII with 12 months postislet transplantation in 10 type 1 diabetes subjects referred with severe hypoglycemia, suitable for islet transplantation. Individuals were assessed with HbA1c, Edmonton Hypoglycemia Score (HYPOscore), continuous glucose monitoring (CGM) and in 8 subjects measurements of glucose variability using standard deviation of glucose (SD glucose) from CGM and continuous overlapping net glycemic action using a 4 hour interval (CONGA4). RESULTS After changing from MDI to CSII before transplantation, 10 subjects reduced median HYPOscore from 2028 to 1085 (P < 0.05) and hypoglycemia events from 24 to 8 per patient-year (P < 0.05). While HbA1c, mean glucose and median percent time hypoglycemic on CGM were unchanged with CSII, SD glucose and CONGA4 reduced significantly (P < 0.05). At 12 months posttransplant 9 of 10 were C-peptide positive, (5 insulin independent). Twelve months postislet transplantation, there were significant reductions in all baseline parameters versus CSII, respectively, HbA1c (6.4% cf 8.2%), median HYPOscore (0 cf 1085), mean glucose (7.1 cf 8.6 mmol L), SD glucose (1.7 cf 3.2 mmol/L), and CONGA4 (1.6 cf 3.0). CONCLUSIONS In subjects with severe hypoglycemia suitable for islet transplantation, CSII decreased hypoglycemia frequency and glycemic variability compared with MDI whereas islet transplantation resolved hypoglycemia and further improved glycemic variability regardless of insulin independence.
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39
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Cross SE, Vaughan RH, Willcox AJ, McBride AJ, Abraham AA, Han B, Johnson JD, Maillard E, Bateman PA, Ramracheya RD, Rorsman P, Kadler KE, Dunne MJ, Hughes SJ, Johnson PRV. Key Matrix Proteins Within the Pancreatic Islet Basement Membrane Are Differentially Digested During Human Islet Isolation. Am J Transplant 2017; 17:451-461. [PMID: 27456745 DOI: 10.1111/ajt.13975] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 07/12/2016] [Indexed: 02/06/2023]
Abstract
Clinical islet transplantation achieves insulin independence in selected patients, yet current methods for extracting islets from their surrounding pancreatic matrix are suboptimal. The islet basement membrane (BM) influences islet function and survival and is a critical marker of islet integrity following rodent islet isolation. No studies have investigated the impact of islet isolation on BM integrity in human islets, which have a unique duplex structure. To address this, samples were taken from 27 clinical human islet isolations (donor age 41-59, BMI 26-38, cold ischemic time < 10 h). Collagen IV, pan-laminin, perlecan and laminin-α5 in the islet BM were significantly digested by enzyme treatment. In isolated islets, laminin-α5 (found in both layers of the duplex BM) and perlecan were lost entirely, with no restoration evident during culture. Collagen IV and pan-laminin were present in the disorganized BM of isolated islets, yet a significant reduction in pan-laminin was seen during the initial 24 h culture period. Islet cytotoxicity increased during culture. Therefore, the human islet BM is substantially disrupted during the islet isolation procedure. Islet function and survival may be compromised as a consequence of an incomplete islet BM, which has implications for islet survival and transplanted graft longevity.
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Affiliation(s)
- S E Cross
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - R H Vaughan
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - A J Willcox
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - A J McBride
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - A A Abraham
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - B Han
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - J D Johnson
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - E Maillard
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - P A Bateman
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - R D Ramracheya
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - P Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - K E Kadler
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - M J Dunne
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - S J Hughes
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
| | - P R V Johnson
- Islet Transplant Research Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Oxford, UK
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40
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Tatum JA, Meneveau MO, Brayman KL. Single-donor islet transplantation in type 1 diabetes: patient selection and special considerations. Diabetes Metab Syndr Obes 2017; 10:73-78. [PMID: 28280376 PMCID: PMC5338842 DOI: 10.2147/dmso.s105692] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes mellitus is an autoimmune disorder of the endocrine pancreas that currently affects millions of people in the United States. Although the disease can be managed with exogenous insulin administration, the ultimate cure for the condition lies in restoring a patient's ability to produce their own insulin. Islet cell allotransplantation provides a means of endogenous insulin production. Though far from perfected, islet transplants are now a proven treatment for type 1 diabetics. However, proper patient selection is critical for achieving optimal outcomes. Given the shortage of transplantable organs, selecting appropriate candidates for whom the procedure will be of greatest benefit is essential. Although many of those who receive islets do not retain insulin independence, grafts do play a significant role in preventing hypoglycemic episodes that can be quite detrimental to quality of life and potentially fatal. Additionally, islet transplant requires lifelong immunosuppression. Antibodies, both preformed and following islet infusion, may play important roles in graft outcomes. Finally, no procedure is without inherent risk and islet transfusions can have serious consequences for recipients' livers in the form of both vascular and metabolic complications. Therefore, patient-specific factors that should be taken into account before islet transplantation include aims of therapy, sensitization, and potential increased risk for hepatic and portal-venous sequelae.
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Affiliation(s)
- Jacob A Tatum
- Department of Surgery, Division of Transplantation, The University of Virginia Health System, Charlottesville, VA, USA
| | - Max O Meneveau
- Department of Surgery, Division of Transplantation, The University of Virginia Health System, Charlottesville, VA, USA
| | - Kenneth L Brayman
- Department of Surgery, Division of Transplantation, The University of Virginia Health System, Charlottesville, VA, USA
- Correspondence: Kenneth L Brayman, Department of Surgery, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA 22908, USA, Tel +1 434 924 9370, Fax +1 434 924 5539, Email
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41
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Schive SW, Foss A, Sahraoui A, Kloster-Jensen K, Hafsahl G, Kvalheim G, Lundgren T, von Zur-Mühlen B, Felldin M, Rafael E, Lempinen M, Korsgren O, Jenssen TG, Mishra V, Scholz H. Cost and clinical outcome of islet transplantation in Norway 2010-2015. Clin Transplant 2016; 31. [PMID: 27862341 DOI: 10.1111/ctr.12871] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2016] [Indexed: 01/10/2023]
Abstract
Islet transplantation is a minimally invasive β-cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4 years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1 nmol L-1 , and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4 years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347 297±60 588 NOK, or 35 424±6182 EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center.
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Affiliation(s)
- Simen W Schive
- Department of Transplant Medicine, Cancer Institute, Oslo University Hospital, Oslo, Norway.,Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Aksel Foss
- Department of Transplant Medicine, Cancer Institute, Oslo University Hospital, Oslo, Norway.,Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Afaf Sahraoui
- Department of Transplant Medicine, Cancer Institute, Oslo University Hospital, Oslo, Norway.,Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Kristine Kloster-Jensen
- Department of Transplant Medicine, Cancer Institute, Oslo University Hospital, Oslo, Norway.,Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Geir Hafsahl
- Department of Radiology, Cancer Institute, Oslo University Hospital, Oslo, Norway
| | - Gunnar Kvalheim
- Department of Cell Therapy, Cancer Institute, Oslo University Hospital, Oslo, Norway
| | - Torbjørn Lundgren
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | | | - Marie Felldin
- Department of Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ehab Rafael
- Department of Nephrology and Transplantation, University Hospital, Malmo, Sweden
| | - Marko Lempinen
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Trond G Jenssen
- Department of Transplant Medicine, Cancer Institute, Oslo University Hospital, Oslo, Norway.,Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
| | - Vinod Mishra
- Department of Finance and Resource Management Unit, Oslo University Hospital, Oslo, Norway
| | - Hanne Scholz
- Department of Transplant Medicine, Cancer Institute, Oslo University Hospital, Oslo, Norway.,Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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42
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Gmyr V, Bonner C, Moerman E, Tournoys A, Delalleau N, Quenon A, Thevenet J, Chetboun M, Kerr-Conte J, Pattou F, Hubert T, Jourdain M. Human Recombinant Antithrombin (ATryn ®) Administration Improves Survival and Prevents Intravascular Coagulation After Intraportal Islet Transplantation in a Piglet Model. Cell Transplant 2016; 26:309-317. [PMID: 27938471 DOI: 10.3727/096368916x693554] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.
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43
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Kaviani M, Azarpira N. Insight into microenvironment remodeling in pancreatic endocrine tissue engineering: Biological and biomaterial approaches. Tissue Eng Regen Med 2016; 13:475-484. [PMID: 30603429 PMCID: PMC6170842 DOI: 10.1007/s13770-016-0014-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 02/03/2016] [Accepted: 02/05/2016] [Indexed: 01/04/2023] Open
Abstract
The treatment of diabetes mellitus, as a chronic and complicated disease, is a valuable purpose. Islet transplantation can provide metabolic stability and insulin independence in type 1 diabetes patients. Diet and insulin therapy are only diabetes controllers and cannot remove all of the diabetes complications. Moreover, islet transplantation is more promising treatment than whole pancreas transplantation because of lesser invasive surgical procedure and morbidity and mortality. According to the importance of extracellular matrix for islet viability and function, microenvironment remodeling of pancreatic endocrine tissue can lead to more success in diabetes treatment by pancreatic islets. Production of bioengineered pancreas and remodeling of pancreas extracellular matrix provide essential microenvironment for re-vascularization, re-innervation and signaling cascades triggering. Therefore, islets show better viability and function in these conditions. Researchers conduct various scaffolds with different biomaterials for the improvement of islet viability, function and transplantation outcome. The attention to normal pancreas anatomy, embryology and histology is critical to understand the pancreatic Langerhans islets niche and finally to achieve efficient engineered structure. Therefore, in the present study, the status and components of the islets niche is mentioned and fundamental issues related to the tissue engineering of this structure is considered. The purpose of this review article is summarization of recent progress in the endocrine pancreas tissue engineering and biomaterials and biological aspects of it.
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Affiliation(s)
- Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Mohamad Rasulallah Research Tower, Khalili street, Shiraz, 7193635899 Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Mohamad Rasulallah Research Tower, Khalili street, Shiraz, 7193635899 Iran
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44
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Pellegrini S, Cantarelli E, Sordi V, Nano R, Piemonti L. The state of the art of islet transplantation and cell therapy in type 1 diabetes. Acta Diabetol 2016; 53:683-91. [PMID: 26923700 DOI: 10.1007/s00592-016-0847-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 02/06/2016] [Indexed: 12/17/2022]
Abstract
In patients with type 1 diabetes (T1D), pancreatic β cells are destroyed by a selective autoimmune attack and their replacement with functional insulin-producing cells is the only possible cure for this disease. The field of islet transplantation has evolved significantly from the breakthrough of the Edmonton Protocol in 2000, since significant advances in islet isolation and engraftment, together with improved immunosuppressive strategies, have been reported. The main limitations, however, remain the insufficient supply of human tissue and the need for lifelong immunosuppression therapy. Great effort is then invested in finding innovative sources of insulin-producing β cells. One old alternative with new recent perspectives is the use of non-human donor cells, in particular porcine β cells. Also the field of preexisting β cell expansion has advanced, with the development of new human β cell lines. Yet, large-scale production of human insulin-producing cells from stem cells is the most recent and promising alternative. In particular, the optimization of in vitro strategies to differentiate human embryonic stem cells into mature insulin-secreting β cells has made considerable progress and recently led to the first clinical trial of stem cell treatment for T1D. Finally, the discovery that it is possible to derive human induced pluripotent stem cells from somatic cells has raised the possibility that a sufficient amount of patient-specific β cells can be derived from patients through cell reprogramming and differentiation, suggesting that in the future there might be a cell therapy without immunosuppression.
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Affiliation(s)
- Silvia Pellegrini
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elisa Cantarelli
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rita Nano
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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45
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Plaisance V, Brajkovic S, Tenenbaum M, Favre D, Ezanno H, Bonnefond A, Bonner C, Gmyr V, Kerr-Conte J, Gauthier BR, Widmann C, Waeber G, Pattou F, Froguel P, Abderrahmani A. Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL. PLoS One 2016; 11:e0163046. [PMID: 27636901 PMCID: PMC5026355 DOI: 10.1371/journal.pone.0163046] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 09/01/2016] [Indexed: 01/07/2023] Open
Abstract
Elevated plasma concentration of the pro-atherogenic oxidized low density lipoprotein cholesterol (LDL) triggers adverse effects in pancreatic beta-cells and is associated with type 2 diabetes. Here, we investigated whether the endoplasmic reticulum (ER) stress is a key player coupling oxidative stress to beta-cell dysfunction and death elicited by human oxidized LDL. We found that human oxidized LDL activates ER stress as evidenced by the activation of the inositol requiring 1α, and the elevated expression of both DDIT3 (also called CHOP) and DNAJC3 (also called P58IPK) ER stress markers in isolated human islets and the mouse insulin secreting MIN6 cells. Silencing of Chop and inhibition of ER stress markers by the chemical chaperone phenyl butyric acid (PBA) prevented cell death caused by oxidized LDL. Finally, we found that oxidative stress accounts for activation of ER stress markers induced by oxidized LDL. Induction of Chop/CHOP and p58IPK/P58IPK by oxidized LDL was mimicked by hydrogen peroxide and was blocked by co-treatment with the N-acetylcystein antioxidant. As a conclusion, the harmful effects of oxidized LDL in beta-cells requires ER stress activation in a manner that involves oxidative stress. This mechanism may account for impaired beta-cell function in diabetes and can be reversed by antioxidant treatment.
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Affiliation(s)
- Valérie Plaisance
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
| | - Saška Brajkovic
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
- Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and Lausanne University, Lausanne, Switzerland
| | - Mathie Tenenbaum
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
| | - Dimitri Favre
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
- Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and Lausanne University, Lausanne, Switzerland
| | - Hélène Ezanno
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
| | - Amélie Bonnefond
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
- Department of Genomic of Common Disease, Imperial College London, London, United Kingdom
| | | | - Valéry Gmyr
- Univ. Lille, Inserm, CHU Lille, U1190 - EGID, Lille, France
| | | | - Benoit R. Gauthier
- Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain
| | - Christian Widmann
- Department of Physiology, Lausanne University, Lausanne, Switzerland
| | - Gérard Waeber
- Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and Lausanne University, Lausanne, Switzerland
| | | | - Philippe Froguel
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
- Department of Genomic of Common Disease, Imperial College London, London, United Kingdom
| | - Amar Abderrahmani
- Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France
- Department of Genomic of Common Disease, Imperial College London, London, United Kingdom
- * E-mail:
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46
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Forbes S, Oram RA, Smith A, Lam A, Olateju T, Imes S, Malcolm AJ, Shapiro AMJ, Senior PA. Validation of the BETA-2 Score: An Improved Tool to Estimate Beta Cell Function After Clinical Islet Transplantation Using a Single Fasting Blood Sample. Am J Transplant 2016; 16:2704-13. [PMID: 27017888 PMCID: PMC5074289 DOI: 10.1111/ajt.13807] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 03/01/2016] [Accepted: 03/19/2016] [Indexed: 01/25/2023]
Abstract
The beta score, a composite measure of beta cell function after islet transplantation, has limited sensitivity because of its categorical nature and requires a mixed-meal tolerance test (MMTT). We developed a novel score based on a single fasting blood sample. The BETA-2 score used stepwise forward linear regression incorporating glucose (in millimoles per liter), C-peptide (in nanomoles per liter), hemoglobin A1c (as a percentage) and insulin dose (U/kg per day) as continuous variables from the original beta score data set (n = 183 MMTTs). Primary and secondary analyses assessed the score's ability to detect glucose intolerance (90-min MMTT glucose ≥8 mmol/L) and insulin independence, respectively. A validation cohort of islet transplant recipients (n = 114 MMTTs) examined 12 mo after transplantation was used to compare the score's ability to detect these outcomes. The BETA-2 score was expressed as follows (range 0-42): [Formula: see text] A score <20 and ≥15 detected glucose intolerance and insulin independence, respectively, with >82% sensitivity and specificity. The BETA-2 score demonstrated greater discrimination than the beta score for these outcomes (p < 0.05). Using a fasting blood sample, the BETA-2 score estimates graft function as a continuous variable and shows greater discrimination of glucose intolerance and insulin independence after transplantation versus the beta score, allowing frequent assessments of graft function. Studies examining its utility to track long-term graft function are required.
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Affiliation(s)
- S Forbes
- Department of Medicine, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
- BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - R A Oram
- Department of Medicine, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
| | - A Smith
- Department of Medicine, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
- Department of Surgery, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
| | - A Lam
- Department of Medicine, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
| | - T Olateju
- Department of Medicine, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
| | - S Imes
- Department of Medicine, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
- Department of Surgery, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
| | - A J Malcolm
- Department of Medicine, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
- Department of Surgery, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
| | - A M J Shapiro
- Department of Surgery, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
| | - P A Senior
- Department of Medicine, Clinical Islet Transplant Program, University of Alberta & Alberta Health Services, Edmonton, Alberta, Canada
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Well, I Wouldn't be Any Worse Off, Would I, Than I am Now? A Qualitative Study of Decision-Making, Hopes, and Realities of Adults With Type 1 Diabetes Undergoing Islet Cell Transplantation. Transplant Direct 2016; 2:e72. [PMID: 27500262 PMCID: PMC4946514 DOI: 10.1097/txd.0000000000000581] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 02/14/2016] [Indexed: 01/21/2023] Open
Abstract
Background For selected individuals with type 1 diabetes, pancreatic islet transplantation (IT) prevents recurrent severe hypoglycemia and optimizes glycemia, although ongoing systemic immunosuppression is needed. Our aim was to explore candidates and recipients' expectations of transplantation, their experience of being on the waiting list, and (for recipients) the procedure and life posttransplant. Methods Cross-sectional qualitative research design using semistructured interviews with 16 adults (8 pretransplant, 8 posttransplant; from 4 UK centers (n = 13) and 1 Canadian center (n = 3)). Interviews were audio-recorded, transcribed, and underwent inductive thematic analysis. Results Interviewees were aged (mean ± SD) 52 ± 10 years (range, 30-64); duration of diabetes, 36 ± 9 years (range, 21-56); 12 (75%) were women. Narrative accounts centered on expectations, hopes, and realities; decision-making; waiting and uncertainty; the procedure, hospital stay, and follow-up. Expected benefits included fewer severe hypoglycemic episodes, reduced need for insulin, preventing onset/progression of complications and improved psychological well-being. These were realized for most, at least in the short term. Most interviewees described well-informed, shared decision-making with clinicians and family, and managing their expectations. Although life “on the list” could be stressful, and immunosuppressant side effects were severe, interviewees reported “no regrets.” Posttransplant, interviewees experienced increased confidence, through freedom from hypoglycemia and regained glycemic control, which tempered any disappointment about continued reliance on insulin. Most viewed their transplant as a success, though several reflected upon setbacks and hidden hopes for becoming “insulin-free.” Conclusions Independently undertaken interviews demonstrated realistic and balanced expectations of IT and indicate how to optimize the process and support for future IT candidates.
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Zhu H, Yu L, He Y, Lyu Y, Wang B. Microencapsulated Pig Islet Xenotransplantation as an Alternative Treatment of Diabetes. TISSUE ENGINEERING PART B-REVIEWS 2015; 21:474-89. [PMID: 26028249 DOI: 10.1089/ten.teb.2014.0499] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Haitao Zhu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Heart Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Liang Yu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Yayi He
- Department of Endocrinology, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Yi Lyu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, China
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Affiliation(s)
- Bernhard J Hering
- Schulze Diabetes Institute, University of Minnesota, MMC 195, 420 Delaware Street S.E. Minneapolis, MN 55455, USA
| | - Melena D Bellin
- Schulze Diabetes Institute, University of Minnesota, MMC 195, 420 Delaware Street S.E. Minneapolis, MN 55455, USA
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Lablanche S, Borot S, Wojtusciszyn A, Bayle F, Tétaz R, Badet L, Thivolet C, Morelon E, Frimat L, Penfornis A, Kessler L, Brault C, Colin C, Tauveron I, Bosco D, Berney T, Benhamou PY. Five-Year Metabolic, Functional, and Safety Results of Patients With Type 1 Diabetes Transplanted With Allogenic Islets Within the Swiss-French GRAGIL Network. Diabetes Care 2015; 38:1714-22. [PMID: 26068866 DOI: 10.2337/dc15-0094] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 05/25/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To describe the 5-year outcomes of islet transplantation within the Swiss-French GRAGIL Network. RESEARCH DESIGN AND METHODS Retrospective analysis of all subjects enrolled in the GRAGIL-1c and GRAGIL-2 islet transplantation trials. Parameters related to metabolic control, graft function, and safety outcomes were studied. RESULTS Forty-four patients received islet transplantation (islet transplantation alone [ITA] 24 patients [54.5%], islet after kidney [IAK] transplantation 20 patients [45.5%]) between September 2003 and April 2010. Recipients received a total islet mass of 9,715.75 ± 3,444.40 IEQ/kg. Thirty-four patients completed a 5-year follow-up, and 10 patients completed a 4-year follow-up. At 1, 4, and 5 years after islet transplantation, respectively, 83%, 67%, and 58% of the ITA recipients and 80%, 70%, and 60% of the IAK transplant recipients reached HbA1c under 7% (53 mmol/mol) and were free of severe hypoglycemia, while none of the ITA recipients and only 10% of the IAK transplant recipients met this composite criterion at the preinfusion stage. Thirty-three of 44 patients (75%) experienced insulin independence during the entire follow-up period, with a median duration of insulin independence of 19.25 months (interquartile range 2-58). Twenty-nine of 44 recipients (66%) exhibited at least one adverse event; 18 of 55 adverse events (33%) were possibly related to immunosuppression; and complications related to the islet infusion (n = 84) occurred in 10 recipients (11.9%). CONCLUSIONS In a large cohort with a 5-year follow-up and in a multicenter network setting, islet transplantation was safe and efficient in restoring good and lasting glycemic control and preventing severe hypoglycemia in patients with type 1 diabetes.
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Affiliation(s)
- Sandrine Lablanche
- Department of Endocrinology, Pôle DigiDune, Grenoble University Hospital, Joseph Fourier University, Grenoble, France
| | - Sophie Borot
- Centre Hospitalier Universitaire Jean Minjoz, Service d'Endocrinologie-Métabolisme et Diabétologie-Nutrition, Besançon, France
| | - Anne Wojtusciszyn
- Centre Hospitalier de Montpellier, Pôle Rein Hypertension Métabolisme, Service d'Endocrinologie, Montpellier, France
| | - Francois Bayle
- Department of Nephrology, Pôle DigiDune, Grenoble University Hospital, Joseph Fourier University, Grenoble, France
| | - Rachel Tétaz
- Department of Nephrology, Pôle DigiDune, Grenoble University Hospital, Joseph Fourier University, Grenoble, France
| | - Lionel Badet
- Hospices Civils de Lyon, Service d'Urologie et de Chirurgie de la Transplantation, Pôle Chirurgie, Lyon, France
| | - Charles Thivolet
- Hospices Civils de Lyon, Service d'Endocrinologie Diabète Nutrition, Lyon, France
| | - Emmanuel Morelon
- Hospices Civils de Lyon, Service de Néphrologie Médecine de la Transplantation et Immunologie Clinique, Lyon, France
| | - Luc Frimat
- Centre Hospitalier Universitaire de Nancy, Service de Néphrologie, Nancy, France
| | - Alfred Penfornis
- Service d'Endocrinologie, Diabétologie et Maladies Métaboliques, Centre Hospitalier Sud-Francilien, Corbeil-Essonnes, France
| | - Laurence Kessler
- Hôpitaux Universitaires de Strasbourg, Service d'Endocrinologie Diabète et Maladies Métaboliques, Pôle NUDE, Strasbourg, France
| | - Coralie Brault
- Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, and Université de Lyon, EA Santé-Individu-Société 4129, Lyon, France
| | - Cyrille Colin
- Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, and Université de Lyon, EA Santé-Individu-Société 4129, Lyon, France
| | - Igor Tauveron
- CHU de Clermont-Ferrand, Service Endocrinologie-Diabète-Maladies Métaboliques, Clermont Ferrand Université, Clermont-Ferrand, France
| | - Domenico Bosco
- Departement of Surgery, Islet Isolation, and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - Thierry Berney
- Departement of Surgery, Islet Isolation, and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - Pierre-Yves Benhamou
- Department of Endocrinology, Pôle DigiDune, Grenoble University Hospital, Joseph Fourier University, Grenoble, France
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