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Drachenberg CB, Buettner-Herold M, Aguiar PV, Horsfield C, Mikhailov AV, Papadimitriou JC, Seshan SV, Perosa M, Boggi U, Uva P, Rickels M, Grzyb K, Arend L, Cuatrecasas M, Toniolo MF, Farris AB, Renaudin K, Zhang L, Roufousse C, Gruessner A, Gruessner R, Kandaswamy R, White S, Burke G, Cantarovich D, Parsons RF, Cooper M, Kudva YC, Kukla A, Haririan A, Parajuli S, Merino-Torres JF, Argente-Pla M, Meier R, Dunn T, Ugarte R, Rao JS, Vistoli F, Stratta R, Odorico J. Banff 2022 pancreas transplantation multidisciplinary report: Refinement of guidelines for T cell-mediated rejection, antibody-mediated rejection and islet pathology. Assessment of duodenal cuff biopsies and noninvasive diagnostic methods. Am J Transplant 2024; 24:362-379. [PMID: 37871799 DOI: 10.1016/j.ajt.2023.10.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/02/2023] [Accepted: 10/11/2023] [Indexed: 10/25/2023]
Abstract
The Banff pancreas working schema for diagnosis and grading of rejection is widely used for treatment guidance and risk stratification in centers that perform pancreas allograft biopsies. Since the last update, various studies have provided additional insight regarding the application of the schema and enhanced our understanding of additional clinicopathologic entities. This update aims to clarify terminology and lesion description for T cell-mediated and antibody-mediated allograft rejections, in both active and chronic forms. In addition, morphologic and immunohistochemical tools are described to help distinguish rejection from nonrejection pathologies. For the first time, a clinicopathologic approach to islet pathology in the early and late posttransplant periods is discussed. This update also includes a discussion and recommendations on the utilization of endoscopic duodenal donor cuff biopsies as surrogates for pancreas biopsies in various clinical settings. Finally, an analysis and recommendations on the use of donor-derived cell-free DNA for monitoring pancreas graft recipients are provided. This multidisciplinary effort assesses the current role of pancreas allograft biopsies and offers practical guidelines that can be helpful to pancreas transplant practitioners as well as experienced pathologists and pathologists in training.
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Affiliation(s)
| | - Maike Buettner-Herold
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) and University Hospital, Erlangen, Germany
| | | | - Catherine Horsfield
- Department of Histopathology/Cytology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Alexei V Mikhailov
- Department of Pathology, Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina, USA
| | - John C Papadimitriou
- Department of Pathology, University of Maryland School of Medicine, Maryland, USA
| | - Surya V Seshan
- Division of Renal Pathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA
| | - Marcelo Perosa
- Beneficência Portuguesa and Bandeirantes Hospital of São Paulo, São Paulo, Brazil
| | - Ugo Boggi
- Department of Surgery, University of Pisa, Pisa, The province of Pisa, Italy
| | - Pablo Uva
- Kidney/Pancreas Transplant Program, Instituto de Trasplantes y Alta Complejidad (ITAC - Nephrology), Buenos Aires, Argentina
| | - Michael Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Philadelphia, USA
| | - Krzyztof Grzyb
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Lois Arend
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | | | | | - Alton B Farris
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
| | | | - Lizhi Zhang
- Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Candice Roufousse
- Department of Immunology and Inflammation, Imperial College of London, London, United Kingdom
| | - Angelika Gruessner
- Department of Nephrology/Medicine, State University of New York, New York, USA
| | - Rainer Gruessner
- Department of Surgery, State University of New York, New York, USA
| | - Raja Kandaswamy
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Steven White
- Department of Surgery, Newcastle Upon Tyne NHS Foundation Trust, Newcastle upon Tyne, England, United Kingdom
| | - George Burke
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | | | - Ronald F Parsons
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Matthew Cooper
- Division of Transplant Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Yogish C Kudva
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Aleksandra Kukla
- Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, USA
| | - Abdolreza Haririan
- Department of Medicine, University of Maryland School of Medicine, Maryland, USA
| | - Sandesh Parajuli
- Department of Medicine, UWHealth Transplant Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Juan Francisco Merino-Torres
- Department of Endocrinology and Nutrition, University Hospital La Fe, La Fe Health Research Institute, University of Valencia, Valencia, Spain
| | - Maria Argente-Pla
- University Hospital La Fe, Health Research Institute La Fe, Valencia, Spain
| | - Raphael Meier
- Department of Surgery, University of Maryland School of Medicine, Maryland, USA
| | - Ty Dunn
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, University of Pennsylvania, Pennsylvania, Philadelphia, USA
| | - Richard Ugarte
- Department of Medicine, University of Maryland School of Medicine, Maryland, USA
| | - Joseph Sushil Rao
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, USA; Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Fabio Vistoli
- Department of Surgery, University of Pisa, Pisa, The province of Pisa, Italy
| | - Robert Stratta
- Department of Surgery, Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina, USA
| | - Jon Odorico
- Division of Transplantation, Department of Surgery, UWHealth Transplant Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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Ashraf MT, Ahmed Rizvi SH, Kashif MAB, Shakeel Khan MK, Ahmed SH, Asghar MS. Efficacy of anti-CD3 monoclonal antibodies in delaying the progression of recent-onset type 1 diabetes mellitus: A systematic review, meta-analyses and meta-regression. Diabetes Obes Metab 2023; 25:3377-3389. [PMID: 37580969 DOI: 10.1111/dom.15237] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/11/2023] [Accepted: 07/22/2023] [Indexed: 08/16/2023]
Abstract
AIM Type 1 diabetes mellitus is widely recognized as a chronic autoimmune disease characterized by the pathogenic destruction of beta cells, resulting in the loss of endogenous insulin production. Insulin administration remains the primary therapy for symptomatic treatment. Recent studies showed that disease-modifying agents, such as anti-CD3 monoclonal antibodies, have shown promising outcomes in improving the management of the disease. In late 2022, teplizumab received approval from the US Food and Drug Administration (FDA) as the first disease-modifying agent for the treatment of type 1 diabetes. This review aims to evaluate the clinical evidence regarding the efficacy of anti-CD3 monoclonal antibodies in the prevention and treatment of type 1 diabetes. METHODS A comprehensive search of PubMed, Google Scholar, Scopus and Cochrane Central Register of Controlled Trials (CENTRAL) was conducted up to December 2022 to identify relevant randomized controlled trials. Meta-analysis was performed using a random-effects model, and odds ratios with 95% confidence intervals (CIs) were calculated to quantify the effects. The Cochrane risk of bias tool was employed for quality assessment. RESULTS In total, 11 randomized controlled trials involving 1397 participants (908 participants in the intervention arm, 489 participants in the control arm) were included in this review. The mean age of participants was 15 years, and the mean follow-up time was 2.04 years. Teplizumab was the most commonly studied intervention. Compared with placebo, anti-CD3 monoclonal antibody treatment significantly increased the C-peptide concentration in the area under the curve at shorter timeframes (mean difference = 0.114, 95% CI: 0.069 to 0.159, p = .000). Furthermore, anti-CD3 monoclonal antibodies significantly reduced the patients' insulin intake across all timeframes (mean difference = -0.123, 95% CI: -0.151 to -0.094, p < .001). However, no significant effect on glycated haemoglobin concentration was observed. CONCLUSION The findings of this review suggest that anti-CD3 monoclonal antibody treatment increases endogenous insulin production and improves the lifestyle of patients by reducing insulin dosage. Future studies should consider the limitations, including sample size, heterogeneity and duration of follow-up, to validate the generalizability of these findings further.
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Affiliation(s)
- Muhammad Talal Ashraf
- Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | | | | | | | - Syed Hassan Ahmed
- Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan
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Alpha-Lipoic Acid Inhibits Spontaneous Diabetes and Autoimmune Recurrence in Non-Obese Diabetic Mice by Enhancing Differentiation of Regulatory T Cells and Showed Potential for Use in Cell Therapies for the Treatment of Type 1 Diabetes. Int J Mol Sci 2022; 23:ijms23031169. [PMID: 35163121 PMCID: PMC8835933 DOI: 10.3390/ijms23031169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/12/2022] [Accepted: 01/17/2022] [Indexed: 12/10/2022] Open
Abstract
Type 1 diabetes (T1D) is caused by the destruction of β cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective treatment for T1D. However, the survival of islet grafts is often disrupted by recurrent autoimmunity. Alpha-lipoic acid (ALA) has been reported to have immunomodulatory effects and, therefore, may have therapeutic potential in the treatment of T1D. In this study, we investigated the therapeutic potential of ALA in autoimmunity inhibition. We treated non-obese diabetic (NOD) mice with spontaneous diabetes and islet-transplantation mice with ALA. The onset of diabetes was decreased and survival of the islet grafts was extended. The populations of Th1 cells decreased, and regulatory T cells (Tregs) increased in ALA-treated mice. The in vitro Treg differentiation was significantly increased by treatment with ALA. The adoptive transfer of ALA-differentiated Tregs into NOD recipients improved the outcome of the islet grafts. Our results showed that in vivo ALA treatment suppressed spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Tregs. Our study also demonstrated the therapeutic potential of ALA in Treg-based cell therapies and islet transplantation used in the treatment of T1D.
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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: 16] [Impact Index Per Article: 4.0] [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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Lin JR, Huang SH, Wu CH, Chen YW, Hong ZJ, Cheng CP, Sytwu HK, Lin GJ. Valproic Acid Suppresses Autoimmune Recurrence and Allograft Rejection in Islet Transplantation through Induction of the Differentiation of Regulatory T Cells and Can Be Used in Cell Therapy for Type 1 Diabetes. Pharmaceuticals (Basel) 2021; 14:ph14050475. [PMID: 34067829 PMCID: PMC8157191 DOI: 10.3390/ph14050475] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/13/2021] [Accepted: 05/15/2021] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes mellitus (T1D) results from the destruction of insulin-producing β cells in the islet of the pancreas by lymphocytes. Non-obese diabetic (NOD) mouse is an animal model frequently used for this disease. It has been considered that T1D is a T cell-mediated autoimmune disease. Both CD4+ and CD8+ T cells are highly responsible for the destruction of β cells within the pancreatic islets of Langerhans. Previous studies have revealed that regulatory T (Treg) cells play a critical role in the homeostasis of the immune system as well as immune tolerance to autoantigens, thereby preventing autoimmunity. Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Previous reports have demonstrated that VPA treatment decreases the incidence and severity of collagen-induced arthritis and experimental autoimmune neuritis by increasing the population of Treg cells in these mouse disease models. Given the effect of VPA in the induction of Treg cells’ population, we evaluated the therapeutic potential and the protective mechanism of VPA treatment in the suppression of graft autoimmune rejection and immune recurrence in syngeneic or allogenic islet transplantation mouse models. In our study, we found that the treatment of VPA increased the expression of forkhead box P3 (FOXP3), which is a critical transcription factor that controls Treg cells’ development and function. Our data revealed that 400 mg/kg VPA treatment in recipients effectively prolonged the survival of syngeneic and allogenic islet grafts. The percentage of Treg cells in splenocytes increased in VPA-treated recipients. We also proved that adoptive transfer of VPA-induced Tregs to the transplanted recipients effectively prolonged the survival of islet grafts. The results of this study provide evidence of the therapeutic potential and the underlying mechanism of VPA treatment in syngeneic islet transplantation for T1D. It also provides experimental evidence for cell therapy by adoptive transferring of in vitro VPA-induced Tregs for the suppression of autoimmune recurrence.
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Affiliation(s)
- Jeng-Rong Lin
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Shing-Hwa Huang
- Department of Biology and Anatomy, National Defense Medical Center, Taipei 11490, Taiwan; (S.-H.H.); (C.-P.C.)
- Department of General Surgery, En Chu Kong Hospital, New Taipei 23741, Taiwan;
| | - Chih-Hsiung Wu
- Department of General Surgery, En Chu Kong Hospital, New Taipei 23741, Taiwan;
| | - Yuan-Wu Chen
- School of Dentistry, National Defense Medical Center, Taipei 11490, Taiwan;
- Department of Oral and Maxillofacial Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Zhi-Jie Hong
- Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Chia-Pi Cheng
- Department of Biology and Anatomy, National Defense Medical Center, Taipei 11490, Taiwan; (S.-H.H.); (C.-P.C.)
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan 35053, Taiwan;
- Department of Microbiology and Immunology, National Defense Medical Center, Taipei 11490, Taiwan
| | - Gu-Jiun Lin
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan;
- Department of Biology and Anatomy, National Defense Medical Center, Taipei 11490, Taiwan; (S.-H.H.); (C.-P.C.)
- Correspondence: ; Tel.: +886-287-923-100 (ext. 18709)
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Buron F, Reffet S, Badet L, Morelon E, Thaunat O. Immunological Monitoring in Beta Cell Replacement: Towards a Pathophysiology-Guided Implementation of Biomarkers. Curr Diab Rep 2021; 21:19. [PMID: 33895937 DOI: 10.1007/s11892-021-01386-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/25/2021] [Indexed: 01/23/2023]
Abstract
PURPOSE OF REVIEW Grafted beta cells are lost because of recurrence of T1D and/or allograft rejection, two conditions diagnosed with pancreas graft biopsy, which is invasive and impossible in case of islet transplantation. This review synthetizes the current pathophysiological knowledge and discusses the interest of available immune biomarkers. RECENT FINDINGS Despite the central role of auto-(recurrence of T1D) and allo-(T-cell mediated rejection) immune cellular responses, the latter are not directly monitored in routine. In striking contrast, there have been undisputable progresses in monitoring of auto and alloantibodies. Except for pancreas recipients in whom anti-donor HLA antibodies can be directly responsible for antibody-mediated rejection, autoantibodies (and alloantibodies in islet recipients) have no direct pathogenic effect. However, their fluctuation offers a surrogate marker for the activation status of T cells (because antibody generation depends on T cells). This illustrates the necessity to understand the pathophysiology when interpreting a biomarker and selecting the appropriate treatment.
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Affiliation(s)
- Fanny Buron
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, 5 Place d'Arsonval, 69003, Lyon, France
| | - Sophie Reffet
- Department of Endocrinology and Diabetes, Lyon-Sud Hospital, Hospices Civils de Lyon, 69310, Pierre-Bénite, France
| | - Lionel Badet
- Department of Urology and Transplantation surgery, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Emmanuel Morelon
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, 5 Place d'Arsonval, 69003, Lyon, France
- French National Institute of Health and Medical Research (Inserm) Unit 1111, Lyon, France
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, 5 Place d'Arsonval, 69003, Lyon, France.
- French National Institute of Health and Medical Research (Inserm) Unit 1111, Lyon, France.
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France.
- Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, 5 Place d'Arsonval, 69003, Lyon, France.
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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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Pestana N, Malheiro J, Silva F, Silva A, Ribeiro C, Pedroso S, Almeida M, Dias L, Henriques AC, Martins LS. Impact of Pancreatic Autoantibodies in Pancreas Graft Survival After Pancreas-Kidney Transplantation. Transplant Proc 2020; 52:1370-1375. [PMID: 32245621 DOI: 10.1016/j.transproceed.2020.02.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 02/07/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND In simultaneous pancreas-kidney transplantation (SPKT), persistence or recurrence of pancreatic autoantibodies (PAs) has been associated with pancreas graft (PG) autoimmune-driven injury. Our aim was to analyze the impact of PAs on PG survival. METHODS Between January 1, 2000, and December 31, 2017, we studied 139 patients with post-SPKT anti-glutamic acid decarboxylase (GAD) autoantibody. Alloimmune (ALI) events were defined as PG rejection and/or de novo donor-specific antibodies (DSA). Hence, 3 groups were defined: patients without ALI events or anti-GAD (n = 42), those with ALI events (n = 14), or those only with autoimmune events (positive for anti-GAD and no ALI events; n = 83). RESULTS Male sex was predominant (n = 72, 52%). Median age was 35 years (interquartile range: 31-39) and median follow-up was 6-7 years (interquartile range: 4.1-9.2). Regarding anti-GAD positivity post-SPKT (n = 90, 65%), no differences were observed concerning age, sex, anti-HLA antibodies, HLA mismatch number and de novo DSA. ALI events were present in 10% (n = 14). PG survival 15 years post-SPKT was better in patients without immune events (96%) followed by those with ALI (69%) and autoimmune events (63%) (P = .025). Anti-GAD was associated to higher annualized mean Hb1AC (P = .006) and lower mean C-peptide (P = .013). According to pre- and post-SPKT anti-GAD status, conversion from negative to positive was associated to worse (63%) 10-year PG survival (P = .044), compared to persistence of negative (100%) or positive anti-GAD (88%). Anti-islet cell and anti-insulin autoantibodies had no impact. CONCLUSION Anti-GAD presence post-SPKT was associated to higher pancreas disfunction and lower PG survival. De novo anti-GAD seems to offer a particular risk of PG failure.
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Affiliation(s)
- Nicole Pestana
- Nephrology Department, Hospital Central do Funchal, Funchal, Portugal.
| | - Jorge Malheiro
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - Filipa Silva
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - Andreia Silva
- Nephrology Department, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
| | - Catarina Ribeiro
- Nephrology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Porto, Portugal
| | - Sofia Pedroso
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - Manuela Almeida
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - Leonídio Dias
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - António Castro Henriques
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - La Salete Martins
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
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9
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Argente-Pla M, Martínez-Millana A, Del Olmo-García MI, Espí-Reig J, Pérez-Rojas J, Traver-Salcedo V, Merino-Torres JF. Autoimmune Diabetes Recurrence After Pancreas Transplantation: Diagnosis, Management, and Literature Review. Ann Transplant 2019; 24:608-616. [PMID: 31767825 PMCID: PMC6896746 DOI: 10.12659/aot.920106] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Pancreas transplantation can be a viable treatment option for patients with type 1 diabetes mellitus (T1DM), especially for those who are candidates for kidney transplantation. T1DM may rarely recur after pancreas transplantation, causing the loss of pancreatic graft. The aim of this study was to describe the prevalence of T1DM recurrence after pancreas transplantation in our series. Material/Methods Eighty-one patients transplanted from 2002 to 2015 were included. Autoantibody testing (GADA and IA-2) was performed before pancreas transplantation and during the follow-up. Results The series includes 48 males and 33 females, mean age 37.4±5.7 years and mean duration of diabetes 25.5±6.5 years. Patients received simultaneous pancreas kidney (SPK) transplantation. After SPK transplantation, 56 patients retained pancreatic graft, 8 patients died, and 17 patients lost their pancreatic graft. T1DM recurrence occurred in 2 of the 81 transplanted patients, yielding a prevalence of 2.5%, with an average time of appearance of 3.3 years after transplant. Pancreatic enzymes were normal in the 2 patients, ruling out pancreatic rejection. T1DM recurrence was confirmed histologically, showing selective lymphoid infiltration of the pancreatic islets. Conclusions T1DM recurrence after pancreas transplantation is infrequent; however, it is one of the causes of pancreatic graft loss that should always be ruled out. Negative autoimmunity prior to transplantation does not ensure that T1DM does not recur.
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Affiliation(s)
- María Argente-Pla
- Department of Endocrinology and Nutrition, La Fe University and Polytechnic Hospital, Valencia, Spain.,Mixed Research Unit of Endocrinology, Nutrition and Dietetics, La Fe Health Research Institute, Valencia, Spain
| | | | - María Isabel Del Olmo-García
- Department of Endocrinology and Nutrition, La Fe University and Polytechnic Hospital, Valencia, Spain.,Mixed Research Unit of Endocrinology, Nutrition and Dietetics, La Fe Health Research Institute, Valencia, Spain
| | - Jordi Espí-Reig
- Department of Nephrology, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Judith Pérez-Rojas
- Department of Pathological Anatomy, La Fe University and Polytechnic Hospital, Valencia, Spain
| | | | - Juan Francisco Merino-Torres
- Department of Endocrinology and Nutrition, La Fe University and Polytechnic Hospital, Valencia, Spain.,Mixed Research Unit of Endocrinology, Nutrition and Dietetics, La Fe Health Research Institute, Valencia, Spain.,Department of Medicine, University of Valencia, Valencia, Spain
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10
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Rickels MR, Robertson RP. Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions. Endocr Rev 2019; 40:631-668. [PMID: 30541144 PMCID: PMC6424003 DOI: 10.1210/er.2018-00154] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/26/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.
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Affiliation(s)
- Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - R Paul Robertson
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- Division of Endocrinology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
- Pacific Northwest Diabetes Research Institute, Seattle, Washington
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11
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Aigha II, Memon B, Elsayed AK, Abdelalim EM. Differentiation of human pluripotent stem cells into two distinct NKX6.1 populations of pancreatic progenitors. Stem Cell Res Ther 2018; 9:83. [PMID: 29615106 PMCID: PMC5883581 DOI: 10.1186/s13287-018-0834-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 03/09/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The expression of a specific combination of transcription factors (TFs) in the multipotent progenitor cells (MPCs) is critical for determining pancreatic cell fate. NKX6.1 expression in PDX1+ MPCs is required for functional β cell generation. We have recently demonstrated the generation of a novel population of human pluripotent stem cell (hPSC)-derived MPCs that exclusively express NKX6.1, independently of PDX1 (PDX1-/NKX6.1+). Therefore, the aim of this study was to characterize this novel population to elucidate its role in pancreatic development. METHODS The hPSCs were exposed to two differentiation protocols to generate MPCs that were analyzed using different techniques. RESULTS Based on the expression of PDX1 and NKX6.1, we generated three different populations of MPCs, two of them were NKX6.1+. One of these NKX6.1 populations coexpressed PDX1 (PDX1+/NKX6.1+) which is known to mature into functional β cells, and an additional novel population did not express PDX1 (PDX1-/NKX6.1+) with an undefined role in pancreatic cell fate. This novel population was enriched using our recently established protocol, allowing their reorganization in three-dimensional (3D) structures. Since NKX6.1 induction in MPCs can direct them to endocrine and/or ductal cells in humans, we examined the coexpression of endocrine and ductal markers. We found that the expression of the pancreatic endocrine progenitor markers chromogranin A (CHGA) and neurogenin 3 (NGN3) was not detected in the NKX6.1+ 3D structures, while few structures were positive for NKX2.2, another endocrine progenitor marker, thereby shedding light on the origin of this novel population and its role in pancreatic endocrine development. Furthermore, SOX9 was highly expressed in the 3D structures, but cytokeratin 19, a main ductal marker, was not detected in these structures. CONCLUSIONS These data support the existence of two independent NKX6.1+ MPC populations during human pancreatic development and the novel PDX1-/NKX6.1+ population may be involved in a unique trajectory to generate β cells in humans.
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Affiliation(s)
- Idil I Aigha
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar
| | - Bushra Memon
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar
| | - Ahmed K Elsayed
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar.,Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Essam M Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar.
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12
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Polastri L, Galbiati F, Folli F, Davalli AM. Effects of Carboxypeptidase E Overexpression on Insulin mRNA Levels, Regulated Insulin Secretion, and Proinsulin Processing of Pituitary GH3 Cells Transfected with a Furin-Cleavable Human Proinsulin cDNA. Cell Transplant 2017. [DOI: 10.3727/000000002783985260] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
We recently developed two rat pituitary GH3 cell clones engineered to secrete human insulin (InsGH3). InsGH3 cells convert proinsulin into mature insulin, which is partially stored into a readily releasable pool of secretory granules. The efficiency of these processes, however, is relatively low in these cells, either in vitro or in vivo. This study was aimed at determining whether carboxypeptidase E (Cpe) overexpression can increase proinsulin processing and regulated secretion by InsGH3 clones. Indeed, in its membrane-bound form Cpe works as sorting receptor for the regulated secretory pathway of many hormones while, in its soluble form, Cpe takes part to the late step of insulin maturation. We obtained two Cpe-overexpressing cell lines from two different InsGH3 clones (InsGH3/C1 and C7). In the Cpe-overexpressing cell lines, derived from InsGH3 of clone 1 (InsGH3/C1-HACpe), in which the membrane-bound form of exogenous Cpe is accounted for by 90% of total Cpe immunoreactivity, we observed an increase in proinsulin gene expression, and in basal and stimulated insulin secretion compared with the original clone. In contrast, in the Cpe-overexpressing cell line derived from InsGH3 of clone 7 (InsGH3/C7-HACpe), where the exogenous membrane-bound form was only 60% of total Cpe, we detected a decrease in basal insulin release and a modest, albeit significant, increase in intracellular proinsulin processing. In conclusion, Cpe overexpression can increase regulated insulin secretion and proinsulin processing in InsGH3 cells; however, such improvements appear quantitatively and qualitatively modest.
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Affiliation(s)
- Luca Polastri
- Department of Medicine, San Raffaele Scientific Institute, Milan, Italy
| | | | - Franco Folli
- Department of Unit for Metabolic Diseases, San Raffaele Scientific Institute, Milan, Italy
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13
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Pouliquen E, Baltzinger P, Lemle A, Chen CC, Parissiadis A, Borot S, Frimat L, Girerd S, Berney T, Lablanche S, Benhamou PY, Morelon E, Badet L, Dubois V, Kessler L, Thaunat O. Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function. Am J Transplant 2017; 17:462-473. [PMID: 27343461 DOI: 10.1111/ajt.13936] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 05/24/2016] [Accepted: 06/22/2016] [Indexed: 01/25/2023]
Abstract
Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.
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Affiliation(s)
- E Pouliquen
- Hospices Civils de Lyon, Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France.,INSERM U1111, Université de Lyon, Lyon, France
| | - P Baltzinger
- Hôpitaux Universitaires de Strasbourg, Service d'Endocrinologie Diabète et Maladies Métaboliques, Pôle MIRNED, EA 7293 Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - A Lemle
- Hôpitaux Universitaires de Strasbourg, Service d'Endocrinologie Diabète et Maladies Métaboliques, Pôle MIRNED, EA 7293 Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - C-C Chen
- INSERM U1111, Université de Lyon, Lyon, France
| | - A Parissiadis
- Laboratoire d' histocompatibilité, Etablissement Français de Sang, Strasbourg, France
| | - S Borot
- Centre Hospitalier Universitaire Jean Minjoz, Service d'Endocrinologie-Métabolisme et Diabétologie-Nutrition, Besançon, France
| | - L Frimat
- Centre Hospitalier Universitaire de Nancy, Service de Néphrologie, Nancy, France
| | - S Girerd
- Centre Hospitalier Universitaire de Nancy, Service de Néphrologie, Nancy, France
| | - T Berney
- Departement of Surgery, Islet Isolation, and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - S Lablanche
- Departement of Surgery, Islet Isolation, and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - P Y Benhamou
- Département d'Endocrinologie, Pôle DigiDune, Hôpital Universitaire de Grenoble, Université Grenoble Alpes, Grenoble, France
| | - E Morelon
- Hospices Civils de Lyon, Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France.,INSERM U1111, Université de Lyon, Lyon, France
| | - L Badet
- Hospices Civils de Lyon, Service d'Urologie et de Chirurgie de la Transplantation, Pôle Chirurgie, Hôpital Edouard Herriot, Lyon, France
| | - V Dubois
- Laboratoire d'Histocompatibilité, Etablissement Français du Sang, Lyon, France
| | - L Kessler
- Hôpitaux Universitaires de Strasbourg, Service d'Endocrinologie Diabète et Maladies Métaboliques, Pôle MIRNED, EA 7293 Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - O Thaunat
- Hospices Civils de Lyon, Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France.,INSERM U1111, Université de Lyon, Lyon, France
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14
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Ribeiro RS, Cristelli M, Amor AJ, Guerrero V, Ferrer J, Ricart MJ, Esmatjes E. The Effect of Corticosteroid Withdrawal on Glucose Metabolism and Anti-GAD Antibodies in Simultaneous Pancreas-Kidney Transplant Patients. Prog Transplant 2016; 26:249-54. [PMID: 27317270 DOI: 10.1177/1526924816654371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
CONTEXT Corticosteroid withdrawal may reduce insulin resistance; however, it could also influence pancreatic autoantibody profile in simultaneous pancreas-kidney (SPK) transplant patients. OBJECTIVE To evaluate the effect of corticosteroid withdrawal on glucose metabolism and anti-glutamic acid decarboxylase (GAD) antibody titers in SPK patients with type 1 diabetes after 12 months of follow-up. DESIGN In this retrospective study, fasting glucose and glycated hemoglobin (A1c) were compared before and after 3, 6, and 12 months of corticosteroid withdrawal in 80 SPK patients. In addition, weight, anti-GAD, and C-peptide levels were compared before and after withdrawal. Finally, fasting and postglucose, insulin, and C-peptide levels were compared before and after withdrawal in 25 patients undergoing oral glucose tolerance test (OGTT). RESULTS Fasting glucose levels did not change during corticosteroid discontinuation. After 12 months, A1c slightly increased from 4.6% (0.4%) to 4.8% (0.6%) (P < .01) and C-peptide decreased from 2.8 (1.1) ng/mL to 2.4 (1.3) ng/mL (P <. 01). In patients submitted to OGTT, glucose, insulin, and C-peptide levels did not change. There was no alteration in the proportion of anti-GAD positive tests (41% vs 45%). Anti-GAD titers remained stable or decreased in 70% of positive patients. CONCLUSION Corticosteroid withdrawal has no significant effect on glucose metabolism and on anti-GAD profile among SPK patients.
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Affiliation(s)
- Rogério Silicani Ribeiro
- Diabetes Unit, Hospital Clínic de Barcelona, Barcelona, Spain Diabetes Program, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Marina Cristelli
- Renal Transplant Unit, Hospital Clínic de Barcelona, Barcelona, Spain Hospital do Rim, Universidade Federal de São Paulo, Sao Paulo, Brazil
| | - Antonio J Amor
- Diabetes Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Vanessa Guerrero
- Renal Transplant Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Joana Ferrer
- Surgery Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - María José Ricart
- Renal Transplant Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Enric Esmatjes
- Diabetes Unit, Hospital Clínic de Barcelona, Barcelona, Spain
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15
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Vendrame F, Hopfner Y, Diamantopoulos S, Virdi SK, Allende G, Snowhite IV, Reijonen HK, Chen L, Ruiz P, Ciancio G, Hutton JC, Messinger S, Burke GW, Pugliese A. Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas-Kidney Transplants. Am J Transplant 2016; 16:235-45. [PMID: 26317167 PMCID: PMC5053280 DOI: 10.1111/ajt.13426] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 05/29/2015] [Accepted: 06/15/2015] [Indexed: 01/25/2023]
Abstract
Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreas-kidney allografts for T1D recurrence and its risk factors. With long-term follow-up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal testing for T1D-associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors. Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor-recipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D-predisposing HLA-DR3/DR4 genotype in the recipient and donor-recipient sharing of HLA-DR alleles, especially HLA-DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances.
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Affiliation(s)
- F. Vendrame
- Diabetes Research InstituteLeonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - Y‐Y. Hopfner
- Diabetes Research InstituteLeonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - S. Diamantopoulos
- Diabetes Research InstituteLeonard Miller School of MedicineUniversity of MiamiMiamiFL,Department of Pediatrics, Leonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - S. K. Virdi
- Diabetes Research InstituteLeonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - G. Allende
- Diabetes Research InstituteLeonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - I. V. Snowhite
- Diabetes Research InstituteLeonard Miller School of MedicineUniversity of MiamiMiamiFL
| | | | - L. Chen
- Department of Surgery, Division of Transplantation, Leonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - P. Ruiz
- Department of Surgery, Division of Transplantation, Leonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - G. Ciancio
- Department of Surgery, Division of Transplantation, Leonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - J. C. Hutton
- Barbara Davis Center for Childhood DiabetesUniversity of Colorado DenverAuroraCO
| | - S. Messinger
- Department of Epidemiology and Public Health Sciences, Division of Biostatistics, Leonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - G. W. Burke
- Diabetes Research InstituteLeonard Miller School of MedicineUniversity of MiamiMiamiFL,Department of Surgery, Division of Transplantation, Leonard Miller School of MedicineUniversity of MiamiMiamiFL
| | - A. Pugliese
- Diabetes Research InstituteLeonard Miller School of MedicineUniversity of MiamiMiamiFL,Department of Medicine, Division of Endocrinology and Metabolism, Leonard Miller School of MedicineUniversity of MiamiMiamiFL,Department of Microbiology and ImmunologyLeonard Miller School of MedicineUniversity of MiamiMiamiFL
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16
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Quiskamp N, Bruin JE, Kieffer TJ. Differentiation of human pluripotent stem cells into β-cells: Potential and challenges. Best Pract Res Clin Endocrinol Metab 2015; 29:833-47. [PMID: 26696513 DOI: 10.1016/j.beem.2015.10.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) hold great potential as the basis for cell-based therapies of degenerative diseases, including diabetes. Current insulin-based therapies for diabetes do not prevent hyperglycaemia or the associated long-term organ damage. While transplantation of pancreatic islets can achieve insulin independence and improved glycemic control, it is limited by donor tissue scarcity, challenges of purifying islets from the pancreas, and the need for immunosuppression to prevent rejection of transplants. Large-scale production of β-cells from stem cells is a promising alternative. Recent years have seen considerable progress in the optimization of in vitro differentiation protocols to direct hESCs/iPSCs into mature insulin-secreting β-cells and clinical trials are now under way to test the safety and efficiency of hESC-derived pancreatic progenitor cells in patients with type 1 diabetes. Here, we discuss key milestones leading up to these trials in addition to recent developments and challenges for hESC/iPSC-based diabetes therapies and disease modeling.
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Affiliation(s)
- Nina Quiskamp
- Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
| | - Jennifer E Bruin
- Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
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17
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Zaidi A, Meng Q, Popkin D. Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir? IMMUNOTHERAPY (LOS ANGELES, CALIF.) 2015; 1:104. [PMID: 27110598 PMCID: PMC4841618 DOI: 10.4172/imt.1000104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Current anti-retroviral treatment (ART) for HIV is effective in maintaining HIV at undetectable levels. However, cessation of ART results in immediate and brisk rebound of viremia to high levels. This rebound is driven by an HIV reservoir mainly enriched in memory CD4+ T cells. In order to provide any form of functional HIV Cure, elimination of this viral reservoir has become the focus of current HIV cure strategies. Alefacept was initially developed for the treatment of chronic plaque psoriasis. Alefacept is a chimeric fusion protein consisting of the CD2-binding portion of human leukocyte function antigen-3 (LFA3) linked to the Fc region of human IgG1 (LFA3-Fc). Alefacept was designed to inhibit memory T cell activation that contributes to the chronic autoimmune disease psoriasis by blocking the CD2 coreceptor. However, it was found to deplete memory T cells that express high levels of CD2 via NK cell-mediated antibody dependent cell cytotoxicity (ADCC) in vivo. Phase II and phase III clinical trials of alefacept with psoriasis patients demonstrated promising results and an excellent safety profile. Subsequently, alefacept has been successfully repurposed for other memory T cell-mediated autoimmune diseases including skin diseases other than psoriasis, organ transplantation and type I diabetes (T1D). Herein, we review our specific strategy to repurpose the FDA approved biologic alefacept to decrease and hopefully someday eliminate the HIV reservoir, for which CD2hi memory CD4+ T cells are a significant contributor.
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Affiliation(s)
- Asifa Zaidi
- Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Qinglai Meng
- Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Daniel Popkin
- Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
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18
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Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents. Persistence of autoreactive memory T cells likely contributes to the difficulty in preventing disease progression in new-onset T1D and maintaining allogeneic islet transplants by regular immunosuppressive regimens. The majority of immune interventions that have demonstrated some success in preserving beta cell function in the new-onset period have been shown to deplete or modulate memory T cells. Based on these and other considerations, preservation of residual beta cells early after diagnosis or restoration of beta cell mass by use of stem cell or transplantation technology will require a successful strategy to control the autoreactive memory T cell compartment, which could include depletion, inhibition of homeostatic cytokines, induction of hyporesponsiveness, or a combination of these approaches.
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Affiliation(s)
- Mario R Ehlers
- Clinical Trials Group, Immune Tolerance Network, 185 Berry Street, Suite 3515, San Francisco, CA, 94107, USA.
| | - Mark R Rigby
- Translational Medicine, Immunology Development, Janssen R&D, Pharmaceutical Companies of Johnson & Johnson, Spring House, PA, 19477, USA.
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19
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Mujtaba MA, Fridell J, Book B, Faiz S, Sharfuddin A, Wiebke E, Rigby M, Taber T. Re-exposure to beta cell autoantigens in pancreatic allograft recipients with preexisting beta cell autoantibodies. Clin Transplant 2015; 29:991-6. [PMID: 26289931 DOI: 10.1111/ctr.12619] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2015] [Indexed: 11/28/2022]
Abstract
Re-exposure to beta cell autoantigens and its relevance in the presence of donor-specific antibodies (DSA) in pancreatic allograft recipients is not well known. Thirty-three patients requiring a pancreas transplant were enrolled in an IRB approved study. They underwent prospective monitoring for DSA and beta cell autoantibody (BCAA) levels to GAD65, insulinoma-associated antigen 2 (IA-2), insulin (micro-IAA [mIAA]), and islet-specific zinc transporter isoform-8 (ZnT8). Twenty-five (75.7%) had pre-transplant BCAA. Twenty had a single antibody (mIAA n = 15, GAD65 n = 5); five had two or more BCAA (GAD65 + mIAA n = 2, GAD65 + mIAA+IA-2 n = 2, GA65 + mIAA+IA-2 + ZnT8 = 1). No changes in GAD65 (p > 0.29), IA-2 (>0.16), and ZnT8 (p > 0.07) were observed between pre-transplant and post-transplant at 6 or 12 months. A decrease in mIAA from pre- to post-6 months (p < 0.0001), 12 months (p < 0.0001), and from post-6 to post-12 months (p = 0.0002) was seen. No new BCAA was observed at one yr. Seven (21.0%) developed de novo DSA. The incidence of DSA was 24% in patients with BCAA vs. 25% in patients without BCAA (p = 0.69). Pancreatic allograft function of patients with vs. without BCAA, and with and without BCAA + DSA was comparable until last follow-up (three yr). Re-exposure to beta cell autoantigens by pancreas transplant may not lead to increased levels or development of new BCAA or pancreatic allograft dysfunction.
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Affiliation(s)
- Muhammad Ahmad Mujtaba
- Division of Nephrology/Transplant, Department of Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Jonathan Fridell
- Division of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Benita Book
- Transplant Immunology Lab, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sara Faiz
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | - Asif Sharfuddin
- Division of Nephrology/Transplant, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Eric Wiebke
- Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mark Rigby
- Transplant Immunology Lab, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tim Taber
- Division of Nephrology/Transplant, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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The current challenges for pancreas transplantation for diabetes mellitus. Pharmacol Res 2015; 98:45-51. [DOI: 10.1016/j.phrs.2015.01.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Revised: 01/26/2015] [Accepted: 01/27/2015] [Indexed: 12/27/2022]
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Johannesson B, Sui L, Freytes DO, Creusot RJ, Egli D. Toward beta cell replacement for diabetes. EMBO J 2015; 34:841-55. [PMID: 25733347 DOI: 10.15252/embj.201490685] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 01/22/2015] [Indexed: 12/31/2022] Open
Abstract
The discovery of insulin more than 90 years ago introduced a life-saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserved for cases with simultaneous transplantation of a kidney, where immunosuppression is already a requirement. Recent advances in cell reprogramming and beta cell differentiation now allow the generation of personalized stem cells, providing an unlimited source of beta cells for research and for developing autologous cell therapies. In this review, we will discuss the utility of stem cell-derived beta cells to investigate the mechanisms of beta cell failure in diabetes, and the challenges to develop beta cell replacement therapies. These challenges include appropriate quality controls of the cells being used, the ability to generate beta cell grafts of stable cellular composition, and in the case of type 1 diabetes, protecting implanted cells from autoimmune destruction without compromising other aspects of the immune system or the functionality of the graft. Such novel treatments will need to match or exceed the relative safety and efficacy of available care for diabetes.
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Affiliation(s)
| | - Lina Sui
- Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Donald O Freytes
- The New York Stem Cell Foundation Research Institute, New York, NY, USA
| | - Remi J Creusot
- Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Dieter Egli
- The New York Stem Cell Foundation Research Institute, New York, NY, USA Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
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Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence in non-obese diabetic mice by inducing differentiation of regulatory T cells. Toxicol Appl Pharmacol 2015; 282:207-14. [DOI: 10.1016/j.taap.2014.11.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 11/19/2014] [Accepted: 11/24/2014] [Indexed: 12/20/2022]
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Monti P, Vignali D, Piemonti L. Monitoring Inflammation, Humoral and Cell-mediated Immunity in Pancreas and Islet Transplants. Curr Med Chem 2015; 11:135-43. [PMID: 25777058 PMCID: PMC5398085 DOI: 10.2174/1573399811666150317125820] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 02/19/2015] [Accepted: 02/19/2015] [Indexed: 12/23/2022]
Abstract
Type 1 diabetes (T1D) is caused by the chronic autoimmune destruction of insulin producing beta cells. Beta cell replacement therapy through whole pancreas or islet transplantation is a therapeutic option for patients in which a stable glucose control is not achievable with exogenous insulin therapy. Long-term insulin independence is, however, hampered by the recipient immune response that includes activation of inflammatory pathways and specific allo- and autoimmunity. The identification and monitoring of soluble and cellular biomarkers are of critical relevance for the prediction of graft damage, for the evaluation of responses to immune-modulating therapy, and for target pathways identification to generate novel drugs or therapeutic approaches. The final objective of immune monitoring is to find ways to improve the outcome of pancreas and islet transplantation. In this review, we discuss the available tools to monitor the innate, humoral and cellular responses after islet and pancreas transplantation, and the most relevant findings generated by these measurements.
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Affiliation(s)
- Paolo Monti
- Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
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Affiliation(s)
- Robin Goland
- Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA ; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA ; Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Dieter Egli
- Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA ; Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA ; The New York Stem Cell Foundation Research Institute (NYSCF), New York, NY 10032, USA
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25
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Martins LS. Autoimmune diabetes recurrence should be routinely monitored after pancreas transplantation. World J Transplant 2014; 4:183-187. [PMID: 25346891 PMCID: PMC4208081 DOI: 10.5500/wjt.v4.i3.183] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 05/21/2014] [Accepted: 07/17/2014] [Indexed: 02/05/2023] Open
Abstract
Autoimmune type 1 diabetes recurrence in pancreas grafts was first described 30 years ago, but it is not yet completely understood. In fact, the number of transplants affected and possibly lost due to this disease may be falsely low. There may be insufficient awareness to this entity by clinicians, leading to underdiagnosis. Some authors estimate that half of the immunological losses in pancreas transplantation are due to autoimmunity. Pancreas biopsy is the gold standard for the definitive diagnosis. However, as an invasive procedure, it is not the ideal approach to screen the disease. Pancreatic autoantibodies which may be detected early before graft dysfunction, when searched for, are probably the best initial tool to establish the diagnosis. The purpose of this review is to revisit the autoimmune aspects of type 1 diabetes and to analyse data about the identified autoantibodies, as serological markers of the disease. Therapeutic strategies used to control the disease, though with unsatisfactory results, are also addressed. In addition, the author’s own experience with the prospective monitoring of pancreatic autoantibodies after transplantation and its correlation with graft outcome will be discussed.
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Martins LS, Henriques AC, Fonseca IM, Rodrigues AS, Oliverira JC, Dores JM, Dias LS, Cabrita AM, Silva JD, Noronha IL. Pancreatic autoantibodies after pancreas-kidney transplantation - do they matter? Clin Transplant 2014; 28:462-9. [PMID: 24655222 DOI: 10.1111/ctr.12337] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2014] [Indexed: 02/05/2023]
Abstract
Type 1 diabetes recurrence has been documented in simultaneous pancreas-kidney transplants (SPKT), but this diagnosis may be underestimated. Antibody monitoring is the most simple, noninvasive, screening test for pancreas autoimmune activity. However, the impact of the positive autoimmune markers on pancreas graft function remains controversial. In our cohort of 105 SPKT, we studied the cases with positive pancreatic autoantibodies. They were immunosuppressed with antithymocyte globulin, tacrolimus, mycophenolate, and steroids. The persistence or reappearance of these autoantibodies after SPKT and factors associated with their evolution and with graft outcome were analyzed. Pancreatic autoantibodies were prospectively monitored. Serum samples were collected before transplantation and at least once per year thereafter. At the end of the follow-up (maximum 138 months), 43.8% of patients were positive (from pre-transplant or after recurrence) for at least one autoantibody - the positive group. Antiglutamic acid decarboxylase was the most prevalent (31.4%), followed by anti-insulin (8.6%) and anti-islet cell autoantibodies (3.8%). Bivariate analysis showed that the positive group had higher fasting glucose, higher glycated hemoglobin (HbA1c), lower C-peptide levels, and a higher number of HLA-matches. Analyzing the sample divided into four groups according to pre-/post-transplant autoantibodies profile, the negative/positive group tended to present the higher HbA1c values. Multivariate analysis confirmed the significant association between pancreas autoimmunity and HbA1c and C-peptide levels. Positivity for these autoantibodies pre-transplantation did not influence pancreas survival. The unfavorable glycemic profile observed in the autoantibody-positive SPKT is a matter of concern, which deserves further attention.
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Affiliation(s)
- La Salete Martins
- Nephrology Department, Hospital Santo António, Centro Hospitalar do Porto, Porto, Portugal; Transplantation Department, Hospital Santo António, Centro Hospitalar do Porto, Porto, Portugal
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Azzi J, Geara AS, El-Sayegh S, Abdi R. Immunological aspects of pancreatic islet cell transplantation. Expert Rev Clin Immunol 2014; 6:111-24. [DOI: 10.1586/eci.09.67] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Gruessner RWG, Pugliese A, Reijonen HK, Gruessner S, Jie T, Desai C, Sutherland DER, Burke III GW. Development of diabetes mellitus in living pancreas donors and recipients. Expert Rev Clin Immunol 2014; 7:543-51. [DOI: 10.1586/eci.11.19] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Coppieters KT, Harrison LC, von Herrath MG. Trials in type 1 diabetes: Antigen-specific therapies. Clin Immunol 2013; 149:345-55. [PMID: 23490422 PMCID: PMC5777514 DOI: 10.1016/j.clim.2013.02.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 02/05/2013] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) results from an aberrant immunological response against the insulin-producing beta cells in the islets of the pancreas. The ideal therapy would restore immune balance in a safe and lasting fashion, stopping the process of beta cell decay. The efficacy of immune suppressive agents such as cyclosporin underscores the notion that T1D can in principle be prevented, albeit at an unacceptable long-term safety risk. Immune modulatory drugs such as monoclonal anti-CD3 antibody, on the other hand, have recently had rather disappointing results in phase 3 trials, possibly due to inadequate dosing or choice of inappropriate endpoints. Therefore, it is argued that striking the right balance between safety and efficacy, together with careful trial design, will be paramount in preventing T1D. Here we outline the concept of antigen-specific tolerization as a strategy to safely induce long-term protection against T1D, focusing on available clinical trial data, key knowledge gaps and potential future directions.
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Affiliation(s)
| | - Leonard C. Harrison
- The Walter and Eliza Hall Institute of Medical Research and Department of Clinical Immunology and Burnet Clinical Research Unit, The Royal Melbourne Hospital, Melbourne, Australia
| | - Matthias G. von Herrath
- Type 1 Diabetes R&D Center, Novo Nordisk Inc., Seattle, WA, USA
- Type 1 Diabetes Center, The La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
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Chia JS, McRae JL, Thomas HE, Fynch S, Elkerbout L, Hill P, Murray-Segal L, Robson SC, Chen JF, d’Apice AJ, Cowan PJ, Dwyer KM. The protective effects of CD39 overexpression in multiple low-dose streptozotocin-induced diabetes in mice. Diabetes 2013; 62:2026-35. [PMID: 23364452 PMCID: PMC3661652 DOI: 10.2337/db12-0625] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Islet allograft survival limits the long-term success of islet transplantation as a potential curative therapy for type 1 diabetes. A number of factors compromise islet survival, including recurrent diabetes. We investigated whether CD39, an ectonucleotidase that promotes the generation of extracellular adenosine, would mitigate diabetes in the T cell-mediated multiple low-dose streptozotocin (MLDS) model. Mice null for CD39 (CD39KO), wild-type mice (WT), and mice overexpressing CD39 (CD39TG) were subjected to MLDS. Adoptive transfer experiments were performed to delineate the efficacy of tissue-restricted overexpression of CD39. The role of adenosine signaling was examined using mutant mice and pharmacological inhibition. The susceptibility to MLDS-induced diabetes was influenced by the level of expression of CD39. CD39KO mice developed diabetes more rapidly and with higher frequency than WT mice. In contrast, CD39TG mice were protected. CD39 overexpression conferred protection through the activation of adenosine 2A receptor and adenosine 2B receptor. Adoptive transfer experiments indicated that tissue-restricted overexpression of CD39 conferred robust protection, suggesting that this may be a useful strategy to protect islet grafts from T cell-mediated injury.
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Affiliation(s)
- Joanne S.J. Chia
- Immunology Research Centre, St Vincent’s Hospital, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Victoria, Australia
| | - Jennifer L. McRae
- Immunology Research Centre, St Vincent’s Hospital, Melbourne, Victoria, Australia
| | | | - Stacey Fynch
- St Vincent’s Institute, Fitzroy, Victoria, Australia
| | | | - Prue Hill
- Department of Pathology, St. Vincent’s Hospital, Melbourne, Victoria, Australia
| | - Lisa Murray-Segal
- Immunology Research Centre, St Vincent’s Hospital, Melbourne, Victoria, Australia
| | - Simon C. Robson
- Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Jiang-Fan Chen
- Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
| | - Anthony J.F. d’Apice
- Immunology Research Centre, St Vincent’s Hospital, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Victoria, Australia
| | - Peter J. Cowan
- Immunology Research Centre, St Vincent’s Hospital, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Victoria, Australia
| | - Karen M. Dwyer
- Immunology Research Centre, St Vincent’s Hospital, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Victoria, Australia
- Corresponding author: Karen M. Dwyer,
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Lin GJ, Huang SH, Chen SJ, Wang CH, Chang DM, Sytwu HK. Modulation by melatonin of the pathogenesis of inflammatory autoimmune diseases. Int J Mol Sci 2013; 14:11742-66. [PMID: 23727938 PMCID: PMC3709754 DOI: 10.3390/ijms140611742] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 05/15/2013] [Accepted: 05/16/2013] [Indexed: 12/14/2022] Open
Abstract
Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease.
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Affiliation(s)
- Gu-Jiun Lin
- Department of Biology and Anatomy, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan; E-Mail:
| | - Shing-Hwa Huang
- Department of General Surgery, Tri-Service General Hospital, No.325, Section 2, Chenggong Rd., Neihu District, Taipei City 114, Taiwan; E-Mail:
| | - Shyi-Jou Chen
- Graduate Institute of Medical Sciences, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan; E-Mails: (S.-J.C.); (C.-H.W.)
- Department of Pediatrics, Tri-Service General Hospital, No.325, Section 2, Chenggong Rd., Neihu District, Taipei City 114, Taiwan
| | - Chih-Hung Wang
- Graduate Institute of Medical Sciences, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan; E-Mails: (S.-J.C.); (C.-H.W.)
- Department of Otolaryngology—Head and Neck Surgery, Tri-Service General Hospital, No.325, Section 2, Chenggong Rd., Neihu District, Taipei City 114, Taiwan
- Institute of Undersea and Hyperbaric Medicine, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan
- Department of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan
| | - Deh-Ming Chang
- Rheumatology/Immunology/Allergy, Tri-Service General Hospital, No.325, Section 2, Chenggong Rd., Neihu District, Taipei City 114, Taiwan; E-Mail:
| | - Huey-Kang Sytwu
- Department of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +886-2-8792-3100 (ext. 18540); Fax: +886-2-8792-1774
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Abstract
OBJECTIVES Triptolide (TPL) possesses profound immunosuppressive effects and has potential in allograft transplantation. We investigated whether TPL treatment prevents autoimmune diabetes in nonobese diabetic (NOD) mice and prolongs the survival of islet grafts against autoimmune attack or allograft rejection. METHODS Diabetic incidence was monitored in TPL-treated NOD mice. Nonobese diabetic or BALB/c islets were transplanted into diabetic recipients treated with TPL. Different T-cell subsets in grafts or spleen were analyzed. The proliferation, apoptosis, cytokines, and activities of AKT, NFκB, and caspases 3, 8, and 9 of T cells were determined. RESULTS Diabetic incidence was reduced and inflammatory cytokines were decreased in islets and spleen under TPL treatment. T-cell proliferation was reduced and the survival of syngeneic or allogeneic grafts was significantly increased in TPL-treated mice. The populations of CD4, CD8, CD4CD69, CD8CD69, and interferon-γ-producing T cells in islet grafts and spleen were reduced. Triptolide treatment increased the apoptosis of T cells in the spleen of recipients. Levels of phosphorylated protein kinase B and phosphorylated inhibitor of kappa B in splenocytes were reduced and caspases 3, 8, and 9 were increased in TPL-treated mice. CONCLUSIONS Triptolide treatment not only reduced the diabetic incidence in NOD mice but also prolonged the survival of syngeneic or allogeneic grafts.
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Huang SH, Lin GJ, Chien MW, Chu CH, Yu JC, Chen TW, Hueng DY, Liu YL, Sytwu HK. Adverse Effect on Syngeneic Islet Transplantation by Transgenic Coexpression of Decoy Receptor 3 and Heme Oxygenase-1 in the Islet of NOD Mice. Transplant Proc 2013; 45:580-4. [DOI: 10.1016/j.transproceed.2012.02.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 02/14/2012] [Indexed: 01/12/2023]
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Coppieters KT, Sehested Hansen B, von Herrath MG. Clinical potential of antigen-specific therapies in type 1 diabetes. Rev Diabet Stud 2012; 9:328-37. [PMID: 23804270 PMCID: PMC3740700 DOI: 10.1900/rds.2012.9.328] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 01/21/2013] [Accepted: 02/08/2013] [Indexed: 12/31/2022] Open
Abstract
In type 1 diabetes (T1D), pancreatic beta-cells are attacked and destroyed by the immune system, which leads to a loss of endogenous insulin secretion. The desirable outcome of therapeutic intervention in autoimmune diseases is the restoration of immune tolerance to prevent organ damage. Past trials with immune suppressive drugs highlight the fact that T1D is in principle a curable condition. However, the barrier in T1D therapy in terms of drug safety is set particularly high because of the predominantly young population and the good prognosis associated with modern exogenous insulin therapy. Thus, there is a general consensus that chronic immune suppression is associated with unacceptable long-term safety risks. On the other hand, immune-modulatory biologicals have recently failed to confer significant protection in phase 3 clinical trials. However, the concept of antigen-specific tolerization may offer a unique strategy to safely induce long-term protection against T1D. In this review, we analyze the potential reasons for the failure of the different tolerization therapies, and describe how the concept of antigen-specific toleraization may overcome the obstacles associated with clinical therapy in T1D.
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Affiliation(s)
| | | | - Matthias G. von Herrath
- Type 1 Diabetes R&D Center, Novo Nordisk Inc., Seattle, WA, USA
- La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
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Lv H, Lipes MA. Role of impaired central tolerance to α-myosin in inflammatory heart disease. Trends Cardiovasc Med 2012; 22:113-7. [PMID: 22902177 DOI: 10.1016/j.tcm.2012.07.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 07/06/2012] [Accepted: 07/09/2012] [Indexed: 12/15/2022]
Abstract
For more than a half century, autoimmunity has been linked to a diverse array of heart diseases, including rheumatic carditis, myocarditis, Chagas' cardiomyopathy, post-myocardial infarction (Dressler's) syndrome, and idiopathic dilated cardiomyopathy. Why the heart is targeted by autoimmunity in these seemingly unrelated conditions has remained enigmatic. Here, we discuss our recent studies indicating that this susceptibility is mediated by impaired negative selection of autoreactive α-myosin heavy-chain-specific CD4(+) T cells in the thymus of both mice and humans. We describe how this process may place the heart at increased risk for autoimmune attack following ischemic or infectious injury, providing a rationale for the development of antigen-specific tolerogenic therapies.
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Affiliation(s)
- HuiJuan Lv
- Section on Immunobiology at the Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
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Zinc transporter 8 autoantibodies increase the predictive value of islet autoantibodies for function loss of technically successful solitary pancreas transplant. Transplantation 2011; 92:674-7. [PMID: 21792090 DOI: 10.1097/tp.0b013e31822ae65f] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Despite the success rate of solitary pancreas transplantation in type 1 diabetes with preserved kidney function has greatly improved in recent years, a residual proportion of failures persists. METHODS With the aim of investigating autoimmunity as an unrecognized cause of graft failure, we measured autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and the recently discovered zinc transporter 8 antigen (ZnT8A) in 25 recipients of technically successful solitary pancreas transplantation. RESULTS The overall pancreas graft survival was 92%, 88%, and 80% at 2, 4, and 6 years, respectively. Fourteen patients (56%) had one or more autoantibodies before transplantation, with no effect on subsequent pancreas graft outcome. After transplantation, major autoantibody changes (serum conversion from negative to positive, spreading from one to multiple autoantibodies, or titer increase) were observed in 5 of 25 recipients: in four patients, the autoantibody change was followed by the loss of graft function (95% sensitivity, 80% positive predictive value), with a significantly lower graft survival compared with patients without autoantibodies (P<0.0001). The addition of ZnT8A to GADA and IA-2A increased the number of identified autoantibody changes from three to five of 25 recipients and the number of predicted graft function loss from two to four out of five graft losses. CONCLUSIONS Detection of major autoantibody changes after technically successful solitary pancreas transplantation is predictive of subsequent loss of graft function. ZnT8A in addition to GADA and IA-2A are a useful marker to be included in the screening panel of posttransplant immune monitoring.
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Burke GW, Vendrame F, Pileggi A, Ciancio G, Reijonen H, Pugliese A. Recurrence of autoimmunity following pancreas transplantation. Curr Diab Rep 2011; 11:413-9. [PMID: 21660419 PMCID: PMC4018301 DOI: 10.1007/s11892-011-0206-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Pancreas transplantation is a therapeutic option for patients with type 1 diabetes. Advances in immunosuppression have reduced immunologic failures, and these are usually categorized as chronic rejection. Yet studies in our cohort of pancreas transplant recipients identified several patients in whom chronic islet autoimmunity led to recurrent diabetes, despite immunosuppression that prevented rejection. Recurrent diabetes in our cohort is as frequent as chronic rejection, and thus is a significant cause of immunologic graft failure. Our studies demonstrated islet autoimmunity by the presence of autoantibodies and autoreactive T cells, which mediated ß-cell destruction in a transplantation model. Biopsy of the transplanted pancreas revealed variable degrees of ß-cell loss, with or without insulitis, in the absence of pancreas and kidney transplant rejection. Additional research is needed to better understand recurrent disease and to identify new treatment regimens that can suppress autoimmunity, as in our experience this is not effectively inhibited by conventional immunosuppression.
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Affiliation(s)
- George W. Burke
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, 1801 NW 9th Avenue, Miami FL 33136, Tel. 305-355-5000 Fax 305-355-5134
| | - Francesco Vendrame
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, 1450 NW 10th Avenue, Miami, FL 33136 USA, Tel. 305-243-5353 Fax 305-243-4404
| | - Antonello Pileggi
- Diabetes Research Institute and Department of Surgery, Leonard Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136 USA, Tel. 305-243-2924 Fax 305-243-4404
| | - Gaetano Ciancio
- Departments of Urology and Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, 1801 NW 9th Avenue, Miami FL 33136, Tel. 305-355-5000 Fax 305-355-5134
| | - Helena Reijonen
- Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101, Tel. 206-223-8813 Fax 206-223-7638
| | - Alberto Pugliese
- Diabetes Research Institute, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, and Department of Microbiology and Immunology, Leonard Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136 USA, Tel. 305-243-5348 Fax 305-243-4404
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Drachenberg CB, Torrealba JR, Nankivell BJ, Rangel EB, Bajema IM, Kim DU, Arend L, Bracamonte ER, Bromberg JS, Bruijn JA, Cantarovich D, Chapman JR, Farris AB, Gaber L, Goldberg JC, Haririan A, Honsová E, Iskandar SS, Klassen DK, Kraus E, Lower F, Odorico J, Olson JL, Mittalhenkle A, Munivenkatappa R, Paraskevas S, Papadimitriou JC, Randhawa P, Reinholt FP, Renaudin K, Revelo P, Ruiz P, Samaniego MD, Shapiro R, Stratta RJ, Sutherland DER, Troxell ML, Voska L, Seshan SV, Racusen LC, Bartlett ST. Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema. Am J Transplant 2011; 11:1792-802. [PMID: 21812920 DOI: 10.1111/j.1600-6143.2011.03670.x] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.
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Affiliation(s)
- C B Drachenberg
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
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Zhang SH, Wu HY, Zhu L. Current status of pancreas transplantation. Shijie Huaren Xiaohua Zazhi 2011; 19:1651-1658. [DOI: 10.11569/wcjd.v19.i16.1651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreas transplantation has emerged as the treatment of choice for patients with end-stage diabetes mellitus. Over the last four decades, many improvements have been made in the surgical techniques and immunosuppressive regimens, which contributed to increased number of indications and improved allograft survival. Pancreas transplantation can be justified on the basis that patients replace daily injections of insulin with an improved quality of life but at the expense of a major surgical procedure with a relatively higher complication rate, and lifelong immunosuppression. Therefore, efforts to develop more minimally invasive techniques for endocrine replacement therapy such as islet transplantation have been in progress. This article summarizes the current understanding of pancreas transplantation-associated indications, donor selection, surgical techniques, immunosuppression, and rejection.
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Pugliese A, Reijonen HK, Nepom J, Burke GW. Recurrence of autoimmunity in pancreas transplant patients: research update. ACTA ACUST UNITED AC 2011; 1:229-238. [PMID: 21927622 DOI: 10.2217/dmt.10.21] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Type 1 diabetes is an autoimmune disorder leading to loss of pancreatic β-cells and insulin secretion, followed by insulin dependence. Islet and whole pancreas transplantation restore insulin secretion. Pancreas transplantation is often performed together with a kidney transplant in patients with end-stage renal disease. With improved immunosuppression, immunological failures of whole pancreas grafts have become less frequent and are usually categorized as chronic rejection. However, growing evidence indicates that chronic islet autoimmunity may eventually lead to recurrent diabetes, despite immunosuppression to prevent rejection. Thus, islet autoimmunity should be included in the diagnostic work-up of graft failure and ideally should be routinely assessed pretransplant and on follow-up in Type 1 diabetes recipients of pancreas and islet cell transplants. There is a need to develop new treatment regimens that can control autoimmunity, as this may not be effectively suppressed by conventional immunosuppression.
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Affiliation(s)
- Alberto Pugliese
- Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136, USA
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42
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The potential utility of bone marrow or umbilical cord blood transplantation for the treatment of type I diabetes mellitus. Biol Blood Marrow Transplant 2010; 17:455-64. [PMID: 20541025 DOI: 10.1016/j.bbmt.2010.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Accepted: 06/01/2010] [Indexed: 12/11/2022]
Abstract
The pathology of type 1 diabetes mellitus (T1D) involves the autoimmune destruction or malfunction of pancreatic β cells, leading to a lack of insulin. The absence of insulin is life-threatening, necessitating daily hormone injections from an exogenous source. Insulin injections do not adequately mimic the precise regulation of β cells on glucose homeostasis, however, eventually leading to complications in diabetic patients. There currently is no definitive cure for T1D. Pancreas transplantation, although quite successful, is an invasive intervention that is restricted to patients with advanced complications, requires constant immunosuppression, and is severely limited by donor availability. Recent progress in human islet cell isolation and immunosuppressive protocols has restored euglycemia in patients who received islet cells from 2 or 3 pancreas donors. However, because of the scarcity of cadaver pancreata and the low yield of islet cells obtained by the procedure, not all patients have access to this surgical intervention. Thus, other therapeutic approaches are needed to arrest immune aggression, preserve β cell mass, and provide efficient replacement. In this sense, bone marrow and umbilical cord blood transplantation are promising possibilities that merit exploration. In this review, we summarize multiple strategies that have been proposed and tested for potential therapeutic benefit in patients with T1D.
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Longoni B, Szilagyi E, Quaranta P, Paoli GT, Tripodi S, Urbani S, Mazzanti B, Rossi B, Fanci R, Demontis GC, Marzola P, Saccardi R, Cintorino M, Mosca F. Mesenchymal stem cells prevent acute rejection and prolong graft function in pancreatic islet transplantation. Diabetes Technol Ther 2010; 12:435-46. [PMID: 20470228 DOI: 10.1089/dia.2009.0154] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Pancreatic islet transplantation is a promising cell-based therapy for type 1 diabetes (insulin-dependent diabetes mellitus), a disease triggered by the immune response against autoantigens of beta-cells. However, the recurrence of immune response after transplantation and the diabetogenic and growth-stunting side effects of immunosuppressants are major challenges to the application of islet transplantation. Mesenchymal stem cells (MSCs) have recently been reported to modulate the immune response in allogeneic transplantation. METHODS The ability of MSCs, either syngeneic or allogeneic to recipients, to prevent acute rejection and improve glycemic control was investigated in rats with diabetes given a marginal mass of pancreatic islets through the portal vein. RESULTS Reduced glucose levels and low-grade rejections were observed up to 15 days after transplantation upon triple-dose administration of MSCs, indicating that MSCs prolong graft function by preventing acute rejection. The efficacy of MSCs was associated with a reduction of pro-inflammatory cytokines and was independent of the administration route. Efficacy was similar for MSCs whether syngeneic or allogeneic to recipients and comparable to that of immunosuppressive therapy. CONCLUSIONS The results show that MSCs modulate the immune response through a down-regulation of pro-inflammatory cytokines, suggesting that MSCs may prevent acute rejection and improve graft function in portal vein pancreatic islet transplantation.
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Affiliation(s)
- Biancamaria Longoni
- Department of Oncology, Transplantation and Advanced Technology in Medicine, University of Pisa, Pisa, Italy.
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Pancreas transplant: recent advances and spectrum of features in pancreas allograft pathology. Adv Anat Pathol 2010; 17:202-8. [PMID: 20418674 DOI: 10.1097/pap.0b013e3181d97635] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
As result of improved surgical techniques and newer immunosuppressive regimens contributing significantly to better graft survival, exocrine pancreas transplantation remains the standard treatment of choice for patients with diabetes mellitus complicated by end-stage renal disease. Histologic assessment continues to play an important role in the diagnosis of graft complications after pancreas transplantation, especially for evaluating allograft rejection where histopathology is still considered the gold standard. This review elaborates on the current types of pancreas transplants and focuses on the patterns of allograft injury that are encountered in posttransplantation pancreas biopsies along with the pertinent differential diagnoses. In addition to optimal histologic assessment, as in any other organ transplant setting, clinical information including indication and duration of transplant as well as other serologic work-up must be taken into consideration during clinical decision making for optimal graft outcome.
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45
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Vendrame F, Pileggi A, Laughlin E, Allende G, Martin-Pagola A, Molano RD, Diamantopoulos S, Standifer N, Geubtner K, Falk BA, Ichii H, Takahashi H, Snowhite I, Chen Z, Mendez A, Chen L, Sageshima J, Ruiz P, Ciancio G, Ricordi C, Reijonen H, Nepom GT, Burke GW, Pugliese A. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes 2010; 59:947-57. [PMID: 20086230 PMCID: PMC2844842 DOI: 10.2337/db09-0498] [Citation(s) in RCA: 154] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients. RESEARCH DESIGN AND METHODS We monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays. RESULTS Autoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within approximately 1 year from hyperglycemia recurrence and revealed beta-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell-directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell-directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for >1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed beta-cell loss in mice receiving autoreactive T-cells but not control T-cells. CONCLUSIONS We demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used.
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Affiliation(s)
- Francesco Vendrame
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Antonello Pileggi
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | | | - Gloria Allende
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Ainhoa Martin-Pagola
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - R. Damaris Molano
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Stavros Diamantopoulos
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Nathan Standifer
- Benaroya Research Institute, Seattle, Washington
- Clinical Immunology, Amgen Inc., Seattle, Washington
| | | | - Ben A. Falk
- Benaroya Research Institute, Seattle, Washington
| | - Hirohito Ichii
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Hidenori Takahashi
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Isaac Snowhite
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Zhibin Chen
- Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Armando Mendez
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Medicine, Division of Endocrinology and Metabolism, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Linda Chen
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Junichiro Sageshima
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Phillip Ruiz
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Gaetano Ciancio
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Camillo Ricordi
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Medicine, Division of Endocrinology and Metabolism, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | | | | | - George W. Burke
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida
| | - Alberto Pugliese
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Department of Medicine, Division of Endocrinology and Metabolism, Leonard Miller School of Medicine, University of Miami, Miami, Florida
- Corresponding author: Alberto Pugliese,
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Abstract
PURPOSE OF REVIEW Type 1 diabetes is a chronic disease that can impact patient survival and quality of life because of acute and chronic complications. Although intensive insulin scheme treatment has been shown to reduce the incidence of diabetes-related complications, only pancreas transplantation has been shown to be able to alter them and in some cases to revert them. In this review, an extensive view of the effect of pancreas transplantation on diabetes-related complication will be described. RECENT FINDINGS This review will focus on patients survival, diabetic nephropathy, neuropathy, cardiovascular event, comparing their incidence in type 1 diabetic patients treated with insulin and in type 1 diabetic patients receiving kidney, kidney-pancreas or pancreas alone graft. The review will focus mostly on the papers published in the last decade, with a particular attention to those on new aspects of graft function analysis like spectroscopy. Moreover, a comparison with islet transplantation procedure will be performed. SUMMARY This review will give an update on the potential of pancreas transplantation, give a guide for clinical practice and help to consider pancreas transplantation as an alternative to insulin treatment for selected patients.
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Ishida-Oku M, Iwase M, Sugitani A, Masutani K, Kitada H, Tanaka M, Iida M. A case of recurrent type 1 diabetes mellitus with insulitis of transplanted pancreas in simultaneous pancreas-kidney transplantation from cardiac death donor. Diabetologia 2010; 53:341-5. [PMID: 19911164 DOI: 10.1007/s00125-009-1593-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2009] [Accepted: 10/08/2009] [Indexed: 11/25/2022]
Abstract
AIMS/HYPOTHESIS A 41-year-old woman undergoing simultaneous pancreas-kidney transplantation from an HLA-mismatched cardiac death donor abruptly developed overt hyperglycaemia under standard immunosuppressive therapy at 48 months after transplantation. Unexpectedly, we found insulitis in the transplanted pancreas and characterised the insulitis. METHODS Pancreas graft biopsies were performed 3 years before and after the development of hyperglycaemia and the specimens were examined histologically. RESULTS Insulitis was absent in the first biopsy, although oxidative DNA changes revealed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining were diffusely present both in islet cells and exocrine cells. No Ki67-positive proliferating cells were seen in the islets. Anti-glutamic acid decarboxylase antibody was undetectable 6 months earlier but increased to 6.3 U/l at the development of hyperglycaemia. The level of anti-insulinoma-associated protein 2 antibody was 18.5 U/l. Insulin secretion was severely suppressed and insulin therapy was resumed. In the second biopsy, although acute allograft rejection was minimal, insulin-positive beta cells were markedly reduced, and glucagon-positive alpha cells predominated. CD3-positive T lymphocytes, CD8-positive cytotoxic T lymphocytes and CD68-positive macrophages infiltrated around and into islets. The infiltrating cells expressed Fas ligand as well as granzyme B. More than 80% of islets were affected by insulitis. 8-OHdG-positive cells were also present in islets and exocrine tissue. The percentage of Ki67-positive cells in total islet cells was 1.5%. There were no TUNEL-positive apoptotic cells in the islet cells. CONCLUSIONS/INTERPRETATION The histological features of insulitis in transplanted pancreas were consistent with common type 1 diabetes mellitus, but the clinical course of the recurrence appeared to be more rapid.
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Affiliation(s)
- M Ishida-Oku
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
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Gagliani N, Ferraro A, Roncarolo MG, Battaglia M. Autoimmune diabetic patients undergoing allogeneic islet transplantation: are we ready for a regulatory T-cell therapy? Immunol Lett 2009; 127:1-7. [PMID: 19643137 DOI: 10.1016/j.imlet.2009.07.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2009] [Revised: 07/14/2009] [Accepted: 07/20/2009] [Indexed: 11/30/2022]
Abstract
Regulatory T cells (Tregs) are thought to be pivotal in controlling both autoimmune and allogeneic undesired immune responses. Recently, an extensive effort has been devoted to design clinical trials with Tregs in T cell-mediated diseases (such as autoimmune diseases or transplantation). Theoretically, this approach can be used also in patients with autoimmunity (e.g., type 1 diabetes) undergoing allogeneic transplantation (e.g., pancreatic islet transplant). However, in this latter case Tregs must control two distinct effector immune responses: a pre-existing response towards self-antigens and a de novo response induced by the newly transplanted allogeneic cells. In this review we summarize results supporting the use of Tregs in controlling either autoimmunity or allo-transplantation. We also provide our view on how Treg therapy can achieve the final goal of immunological tolerance in the extremely challenging clinical setting of type 1 diabetic subjects transplanted with allogeneic islets.
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Affiliation(s)
- Nicola Gagliani
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milano, Italy
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Lin GJ, Huang SH, Chen YW, Hueng DY, Chien MW, Chia WT, Chang DM, Sytwu HK. Melatonin prolongs islet graft survival in diabetic NOD mice. J Pineal Res 2009; 47:284-92. [PMID: 19708865 DOI: 10.1111/j.1600-079x.2009.00712.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Islet transplantation has been established as a potential therapy for type 1 diabetes. However, inflammation, allorejection, and on-going autoimmune damage contribute to early graft loss and failure of islet transplantation. Melatonin is the major secretory product of the pineal gland during the dark period of each day and displays multifunctional properties including the regulation of circadian and seasonal rhythms, antioxidation reactions and immune modulation. Based on the immunosuppressive properties of melatonin, we investigated whether melatonin treatment prolonged the survival of islet grafts in non-obese diabetic (NOD) mice. The mean islet graft survival time was 7.33 +/- 1.51 and 7.75 +/- 2.66 days in untreated controls and in the solvent-treated animals, respectively. Strikingly, the mean survival time of islet grafts in recipients treated with melatonin (200 mg/kg/bw) was 17 +/- 7.76 days. Moreover, melatonin treatment reduced the proliferation of splenocytes in NOD mice. Using a T1 and T2 double transgenic mouse model, we found that T helper 1 (Th1) cells in mice treated with melatonin were significantly decreased. The reduction of Th1 cells and T cell proliferation may result from an increase in the immunosuppressive cytokine IL-10. Our results indicate that melatonin treatment suppresses autoimmune recurrence by inhibiting the proliferation of Th1 cells in NOD mice and thus prolongs the survival of syngeneic islet grafts.
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Affiliation(s)
- Gu-Jiun Lin
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
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Martins L, Malheiro J, Henriques AC, Dias L, Dores J, Oliveira F, Seca R, Almeida R, Sarmento AM, Cabrita A, Teixeira M. Pancreas-kidney transplantation and the evolution of pancreatic autoantibodies. Transplant Proc 2009; 41:913-5. [PMID: 19376387 DOI: 10.1016/j.transproceed.2009.01.068] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The recurrence or persistence of pancreatic autoantibodies after pancreas-kidney transplantation (PKT) is an intriguing finding. We prospectively analyzed 77 PKTs, searching for risk factors for the expression of these autoimmune markers and their impact on pancreas graft function. Among the 77 PKTs, 24.7% had 0 HLA matches, 20.8% displayed delayed graft function, and 14.3% had acute rejection episodes. Immunosuppression included antithymocyte globulin (ATG), tacrolimus, mycophenolate mofetil (MMF), and steroids. Sixty-five patients had both grafts functioning as a follow-up of more than 6 months. In 11 patients anti-glutamic acid decarboxylase (GAD) positivity persists (n = 8) or has recurred (n = 3), 4 of whom show increasing titers. Two patients maintain positive islet cell antibodies (ICA) and anti-GAD antibodies. The 9 patients positive for ICA included 2 who were negative before PKT and 7 who remain positive. The "positive" group (22 patients with positive ICA and/or anti-GAD) did not differ from the global group of 65 functioning PKT in terms of acute rejection episodes, HLA match, and steroid withdrawal. Among the positive patients, there were 2 with borderline glucose levels; however, among the entire "positive" group, the mean fasting glucose, HbA1c, and C-peptide measurements were not significantly different, when compared with the other 65 PKTs. In conclusion, pancreatic autoantibodies may be persistently positive or recur after PKT, despite appropriate immunosuppression. Its impact on long-term pancreas graft survival is unknown. We could not identify risk factors for their expression. An extended follow-up with monitoring and search for other risk factors may be necessary to increase our knowledge in this field.
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Affiliation(s)
- L Martins
- Nephrology Department, Hospital Santo António, Centro Hospitalar do Porto, Portugal.
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