|
1
|
Łaszczych D, Czernicka A, Łaszczych K. Targeting GABA signaling in type 1 diabetes and its complications- an update on the state of the art. Pharmacol Rep 2025; 77:409-424. [PMID: 39833509 DOI: 10.1007/s43440-025-00697-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/04/2025] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that leads to the progressive destruction of insulin-producing β cells, resulting in lifelong insulin dependence and a range of severe complications. Beyond conventional glycemic control, innovative therapeutic strategies are needed to address the underlying disease mechanisms. Recent research has highlighted gamma-aminobutyric acid (GABA) as a promising therapeutic target for T1D due to its dual role in modulating both β cell survival and immune response within pancreatic islets. GABA signaling supports β cell regeneration, inhibits α cell hyperactivity, and promotes α-to-β cell transdifferentiation, contributing to improved islet function. Moreover, GABA's influence extends to mitigating T1D complications, including nephropathy, neuropathy, and retinopathy, as well as regulating central nervous system pathways involved in glucose metabolism. This review consolidates the latest advances in GABA-related T1D therapies, covering animal preclinical and human clinical studies and examining the therapeutic potential of GABA receptor modulation, combination therapies, and dietary interventions. Emphasis is placed on the translational potential of GABA-based approaches to enhance β cell viability and counteract autoimmune processes in T1D. Our findings underscore the therapeutic promise of GABA signaling modulation as a novel approach for T1D treatment and encourage further investigation into this pathway's role in comprehensive diabetes management.
Collapse
Affiliation(s)
- Dariusz Łaszczych
- Faculty of Medicine, Collegium Medicum, Nicolaus Copernicus University in Torun, Jagiellońska 13, 85-067, Bydgoszcz, Poland.
| | | | - Katarzyna Łaszczych
- Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Jedności 8, Sosnowiec, 41-200, Poland
- Ziko Pharmacy, Plebiscytowa 39, Katowice, Poland
| |
Collapse
|
|
2
|
Lai X, Luo J, Luo Y, Zheng Y, Yang H, Zou F. Targeting the autoreactive CD8 + T-cell receptor in type 1 diabetes: Insights from scRNA-seq for immunotherapy. Pharmacol Res 2024; 209:107433. [PMID: 39343113 DOI: 10.1016/j.phrs.2024.107433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 10/01/2024]
Abstract
Type 1 Diabetes (T1D) is an autoimmune disease characterized by the attack and destruction of Pancreatic islet beta cells by T cells. Understanding the role of T-cell receptor (TCR) in the development of T1D is of paramount importance. This study employs single-cell RNA sequencing (scRNA-seq) to delve into the mechanistic actions and potential therapeutic applications of autoreactive stem cell-like CD8 TCR in T1D. By retrieving T-cell data from non-obese diabetic (NOD) mice via the GEO database, it was revealed that CD8+ T cells are the predominant T-cell subset in the pancreatic tissue of T1D mice, along with the identification of T-cell marker genes closely associated with T1D. Moreover, the gene TRAJ23 exhibits a preference for T1D, and its knockout alleviates T1D symptoms and adverse reactions in NOD mice. Additionally, engineered TCR-T cells demonstrate significant cytotoxicity towards β cells in T1D.
Collapse
Affiliation(s)
- Xiaoyang Lai
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Junming Luo
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Yue Luo
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Yijing Zheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Huan Yang
- Department of Endocrinology, Jiujiang University Affiliated Hospital, Jiujiang, PR China
| | - Fang Zou
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
| |
Collapse
|
|
3
|
Lin C, Hu S, Cai X, Lv F, Yang W, Liu G, Yang X, Ji L. The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis. Pharmacol Res 2024; 203:107157. [PMID: 38531504 DOI: 10.1016/j.phrs.2024.107157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/22/2024] [Accepted: 03/22/2024] [Indexed: 03/28/2024]
Abstract
There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.
Collapse
Affiliation(s)
- Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Geling Liu
- Department of Endocrinology (Section I), Tangshan Gongren Hospital, Tangshan, Hebei, China
| | - Xiaolin Yang
- Department of Endocrinology (Section I), Tangshan Gongren Hospital, Tangshan, Hebei, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| |
Collapse
|
|
4
|
Bolla AM, Montefusco L, Pastore I, Lunati ME, Ben Nasr M, Fiorina P. Benefits and Hurdles of Pancreatic β-Cell Replacement. Stem Cells Transl Med 2022; 11:1029-1039. [PMID: 36073717 PMCID: PMC9585952 DOI: 10.1093/stcltm/szac058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/02/2022] [Indexed: 11/13/2022] Open
Abstract
Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological advancements have improved glucose control in an increasing number of patients. Despite this, adequate control is often still difficult to achieve and insulin remains a therapy and not a cure for the disease. β-cell replacement strategies can potentially restore pancreas endocrine function and aim to maintain normoglycemia; both pancreas and islet transplantation have greatly progressed over the last decades and, in subjects with extreme glycemic variability and diabetes complications, represent a concrete and effective treatment option. Some issues still limit the adoption of this approach on a larger scale. One is represented by the strict selection criteria for the recipient who can benefit from a transplant and maintain the lifelong immunosuppression necessary to avoid organ rejection. Second, with regard to islet transplantation, up to 40% of islets can be lost during hepatic engraftment. Recent studies showed very preliminarily but promising results to overcome these hurdles: the ability to induce β-cell maturation from stem cells may represent a solution to the organ shortage, and the creation of semi-permeable membranes that envelope or package cells in either micro- or macro- encapsulation strategies, together with engineering cells to be hypo-immunogenic, pave the way for developing strategies without immunosuppression. The aim of this review is to describe the state of the art in β-cell replacement with a focus on its efficacy and clinical benefits, on the actual limitations and still unmet needs, and on the latest findings and future directions.
Collapse
Affiliation(s)
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy.,International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
5
|
Silva IBB, Kimura CH, Colantoni VP, Sogayar MC. Stem cells differentiation into insulin-producing cells (IPCs): recent advances and current challenges. Stem Cell Res Ther 2022; 13:309. [PMID: 35840987 PMCID: PMC9284809 DOI: 10.1186/s13287-022-02977-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 06/19/2022] [Indexed: 11/10/2022] Open
Abstract
Type 1 diabetes mellitus (T1D) is a chronic disease characterized by an autoimmune destruction of insulin-producing β-pancreatic cells. Although many advances have been achieved in T1D treatment, current therapy strategies are often unable to maintain perfect control of glycemic levels. Several studies are searching for new and improved methodologies for expansion of β-cell cultures in vitro to increase the supply of these cells for pancreatic islets replacement therapy. A promising approach consists of differentiation of stem cells into insulin-producing cells (IPCs) in sufficient number and functional status to be transplanted. Differentiation protocols have been designed using consecutive cytokines or signaling modulator treatments, at specific dosages, to activate or inhibit the main signaling pathways that control the differentiation of induced pluripotent stem cells (iPSCs) into pancreatic β-cells. Here, we provide an overview of the current approaches and achievements in obtaining stem cell-derived β-cells and the numerous challenges, which still need to be overcome to achieve this goal. Clinical translation of stem cells-derived β-cells for efficient maintenance of long-term euglycemia remains a major issue. Therefore, research efforts have been directed to the final steps of in vitro differentiation, aiming at production of functional and mature β-cells and integration of interdisciplinary fields to generate efficient cell therapy strategies capable of reversing the clinical outcome of T1D.
Collapse
Affiliation(s)
- Isaura Beatriz Borges Silva
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo, SP, 05360-130, Brazil.,Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-000, Brazil
| | - Camila Harumi Kimura
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo, SP, 05360-130, Brazil
| | - Vitor Prado Colantoni
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo, SP, 05360-130, Brazil.,Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-000, Brazil
| | - Mari Cleide Sogayar
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo, SP, 05360-130, Brazil. .,Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
| |
Collapse
|
|
6
|
Baker JR, Farazuddin M, Wong PT, O'Konek JJ. The unfulfilled potential of mucosal immunization. J Allergy Clin Immunol 2022; 150:1-11. [PMID: 35569567 PMCID: PMC9098804 DOI: 10.1016/j.jaci.2022.05.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/02/2022] [Accepted: 05/04/2022] [Indexed: 01/31/2023]
Abstract
Recent events involving the global coronavirus pandemic have focused attention on vaccination strategies. Although tremendous advances have been made in subcutaneous and intramuscular vaccines during this time, one area that has lagged in implementation is mucosal immunization. Mucosal immunization provides several potential advantages over subcutaneous and intramuscular routes, including protection from localized infection at the site of entry, clearance of organisms on mucosal surfaces, induction of long-term immunity through establishment of central and tissue-resident memory cells, and the ability to shape regulatory responses. Despite these advantages, significant barriers remain to achieving effective mucosal immunization. The epithelium itself provides many obstacles to immunization, and the activation of immune recognition and effector pathways that leads to mucosal immunity has been difficult to achieve. This review will highlight the potential advantages of mucosal immunity, define the barriers to mucosal immunization, examine the immune mechanisms that need to be activated on mucosal surfaces, and finally address recent developments in methods for mucosal vaccination that have shown promise in generating immunity on mucosal surfaces in human trials.
Collapse
Affiliation(s)
- James R Baker
- From the Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich.
| | - Mohammad Farazuddin
- From the Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich
| | - Pamela T Wong
- From the Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich
| | - Jessica J O'Konek
- From the Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich
| |
Collapse
|
|
7
|
Ben Nasr M, Robbins D, Parone P, Usuelli V, Tacke R, Seelam AJ, Driver E, Le T, Sabouri-Ghomi M, Guerrettaz L, Shoemaker D, Fiorina P. Pharmacologically Enhanced Regulatory Hematopoietic Stem Cells Revert Experimental Autoimmune Diabetes and Mitigate Other Autoimmune Disorders. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1554-1565. [PMID: 35321879 DOI: 10.4049/jimmunol.2100949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 01/14/2022] [Indexed: 12/19/2022]
Abstract
Type 1 diabetes (T1D) is characterized by the loss of immune self-tolerance, resulting in an aberrant immune responses against self-tissue. A few therapeutics have been partially successful in reverting or slowing down T1D progression in patients, and the infusion of autologous hematopoietic stem cells (HSCs) is emerging as an option to be explored. In this study, we proposed to pharmacologically enhance by ex vivo modulation with small molecules the immunoregulatory and trafficking properties of HSCs to provide a safer and more efficacious treatment option for patients with T1D and other autoimmune disorders. A high-throughput targeted RNA sequencing screening strategy was used to identify a combination of small molecules (16,16-dimethyl PGE2 and dexamethasone), which significantly upregulate key genes involved in trafficking (e.g., CXCR4) and immunoregulation (e.g., programmed death ligand 1). The pharmacologically enhanced, ex vivo-modulated HSCs (regulatory HSCs [HSC.Regs]) have strong trafficking properties to sites of inflammation in a mouse model of T1D, reverted autoimmune diabetes in NOD mice, and delayed experimental multiple sclerosis and rheumatoid arthritis in preclinical models. Mechanistically, HSC.Regs reduced lymphocytic infiltration of pancreatic β cells and inhibited the activity of autoreactive T cells. Moreover, when tested in clinically relevant in vitro autoimmune assays, HSC.Regs abrogated the autoimmune response. Ex vivo pharmacological modulation enhances the immunoregulatory and trafficking properties of HSCs, thus generating HSC.Regs, which mitigated autoimmune diabetes and other autoimmune disorders.
Collapse
Affiliation(s)
- Moufida Ben Nasr
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA.,International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, DIBIC L. Sacco, University of Milan, Milan, Italy
| | | | | | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, DIBIC L. Sacco, University of Milan, Milan, Italy
| | | | - Andy-Joe Seelam
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, DIBIC L. Sacco, University of Milan, Milan, Italy
| | | | - Thuy Le
- Fate Therapeutics, San Diego, CA; and
| | | | | | | | - Paolo Fiorina
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA; .,International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, DIBIC L. Sacco, University of Milan, Milan, Italy.,Division of Endocrinology, Fatebenefratelli-Sacco Hospital, Milan, Italy
| |
Collapse
|
|
8
|
Vallianou NG, Stratigou T, Geladari E, Tessier CM, Mantzoros CS, Dalamaga M. Diabetes type 1: Can it be treated as an autoimmune disorder? Rev Endocr Metab Disord 2021; 22:859-876. [PMID: 33730229 DOI: 10.1007/s11154-021-09642-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Type 1 Diabetes Mellitus (T1DM) is characterized by progressive autoimmune-mediated destruction of the pancreatic beta-cells leading to insulin deficiency and hyperglycemia. It is associated with significant treatment burden and necessitates life-long insulin therapy. The role of immunotherapy in the prevention and management of T1DM is an evolving area of interest which has the potential to alter the natural history of this disease.In this review, we give insight into recent clinical trials related to the use of immunotherapeutic approaches for T1DM, such as proinflammatory cytokine inhibition, cell-depletion and cell-therapy approaches, autoantigen-specific treatments and stem cell therapies. We highlight the timing of intervention, aspects of therapy including adverse effects and the emergence of a novel lymphocyte crucial in T1DM autoimmunity. We also discuss the role of cardiac autoimmunity and its link to excess CVD risk in T1DM.We conclude that significant advances have been made in development of immunotherapeutic targets and agents for the treatment and prevention of T1DM. These immune-based therapies promise preservation of beta-cells and decreasing insulin dependency. In their current state, immunotherapeutic approaches cannot yet halt the progression from a preclinical state to overt T1DM nor can they replace standard insulin therapy in existing T1DM. It remains to be seen whether immunotherapy will ultimately play a key role in the prevention of progression to overt T1DM and whether it may find a place in our therapeutic armamentarium to improve clinical outcomes and quality of life in established T1DM.
Collapse
Affiliation(s)
- Natalia G Vallianou
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | - Theodora Stratigou
- Department of Endocrinology, Diabetes and Metabolic Diseases, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527, Athens, Goudi, Greece
| | - Eleni Geladari
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | - Christopher M Tessier
- Endocrinology Section, VA Boston Healthcare System, 1400 VFW Parkway West Roxbury, Boston, MA, 02132, USA.
| | - Christos S Mantzoros
- Endocrinology Section, VA Boston Healthcare System, 1400 VFW Parkway West Roxbury, Boston, MA, 02132, USA
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527, Athens, Goudi, Greece
| |
Collapse
|
|
9
|
Kim SS, Hudgins AD, Yang J, Zhu Y, Tu Z, Rosenfeld MG, DiLorenzo TP, Suh Y. A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation. PLoS One 2021; 16:e0257265. [PMID: 34529725 PMCID: PMC8445446 DOI: 10.1371/journal.pone.0257265] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/31/2021] [Indexed: 01/02/2023] Open
Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D. However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function. Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes. Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases. These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data. Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis. We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes. The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci. These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.
Collapse
Affiliation(s)
- Seung-Soo Kim
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Adam D. Hudgins
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Jiping Yang
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Yizhou Zhu
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Zhidong Tu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Michael G. Rosenfeld
- Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
| | - Teresa P. DiLorenzo
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
- The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Yousin Suh
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, United States of America
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, United States of America
- * E-mail:
| |
Collapse
|
|
10
|
Gao S, Li Y, Xiao D, Zhou M, Cai X, Lin Y. Tetrahedral Framework Nucleic Acids Induce Immune Tolerance and Prevent the Onset of Type 1 Diabetes. NANO LETTERS 2021; 21:4437-4446. [PMID: 33955221 DOI: 10.1021/acs.nanolett.1c01131] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A failure in immune tolerance leads to autoimmune destruction of insulin-producing β-cells, leading to type 1 diabetes (T1D). Inhibiting autoreactive T cells and inducing regulatory T cells (Tregs) to re-establish immune tolerance are promising approaches to prevent the onset of T1D. Here, we investigated the ability of tetrahedral framework nucleic acids (tFNAs) to induce immune tolerance and prevent T1D in nonobese diabetic (NOD) mice. In prediabetic NOD mice, tFNAs treatment led to maintenance of normoglycemia and reduced incidence of diabetes. Moreover, the tFNAs (250 nM) treatment preserved the mass and function of β-cells, increased the frequency of Tregs, and suppressed autoreactive T cells, leading to immune tolerance. Collectively, our results demonstrate that tFNAs treatment aids glycemic control, provides β-cell protection, and prevents the onset of T1D in NOD mice by immunomodulation. These results highlight the potential of tFNAs for the prevention of autoimmune T1D.
Collapse
Affiliation(s)
- Shaojingya Gao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanjing Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Dexuan Xiao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Mi Zhou
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiaoxiao Cai
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.,College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan 610041, China
| |
Collapse
|
|
11
|
Enck K, Tamburrini R, Deborah C, Gazia C, Jost A, Khalil F, Alwan A, Orlando G, Opara EC. Effect of alginate matrix engineered to mimic the pancreatic microenvironment on encapsulated islet function. Biotechnol Bioeng 2020; 118:1177-1185. [PMID: 33270214 DOI: 10.1002/bit.27641] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 11/15/2020] [Accepted: 11/21/2020] [Indexed: 12/13/2022]
Abstract
Islet transplantation is emerging as a therapeutic option for type 1 diabetes, albeit, only a small number of patients meeting very stringent criteria are eligible for the treatment because of the side effects of the necessary immunosuppressive therapy and the relatively short time frame of normoglycemia that most patients achieve. The challenge of the immune-suppressive regimen can be overcome through microencapsulation of the islets in a perm-selective coating of alginate microbeads with poly-l-lysine or poly- l-ornithine. In addition to other issues including the nutrient supply challenge of encapsulated islets a critical requirement for these cells has emerged as the need to engineer the microenvironment of the encapsulation matrix to mimic that of the native pancreatic scaffold that houses islet cells. That microenvironment includes biological and mechanical cues that support the viability and function of the cells. In this study, the alginate hydrogel was modified to mimic the pancreatic microenvironment by incorporation of extracellular matrix (ECM). Mechanical and biological changes in the encapsulating alginate matrix were made through stiffness modulation and incorporation of decellularized ECM, respectively. Islets were then encapsulated in this new biomimetic hydrogel and their insulin production was measured after 7 days in vitro. We found that manipulation of the alginate hydrogel matrix to simulate both physical and biological cues for the encapsulated islets enhances the mechanical strength of the encapsulated islet constructs as well as their function. Our data suggest that these modifications have the potential to improve the success rate of encapsulated islet transplantation.
Collapse
Affiliation(s)
- Kevin Enck
- Wake Forest School of Medicine, Virginia Tech School of Biomedical Engineering & Sciences (SBES), Wake Forest University, Winston-Salem, North Carolina.,Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine (WFIRM), Winston-Salem, North Carolina
| | - Riccardo Tamburrini
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine (WFIRM), Winston-Salem, North Carolina.,Department of Surgery, Wake Forest University, Winston-Salem, North Carolina
| | - Chaimov Deborah
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine (WFIRM), Winston-Salem, North Carolina.,Department of Surgery, Wake Forest University, Winston-Salem, North Carolina
| | - Carlo Gazia
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine (WFIRM), Winston-Salem, North Carolina.,Department of Surgery, Wake Forest University, Winston-Salem, North Carolina
| | - Alec Jost
- Wake Forest School of Medicine, Wake Forest University, Winston-Salem, North Carolina
| | - Fatma Khalil
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine (WFIRM), Winston-Salem, North Carolina
| | - Abdelrahman Alwan
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine (WFIRM), Winston-Salem, North Carolina
| | - Giuseppe Orlando
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine (WFIRM), Winston-Salem, North Carolina.,Department of Surgery, Wake Forest University, Winston-Salem, North Carolina
| | - Emmanuel C Opara
- Wake Forest School of Medicine, Virginia Tech School of Biomedical Engineering & Sciences (SBES), Wake Forest University, Winston-Salem, North Carolina.,Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine (WFIRM), Winston-Salem, North Carolina
| |
Collapse
|
|
12
|
Xu X, Yu H, Sun L, Zheng C, Shan Y, Zhou Z, Wang C, Chen B. Adipose‑derived mesenchymal stem cells ameliorate dibutyltin dichloride‑induced chronic pancreatitis by inhibiting the PI3K/AKT/mTOR signaling pathway. Mol Med Rep 2020; 21:1833-1840. [PMID: 32319628 PMCID: PMC7057804 DOI: 10.3892/mmr.2020.10995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 01/17/2020] [Indexed: 12/20/2022] Open
Abstract
Adipose-derived mesenchymal stem cells (ASCs) play a positive role in tissue injury repair and regeneration. The aim of this study was to determine whether ASCs could ameliorate chronic pancreatitis (CP) induced by the injection of dibutyltin dichloride (DBTC) and to elucidate its potential mechanisms. Furthermore, this study also explored whether there was a significant difference if the ASCs were injected via the inferior vena cava or the left gastric artery. CP was induced in rats by a single intravenous administration of DBTC, and the accumulation of collagen and apoptotic rates of pancreatic acinar cells were analyzed. According to the results, ASCs markedly reduced DBTC-induced pancreatic damage and collagen deposition in the rat model of CP. Moreover, ASCs significantly decreased pancreatic cell apoptosis by regulating the expression levels of caspase-3, BAX and Bcl-2. These effects were observed regardless of whether the injection was in the inferior vena cava or the left gastric artery. It was also found that the expression levels of phosphorylated PI3K, AKT and mTOR in pancreatic tissues of the DBTC-induced CP model group were significantly increased, while the expression levels of phosphorylated PI3K, AKT and mTOR in the two treatment groups were markedly decreased. ASCs noticeably suppressed the PI3K/AKT/mTOR pathway in the pancreatic tissue of DBTC-induced CP. This study indicated that ASCs protect against pancreatic fibrosis by modulating the PI3K/AKT/mTOR pathway, and have the potential to be a new strategy for the treatment of CP in the future.
Collapse
Affiliation(s)
- Xiangxiang Xu
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Huajun Yu
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Linxiao Sun
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Chenlei Zheng
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yunfeng Shan
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhenxu Zhou
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Cheng Wang
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Bicheng Chen
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| |
Collapse
|
|
13
|
Koufakis T, Katsiki N, Zebekakis P, Dimitriadis G, Kotsa K. Therapeutic approaches for latent autoimmune diabetes in adults: One size does not fit all. J Diabetes 2020; 12:110-118. [PMID: 31449359 DOI: 10.1111/1753-0407.12982] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/02/2019] [Accepted: 08/22/2019] [Indexed: 12/20/2022] Open
Abstract
Recent advances in the understanding of latent autoimmune diabetes in adults (LADA) pathophysiology make it increasingly evident that people with LADA comprise a heterogenous group of patients. This makes the establishment of a standard treatment algorithm challenging. On top of its glucose-lowering action, insulin may exert anti-inflammatory effects, rendering it an attractive therapeutic choice for a type of diabetes in which autoinflammation and beta cell insufficiency play major pathogenetic roles. However, there is growing evidence that other antidiabetic drugs, such as metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and thiazolidinediones, might have a role in optimizing glycemic control and preserving beta cell function in individuals with LADA, either alone or in combination with insulin. Although most of these drugs have been routinely used in the daily clinical setting for years, large prospective randomized trials are needed to assess whether they are capable of delaying progression to insulin dependence as well as their effects on diabetic complications. The aim of the present review is to discuss the current state and future perspectives of LADA therapy, emphasizing the need for individualized and patient-centered therapeutic approaches.
Collapse
Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Niki Katsiki
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - George Dimitriadis
- Research Institute and Diabetes Center, Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "Attikon" University Hospital, Athens, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| |
Collapse
|
|
14
|
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors with a key role in glucose and lipid metabolism. PPARs are expressed in many cell types including pancreatic beta cells and immune cells, where they regulate insulin secretion and T cell differentiation, respectively. Moreover, various PPAR agonists prevent diabetes in the non-obese diabetic (NOD) mouse model of type 1 diabetes. PPARs are thus of interest in type 1 diabetes (T1D) as they represent a novel approach targeting both the pancreas and the immune system. In this review, we examine the role of PPARs in immune responses and beta cell biology and their potential as targets for treatment of T1D.
Collapse
|
|
15
|
Zhang C, Zhang Y, Li H, Liu X. The potential of proteins, hydrolysates and peptides as growth factors forLactobacillusandBifidobacterium: current research and future perspectives. Food Funct 2020; 11:1946-1957. [DOI: 10.1039/c9fo02961c] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Probiotics are live microorganisms that provide health benefits to the host when consumed in adequate concentrations.
Collapse
Affiliation(s)
- Chi Zhang
- Beijing Technology and Business University
- China
| | | | - He Li
- Beijing Technology and Business University
- China
| | - Xinqi Liu
- Beijing Technology and Business University
- China
| |
Collapse
|
|
16
|
Koprivica I, Gajic D, Saksida T, Cavalli E, Auci D, Despotovic S, Pejnovic N, Stosic-Grujicic S, Nicoletti F, Stojanovic I. Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice. Eur J Pharmacol 2019; 864:172721. [DOI: 10.1016/j.ejphar.2019.172721] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 10/01/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023]
|
|
17
|
Ungurianu A, Şeremet O, Gagniuc E, Olaru OT, Guţu C, Grǎdinaru D, Ionescu-Tȋrgovişte C, Marginǎ D, Dǎnciulescu-Miulescu R. Preclinical and clinical results regarding the effects of a plant-based antidiabetic formulation versus well established antidiabetic molecules. Pharmacol Res 2019; 150:104522. [PMID: 31698065 DOI: 10.1016/j.phrs.2019.104522] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 09/12/2019] [Accepted: 10/31/2019] [Indexed: 12/15/2022]
Abstract
Diabetes mellitus (DM) is a complex syndrome with debilitating long-term complications, comprising alterations of carbohydrate, protein and lipid metabolisms, along increased oxidative stress and chronic low-grade inflammation. Diet management and plant-based formulations can improve the metabolic status of patients, being used as adjuvants of classic antidiabetic therapy. The purpose of our study was to evaluate the impact of a plant-based antidiabetic formulation (PBAF), containing Vaccinium myrtillus, Ribes nigrum, Rosa canina and Capsicum annuum, on the increased oxidative burden found in diabetes mellitus, comparing it with the effects of metformin and gliclazide. Firstly, we characterized the individual plant-derived components of this formulation and also assessed their in vitro radical scavenging capacity. We devised a preclinical study protocol to examine the impact of the PBAF, along metformin and gliclazide, on tissue histology as well as on the redox status of tissue, mitochondria, serum and serum lipoproteins of alloxan-induced diabetic Wistar rats. Subsequently, we assessed their long-term impact on the redox status of serum and isolated serum lipoproteins of type 2 DM (T2DM) patients, taking into consideration their cardiometabolic profile. In the preclinical stage, we found that PBAF was able to enhance total serum antioxidant defense, while metformin yielded the best results regarding the advanced glycation and protein/lipid oxidation of serum and of serum lipoproteins. The latter also improved overall serum redox status and HDL redox function. Also, antidiabetic treatment seemed to increase mitochondrial redox activity, without overturning overall tissue redox balance. Histologically, liver and brain tissues of treated diabetic rats were fairly similar to those of non-diabetic rats. In T2DM patients, the most striking results involved the effects on serum lipoproteins. The tested PBAF exerted protective antioxidant effects on low-density and, especially, on high density lipoproteins. We conclude that this formulation might constitute a good addition to the well-established pharmacological approach of DM, contributing to the reduction of overall oxidative burden.
Collapse
Affiliation(s)
- Anca Ungurianu
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Traian Vuia 6, Bucharest, 020956, Romania
| | - Oana Şeremet
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Traian Vuia 6, Bucharest, 020956, Romania
| | - Elvira Gagniuc
- University of Agronomic Sciences and Veterinary Medicine, Faculty of Veterinary Medicine, Splaiul Independenței 105, Bucharest, 050097, Romania
| | - Octavian Tudor Olaru
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Traian Vuia 6, Bucharest, 020956, Romania
| | - Claudia Guţu
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Traian Vuia 6, Bucharest, 020956, Romania
| | - Daniela Grǎdinaru
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Traian Vuia 6, Bucharest, 020956, Romania
| | - Constantin Ionescu-Tȋrgovişte
- "N. Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, Ion Movilă 5-7, Bucharest, 030167, Romania
| | - Denisa Marginǎ
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Traian Vuia 6, Bucharest, 020956, Romania.
| | - Rucsandra Dǎnciulescu-Miulescu
- "N. Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, Ion Movilă 5-7, Bucharest, 030167, Romania; "Carol Davila" University of Medicine and Pharmacy, Faculty of Dentistry, Department of Department of Endocrinology, Calea Plevnei 17-23, Bucharest, 020021, Romania
| |
Collapse
|
|
18
|
Karras SN, Koufakis T, Zebekakis P, Kotsa K. Pharmacologic adjunctive to insulin therapies in type 1 diabetes: The journey has just begun. World J Diabetes 2019; 10:234-240. [PMID: 31040899 PMCID: PMC6475707 DOI: 10.4239/wjd.v10.i4.234] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/13/2019] [Accepted: 03/28/2019] [Indexed: 02/05/2023] Open
Abstract
Treatment of type 1 diabetes (T1D) is currently based exclusively on insulin replacement therapy. However, there is a need for better glycemic control, lower hypoglycemia rates, more effective weight management, and further reduction of cardiovascular risk in people with T1D. In this context, agents from the pharmaceutical quiver of type 2 diabetes are being tested in clinical trials, as adjunctive to insulin therapies for T1D patients. Despite the limited amount of relevant evidence and the inter-class variability, it can be said that these agents have a role in optimizing metabolic control, assisting weight management and reducing glycemic variability in people with T1D. Specific safety issues, including the increased risk of hypoglycemia and diabetic ketoacidosis, as well as the effects of these treatments on major cardiovascular outcomes should be further assessed by future studies, before these therapeutic choices become widely available for T1D management.
Collapse
Affiliation(s)
- Spyridon N Karras
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| |
Collapse
|
|
19
|
Vazquez-Mateo C, Collins J, Goldberg SJ, Lawson M, Hernandez-Escalante J, Dooms H. Combining anti-IL-7Rα antibodies with autoantigen-specific immunotherapy enhances non-specific cytokine production but fails to prevent Type 1 Diabetes. PLoS One 2019; 14:e0214379. [PMID: 30908554 PMCID: PMC6433345 DOI: 10.1371/journal.pone.0214379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 03/12/2019] [Indexed: 01/09/2023] Open
Abstract
Autoantigen-specific methods to prevent and treat Type 1 Diabetes (T1D) carry high hopes to permanently cure this disease, but have largely failed in clinical trials. One suggested approach to increase the efficacy of islet antigen-specific vaccination is to combine it with a modulator of the T cell response, with the goal of reducing effector differentiation and promoting regulatory T cells (Tregs). Here we asked if addition of antibodies that block the IL-7/IL-7Rα pathway altered the T cell response to islet antigen vaccination and prevented T1D in non-obese diabetic (NOD) mice. Anti-IL-7Rα monoclonal antibodies (mAbs) reduced the numbers of islet antigen-specific T cells generated after vaccination with islet peptides and alum. However, addition of anti-IL-7Rα antibodies to peptide/alum vaccination unexpectedly increased non-specific IFN-γ, IL-2 and IL-10 cytokine production and did not result in improved prevention of T1D onset. In a second approach, we used a conjugate vaccine to deliver islet autoantigens, using Keyhole Limpet Hemocyanin (KLH) as a carrier. Islet antigen-KLH vaccination led to a significant expansion of antigen-specific Tregs and delayed diabetes onset in NOD mice. These outcomes were not further improved by addition of anti-IL-7Rα antibodies. To the contrary, blocking IL-7Rα during vaccination led to non-specific cytokine production and reduced the efficacy of a KLH-conjugated vaccine to prevent T1D. Our study thus revealed that adding anti-IL-7Rα antibodies during autoantigen immunization did not improve the efficacy of such vaccinations to prevent T1D, despite altering some aspects of the T cell response in a potentially advantageous way. Further refinement of this approach will be required to separate the beneficial from the adverse effects of anti-IL-7Rα antibodies to treat autoimmune disease.
Collapse
Affiliation(s)
- Cristina Vazquez-Mateo
- Arthritis Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Justin Collins
- Arthritis Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Sarah J. Goldberg
- Arthritis Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Maxx Lawson
- Arthritis Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Jaileene Hernandez-Escalante
- Arthritis Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Hans Dooms
- Arthritis Center, Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| |
Collapse
|
|
20
|
Pesenacker AM, Chen V, Gillies J, Speake C, Marwaha AK, Sun A, Chow S, Tan R, Elliott T, Dutz JP, Tebbutt SJ, Levings MK. Treg gene signatures predict and measure type 1 diabetes trajectory. JCI Insight 2019; 4:123879. [PMID: 30730852 DOI: 10.1172/jci.insight.123879] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 02/05/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Multiple therapeutic strategies to restore immune regulation and slow type 1 diabetes (T1D) progression are in development and testing. A major challenge has been defining biomarkers to prospectively identify subjects likely to benefit from immunotherapy and/or measure intervention effects. We previously found that, compared with healthy controls, Tregs from children with new-onset T1D have an altered Treg gene signature (TGS), suggesting that this could be an immunoregulatory biomarker. METHODS nanoString was used to assess the TGS in sorted Tregs (CD4+CD25hiCD127lo) or peripheral blood mononuclear cells (PBMCs) from individuals with T1D or type 2 diabetes, healthy controls, or T1D recipients of immunotherapy. Biomarker discovery pipelines were developed and applied to various sample group comparisons. RESULTS Compared with controls, the TGS in isolated Tregs or PBMCs was altered in adult new-onset and cross-sectional T1D cohorts, with sensitivity or specificity of biomarkers increased by including T1D-associated SNPs in algorithms. The TGS was distinct in T1D versus type 2 diabetes, indicating disease-specific alterations. TGS measurement at the time of T1D onset revealed an algorithm that accurately predicted future rapid versus slow C-peptide decline, as determined by longitudinal analysis of placebo arms of START and T1DAL trials. The same algorithm stratified participants in a phase I/II clinical trial of ustekinumab (αIL-12/23p40) for future rapid versus slow C-peptide decline. CONCLUSION These data suggest that biomarkers based on measuring TGSs could be a new approach to stratify patients and monitor autoimmune activity in T1D. FUNDING JDRF (1-PNF-2015-113-Q-R, 2-PAR-2015-123-Q-R, 3-SRA-2016-209-Q-R, 3-PDF-2014-217-A-N), the JDRF Canadian Clinical Trials Network, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (UM1AI109565 and FY15ITN168), and BCCHRI.
Collapse
Affiliation(s)
- Anne M Pesenacker
- Department of Surgery, University of British Columbia (UBC), and BC Children's Hospital Research Institute (BCCHRI), Vancouver, British Columbia, Canada
| | - Virginia Chen
- Department of Medicine and Centre for Heart Lung Innovation, UBC, and Prevention of Organ Failure (PROOF) Centre of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada
| | - Jana Gillies
- Department of Surgery, University of British Columbia (UBC), and BC Children's Hospital Research Institute (BCCHRI), Vancouver, British Columbia, Canada
| | - Cate Speake
- Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, Washington, USA
| | - Ashish K Marwaha
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Annika Sun
- Department of Surgery, University of British Columbia (UBC), and BC Children's Hospital Research Institute (BCCHRI), Vancouver, British Columbia, Canada
| | - Samuel Chow
- Department of Dermatology, UBC, and BCCHRI, Vancouver, British Columbia, Canada
| | - Rusung Tan
- Department of Pathology, Sidra Medicine, Weill Cornell Medicine, Doha, Qatar
| | - Thomas Elliott
- Department of Medicine, UBC, and BCDiabetes, Vancouver, British Columbia, Canada
| | - Jan P Dutz
- Department of Dermatology, UBC, and BCCHRI, Vancouver, British Columbia, Canada
| | - Scott J Tebbutt
- Department of Medicine and Centre for Heart Lung Innovation, UBC, and Prevention of Organ Failure (PROOF) Centre of Excellence, St. Paul's Hospital, Vancouver, British Columbia, Canada
| | - Megan K Levings
- Department of Surgery, University of British Columbia (UBC), and BC Children's Hospital Research Institute (BCCHRI), Vancouver, British Columbia, Canada
| |
Collapse
|
|
21
|
Akimoto H, Fukuda-Kawaguchi E, Duramad O, Ishii Y, Tanabe K. A Novel Liposome Formulation Carrying Both an Insulin Peptide and a Ligand for Invariant Natural Killer T Cells Induces Accumulation of Regulatory T Cells to Islets in Nonobese Diabetic Mice. J Diabetes Res 2019; 2019:9430473. [PMID: 31781669 PMCID: PMC6855036 DOI: 10.1155/2019/9430473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/03/2019] [Indexed: 12/27/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β cells by autoantigen-reactive diabetogenic cells. Antigen-specific therapies using islet autoantigens for restoring immune tolerance have emerged as promising approaches for the treatment of T1D but have been unsuccessful in humans. Herein, we report that RGI-3100-iB, a novel liposomal formulation carrying both α-galactosylceramide (α-GalCer), which is a representative ligand for invariant natural killer T (iNKT) cells, and insulin B chain 9-23 peptide, which is an epitope for CD4+ T cells, could induce the accumulation of regulatory T cells (Tregs) in islets in a peptide-dependent manner, followed by the remarkable prevention of diabetes onset in nonobese diabetic (NOD) mice. While multiple administrations of a monotherapy using either α-GalCer or insulin B peptide in a liposomal formulation was confirmed to delay/prevent T1D in NOD mice, RGI-3100-iB synergistically enhanced the prevention effect of each monotherapy and alleviated insulitis in NOD mice. Immunopathological analysis showed that Foxp3+ Tregs accumulated in the islets in RGI-3100-iB-treated mice. Cotransfer of diabetogenic T cells and splenocytes of NOD mice treated with RGI-3100-iB, but not liposomal α-GalCer encapsulating an unrelated peptide, to NOD-SCID mice resulted in the prevention of diabetes and elevation of Foxp3 mRNA expression in the islets. These data indicate that the migration of insulin B-peptide-specific Tregs to islet of NOD mice that are involved in the suppression of pathogenic T cells related to diabetes onset and progression could be enhanced by the administration of liposomes containing α-GalCer and insulin B peptide.
Collapse
MESH Headings
- Adoptive Transfer
- Animals
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/prevention & control
- Disease Models, Animal
- Drug Compounding
- Female
- Forkhead Transcription Factors/metabolism
- Galactosylceramides/administration & dosage
- Hypoglycemic Agents/administration & dosage
- Insulin/administration & dosage
- Islets of Langerhans/drug effects
- Islets of Langerhans/immunology
- Islets of Langerhans/metabolism
- Liposomes
- Mice, Inbred NOD
- Mice, SCID
- Natural Killer T-Cells/drug effects
- Natural Killer T-Cells/immunology
- Natural Killer T-Cells/metabolism
- Peptide Fragments/administration & dosage
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/transplantation
Collapse
Affiliation(s)
- Hidetoshi Akimoto
- Research Division, REGiMMUNE Corporation, 35-3 Nihonbashi Hakozaki-cho, BRICK GATE 5F, Chuou-Ku, Tokyo 103-0015, Japan
| | - Emi Fukuda-Kawaguchi
- Research Division, REGiMMUNE Corporation, 35-3 Nihonbashi Hakozaki-cho, BRICK GATE 5F, Chuou-Ku, Tokyo 103-0015, Japan
| | - Omar Duramad
- Research Division, REGiMMUNE Inc, 820 Heinz Ave, Berkeley, CA 94710, USA
| | - Yasuyuki Ishii
- Research Division, REGiMMUNE Corporation, 35-3 Nihonbashi Hakozaki-cho, BRICK GATE 5F, Chuou-Ku, Tokyo 103-0015, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-Ku, Tokyo 162-8666, Japan
| |
Collapse
|
|
22
|
Chen Y, Wu J, Wang J, Zhang W, Xu B, Xu X, Zong L. Targeted delivery of antigen to intestinal dendritic cells induces oral tolerance and prevents autoimmune diabetes in NOD mice. Diabetologia 2018; 61:1384-1396. [PMID: 29546475 DOI: 10.1007/s00125-018-4593-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 02/19/2018] [Indexed: 02/07/2023]
Abstract
AIMS/HYPOTHESIS The intestinal immune system is an ideal target to induce immune tolerance physiologically. However, the efficiency of oral protein antigen delivery is limited by degradation of the antigen in the gastrointestinal tract and poor uptake by antigen-presenting cells. Gut dendritic cells (DCs) are professional antigen-presenting cells that are prone to inducing antigen-specific immune tolerance. In this study, we delivered the antigen heat shock protein 65-6×P277 (H6P) directly to the gut DCs of NOD mice through oral vaccination with H6P-loaded targeting nanoparticles (NPs), and investigated the ability of this antigen to induce immune tolerance to prevent autoimmune diabetes in NOD mice. METHODS A targeting NP delivery system was developed to encapsulate H6P, and the ability of this system to protect and facilitate H6P delivery to gut DCs was assessed. NOD mice were immunised with H6P-loaded targeting NPs orally once a week for 7 weeks and the onset of diabetes was assessed by monitoring blood glucose levels. RESULTS H6P-loaded targeting NPs protected the encapsulated H6P from degradation in the gastrointestinal tract environment and significantly increased the uptake of H6P by DCs in the gut Peyer's patches (4.1 times higher uptake compared with the control H6P solution group). Oral vaccination with H6P-loaded targeting NPs induced antigen-specific T cell tolerance and prevented diabetes in 100% of NOD mice. Immune deviation (T helper [Th]1 to Th2) and CD4+CD25+FOXP3+ regulatory T cells were found to participate in the induction of immune tolerance. CONCLUSIONS/INTERPRETATION In this study, we successfully induced antigen-specific T cell tolerance and prevented the onset of diabetes in NOD mice. To our knowledge, this is the first attempt at delivering antigen to gut DCs using targeting NPs to induce T cell tolerance.
Collapse
Affiliation(s)
- Yulin Chen
- Department of Pharmaceutics, China Pharmaceutical University, 24 TongJiaXiang, Nanjing, 210009, People's Republic of China
| | - Jie Wu
- Minigene Pharmacy Laboratory, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jiajia Wang
- Department of Pharmaceutics, China Pharmaceutical University, 24 TongJiaXiang, Nanjing, 210009, People's Republic of China
| | - Wenjing Zhang
- Department of Pharmaceutics, China Pharmaceutical University, 24 TongJiaXiang, Nanjing, 210009, People's Republic of China
| | - Bohui Xu
- Department of Pharmaceutics, China Pharmaceutical University, 24 TongJiaXiang, Nanjing, 210009, People's Republic of China
| | - Xiaojun Xu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 TongJiaXiang, Nanjing, 210009, People's Republic of China.
| | - Li Zong
- Department of Pharmaceutics, China Pharmaceutical University, 24 TongJiaXiang, Nanjing, 210009, People's Republic of China.
| |
Collapse
|
|
23
|
Tahvili S, Törngren M, Holmberg D, Leanderson T, Ivars F. Paquinimod prevents development of diabetes in the non-obese diabetic (NOD) mouse. PLoS One 2018; 13:e0196598. [PMID: 29742113 PMCID: PMC5942776 DOI: 10.1371/journal.pone.0196598] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 04/16/2018] [Indexed: 12/12/2022] Open
Abstract
Quinoline-3-carboxamides (Q compounds) are immunomodulatory compounds that have shown efficacy both in autoimmune disease and cancer. We have in here investigated the impact of one such compound, paquinimod, on the development of diabetes in the NOD mouse model for type I diabetes (T1D). In cohorts of NOD mice treated with paquinimod between weeks 10 to 20 of age and followed up until 40 weeks of age, we observed dose-dependent reduction in incidence of disease as well as delayed onset of disease. Further, in contrast to untreated controls, the majority of NOD mice treated from 15 weeks of age did not develop diabetes at 30 weeks of age. Importantly, these mice displayed significantly less insulitis, which correlated with selectively reduced number of splenic macrophages and splenic Ly6Chi inflammatory monocytes at end point as compared to untreated controls. Collectively, these results demonstrate that paquinimod treatment can significantly inhibit progression of insulitis to T1D in the NOD mouse. We propose that the effect of paquinimod on disease progression may be related to the reduced number of these myeloid cell populations. Our finding also indicates that this compound could be a candidate for clinical development towards diabetes therapy in humans.
Collapse
Affiliation(s)
- Sahar Tahvili
- Immunology group, Section for Immunology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | | | - Dan Holmberg
- Immunology group, Section for Immunology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Tomas Leanderson
- Immunology group, Section for Immunology, Department of Experimental Medical Science, Lund University, Lund, Sweden
- Active Biotech AB, Lund, Sweden
| | - Fredrik Ivars
- Immunology group, Section for Immunology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| |
Collapse
|
|
24
|
Helminth infection in mice improves insulin sensitivity via modulation of gut microbiota and fatty acid metabolism. Pharmacol Res 2018; 132:33-46. [PMID: 29653264 DOI: 10.1016/j.phrs.2018.04.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 03/14/2018] [Accepted: 04/09/2018] [Indexed: 12/19/2022]
Abstract
Intestinal helminths are prevalent in individuals who live in rural areas of developing countries, where obesity, type 2 diabetes, and metabolic syndrome are rare. In the present study, we analyzed the modulation of the gut microbiota in mice infected with the helminth Strongyloides venezuelensis, and fed either a standard rodent chow diet or high-fat diet (HFD). To investigate the effects of the microbiota modulation on the metabolism, we analyzed the expression of tight-junction proteins present in the gut epithelium, inflammatory markers in the serum and tissue and quantified glucose tolerance and insulin sensitivity and resistance. Additionally, the levels of lipids related to inflammation were evaluated in the feces and serum. Our results show that infection with Strongyloides venezuelensis results in a modification of the gut microbiota, most notably by increasing Lactobacillus spp. These modifications in the microbiota alter the host metabolism by increasing the levels of anti-inflammatory cytokines, switching macrophages from a M1 to M2 pattern in the adipose tissue, increasing the expression of tight junction proteins in the intestinal cells (thereby reducing the permeability) and decreasing LPS in the serum. Taken together, these changes correlate with improved insulin signaling and sensitivity, which could also be achieved with HFD mice treated with probiotics. Additionally, helminth infected mice produce higher levels of oleic acid, which participates in anti-inflammatory pathways. These results suggest that modulation of the microbiota by helminth infection or probiotic treatment causes a reduction in subclinical inflammation, which has a positive effect on the glucose metabolism of the host.
Collapse
|
|
25
|
Holm LJ, Haupt-Jorgensen M, Larsen J, Giacobini JD, Bilgin M, Buschard K. L-serine supplementation lowers diabetes incidence and improves blood glucose homeostasis in NOD mice. PLoS One 2018; 13:e0194414. [PMID: 29543915 PMCID: PMC5854405 DOI: 10.1371/journal.pone.0194414] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 03/03/2018] [Indexed: 12/31/2022] Open
Abstract
Sphingolipids are a diverse group of lipids with important roles in beta-cell biology regulating insulin folding and controlling apoptosis. Sphingolipid biosynthesis begins with the condensation of L-serine and palmitoyl-CoA. Here we tested the effect of L-serine supplementation on autoimmune diabetes development and blood glucose homeostasis in female NOD mice. We found that continuous supplementation of L-serine reduces diabetes incidence and insulitis score. In addition, L-serine treated mice had an improved glucose tolerance test, reduced HOMA-IR, and reduced blood glucose levels. L-serine led to a small reduction in body weight accompanied by reduced food and water intake. L-serine had no effect on pancreatic sphingolipids as measured by mass spectrometry. The data thus suggests that L-serine could be used as a therapeutic supplement in the treatment of Type 1 Diabetes and to improve blood glucose homeostasis.
Collapse
Affiliation(s)
- Laurits J. Holm
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen, Denmark
- * E-mail:
| | | | - Jesper Larsen
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen, Denmark
| | - Jano D. Giacobini
- Cell Death and Metabolism Unit, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Mesut Bilgin
- Cell Death and Metabolism Unit, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Karsten Buschard
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen, Denmark
| |
Collapse
|
|
26
|
Probiotics and antibiotic-associated diarrhea in children: A review and new evidence on Lactobacillus rhamnosus GG during and after antibiotic treatment. Pharmacol Res 2018; 128:63-72. [DOI: 10.1016/j.phrs.2017.08.001] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 08/03/2017] [Accepted: 08/03/2017] [Indexed: 12/13/2022]
|
|
27
|
Sun Z, Gou W, Kim DS, Dong X, Strange C, Tan Y, Adams DB, Wang H. Adipose Stem Cell Therapy Mitigates Chronic Pancreatitis via Differentiation into Acinar-like Cells in Mice. Mol Ther 2017; 25:2490-2501. [PMID: 28784560 PMCID: PMC5675167 DOI: 10.1016/j.ymthe.2017.06.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 06/10/2017] [Accepted: 06/17/2017] [Indexed: 12/11/2022] Open
Abstract
The objective of this study was to assess the capacity of adipose-derived mesenchymal stem cells (ASCs) to mitigate disease progression in an experimental chronic pancreatitis mouse model. Chronic pancreatitis (CP) was induced in C57BL/6 mice by repeated ethanol and cerulein injection, and mice were then infused with 4 × 105 or 1 × 106 GFP+ ASCs. Pancreas morphology, fibrosis, inflammation, and presence of GFP+ ASCs in pancreases were assessed 2 weeks after treatment. We found that ASC infusion attenuated pancreatic damage, preserved pancreas morphology, and reduced pancreatic fibrosis and cell death. GFP+ ASCs migrated to pancreas and differentiated into amylase+ cells. In further confirmation of the plasticity of ASCs, ASCs co-cultured with acinar cells in a Transwell system differentiated into amylase+ cells with increased expression of acinar cell-specific genes including amylase and chymoB1. Furthermore, culture of acinar or pancreatic stellate cell lines in ASC-conditioned medium attenuated ethanol and cerulein-induced pro-inflammatory cytokine production in vitro. Our data show that a single intravenous injection of ASCs ameliorated CP progression, likely by directly differentiating into acinar-like cells and by suppressing inflammation, fibrosis, and pancreatic tissue damage. These results suggest that ASC cell therapy has the potential to be a valuable treatment for patients with pancreatitis.
Collapse
Affiliation(s)
- Zhen Sun
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA; Qingdao Agricultural University, Qingdao, Shandong 266109, China
| | - Wenyu Gou
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Do-Sung Kim
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Xiao Dong
- Qingdao Agricultural University, Qingdao, Shandong 266109, China
| | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Yu Tan
- Bioengineering Department, Clemson University, Clemson, SC 29634, USA
| | - David B Adams
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
| |
Collapse
|
|
28
|
Kurian SM, Ferreri K, Wang CH, Todorov I, Al-Abdullah IH, Rawson J, Mullen Y, Salomon DR, Kandeel F. Gene expression signature predicts human islet integrity and transplant functionality in diabetic mice. PLoS One 2017; 12:e0185331. [PMID: 28968432 PMCID: PMC5624587 DOI: 10.1371/journal.pone.0185331] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 09/11/2017] [Indexed: 11/18/2022] Open
Abstract
There is growing evidence that transplantation of cadaveric human islets is an effective therapy for type 1 diabetes. However, gauging the suitability of islet samples for clinical use remains a challenge. We hypothesized that islet quality is reflected in the expression of specific genes. Therefore, gene expression in 59 human islet preparations was analyzed and correlated with diabetes reversal after transplantation in diabetic mice. Analysis yielded 262 differentially expressed probesets, which together predict islet quality with 83% accuracy. Pathway analysis revealed that failing islet preparations activated inflammatory pathways, while functional islets showed increased regeneration pathway gene expression. Gene expression associated with apoptosis and oxygen consumption showed little overlap with each other or with the 262 probeset classifier, indicating that the three tests are measuring different aspects of islet cell biology. A subset of 36 probesets surpassed the predictive accuracy of the entire set for reversal of diabetes, and was further reduced by logistic regression to sets of 14 and 5 without losing accuracy. These genes were further validated with an independent cohort of 16 samples. We believe this limited number of gene classifiers in combination with other tests may provide complementary verification of islet quality prior to their clinical use.
Collapse
Affiliation(s)
- Sunil M. Kurian
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
| | - Kevin Ferreri
- Department of Translational Research and Cellular Therapeutics, Diabetes, and Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Chia-Hao Wang
- Department of Translational Research and Cellular Therapeutics, Diabetes, and Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Ivan Todorov
- Department of Translational Research and Cellular Therapeutics, Diabetes, and Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Ismail H. Al-Abdullah
- Department of Translational Research and Cellular Therapeutics, Diabetes, and Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Jeffrey Rawson
- Department of Translational Research and Cellular Therapeutics, Diabetes, and Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Yoko Mullen
- Department of Translational Research and Cellular Therapeutics, Diabetes, and Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
| | - Daniel R. Salomon
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
| | - Fouad Kandeel
- Department of Translational Research and Cellular Therapeutics, Diabetes, and Metabolism Research Institute, City of Hope National Medical Center, Duarte, California, United States of America
- * E-mail:
| |
Collapse
|