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Lin J, Wang Z, Wang H, Li Y, Liu Y, He Y, Liu Q, Chen Z, Ji Y. Screening of Diabetes-Associated Autoantigens and Serum Antibody Profiles Using a Phage Display System. Int J Microbiol 2024; 2024:1220644. [PMID: 39483642 PMCID: PMC11527542 DOI: 10.1155/2024/1220644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 07/10/2024] [Accepted: 09/13/2024] [Indexed: 11/03/2024] Open
Abstract
Aims/Introduction: Phage display method is a crucial tool to find novel clinically valuable diabetes-associated autoantigens and identify known autoantigen epitopes that are associated with diabetes and could provide scientific support and guidance for the artificial construction and synthesis of Type I diabetes mellitus (T1DM) novel biomarkers. Materials and Methods: The phage display system was used for the "biopanning" of T1DM serum. Following the sequencing of the phage DNAs, the homologous sequences of the above fusion heptapeptide were further investigated by BLAST to track the origin of the polypeptide sequences. The antibody spectrum revealed new T1DM-associated epitopes and antibodies. Results: A total of 1200 phage DNA were sequenced and 9 conserved polypeptide sequences were collected. It was confirmed that the zinc transporter and islet amyloid protease were among them. The conserved polypeptide sequence 8 and another three distinctive polypeptide sequences derived from Proteus were discovered. Furthermore, we expressed recombinant proteins with homologous polypeptide sequences for the human islet amyloid polypeptide (IAPP) and polypeptide precursor human zinc transporter 8 (ZNT8). Through clinical sample detection for the serum from T1DM (n = 100) and T2DM (n = 200) patients, results demonstrate the importance and relevance of these polypeptides in the recognition and classification of various forms of diabetes. Conclusion: Human pancreatic and concurrent bacterial-derived protein antigens and their epitopes were identified in this research by the phage display system, which is crucial for distinguishing different types of diabetes.
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Affiliation(s)
- Jun Lin
- Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), No. 28, Gaoxin Central 2nd Avenue, Nanshan, Shenzhen 518057, China
| | - Zhenyu Wang
- Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), No. 28, Gaoxin Central 2nd Avenue, Nanshan, Shenzhen 518057, China
| | - Hongtao Wang
- Shenzhen Blot Bio-Products Ltd, Nanshan Knowledge Service Building, 3025 Nanhai Avenue, Nanshan, Shenzhen 518052, China
| | - Yuping Li
- Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), No. 28, Gaoxin Central 2nd Avenue, Nanshan, Shenzhen 518057, China
| | - Yao Liu
- Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), No. 28, Gaoxin Central 2nd Avenue, Nanshan, Shenzhen 518057, China
| | - Yige He
- Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), No. 28, Gaoxin Central 2nd Avenue, Nanshan, Shenzhen 518057, China
| | - Qian Liu
- Shenzhen Blot Bio-Products Ltd, Nanshan Knowledge Service Building, 3025 Nanhai Avenue, Nanshan, Shenzhen 518052, China
| | - Zichuan Chen
- Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), No. 28, Gaoxin Central 2nd Avenue, Nanshan, Shenzhen 518057, China
| | - Yuan Ji
- Shenzhen Institute for Drug Control (Shenzhen Testing Center of Medical Devices), No. 28, Gaoxin Central 2nd Avenue, Nanshan, Shenzhen 518057, China
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Penaforte-Saboia JG, Couri CEB, Albuquerque NV, Linard LLP, Araújo DAC, de Oliveira SKP, Gomes TFP, Pinheiro MM, Castelo MHCG, Fernandes VO, Montenegro Júnior RM. PRE1BRAZIL Protocol: A Randomized Controlled Trial to Evaluate the Effectiveness and Safety of the DPP-4 Inhibitor Alogliptin in Delaying the Progression of Stage 2 Type 1 Diabetes. Diabetes Metab Syndr Obes 2024; 17:857-864. [PMID: 38406268 PMCID: PMC10894513 DOI: 10.2147/dmso.s437635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 12/12/2023] [Indexed: 02/27/2024] Open
Abstract
Background The incidence of Type 1 Diabetes Mellitus (T1DM) is on the rise. Since there is no curative treatment, it is urgent to look for therapies that can delay disease progression and protect pancreatic β-cells. Dipeptidyl peptidase-4 inhibitors (DPP-4i) have shown potential in modulating inflammation and preventing β-cell destruction. This protocol describes an upcoming trial to evaluate the effectiveness of the DPP-4i alogliptin in delaying the progression of stage 2 (presymptomatic) to stage 3 (symptomatic) T1DM. Patients and Methods We propose a two-year, two-arm, multicenter, randomized, open-label clinical trial targeting Brazilian patients aged 18 to 35 with stage 2 T1DM. The study, facilitated by the custom-developed "PRE1BRAZIL" web application, aims to enroll 130 participants. They will be randomly assigned in a 1:1 ratio to either a treatment group (alogliptin 25 mg daily plus regular clinical and laboratory assessments) or a control group (regular assessments only). The primary outcome is the rate of progression to stage 3 T1DM. Secondary outcomes include changes in A1c levels, glucose levels during a 2-hour oral glucose tolerance test (OGTT), C-peptide levels, exogenous insulin requirements, Insulin-Dose Adjusted A1c (IDAA1c), and the incidence of diabetic ketoacidosis (DKA) in those advancing to stage 3. Discussion This protocol outlines the first randomized clinical trial (RCT) to investigate the impact of a DPP-4i in the presymptomatic stage of T1DM. The trial is designed to provide critical insights into the role of DPP-4i in the secondary prevention of T1DM. Utilizing the "PRE1BRAZIL" web application is expected to enhance participant enrollment and reduce operational costs. Registration Brazilian Registry of Clinical Trials.
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Affiliation(s)
- Jaquellyne Gurgel Penaforte-Saboia
- Department of Clinical Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
- Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará/ EBSERH Fortaleza, Fortaleza, CE, Brazil
| | - Carlos Eduardo Barra Couri
- Center for Cell-Based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Natasha Vasconcelos Albuquerque
- Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará/ EBSERH Fortaleza, Fortaleza, CE, Brazil
- Department of Community Health, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Lana Livia Peixoto Linard
- Department of Clinical Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
- Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará/ EBSERH Fortaleza, Fortaleza, CE, Brazil
| | | | | | - Thisciane Ferreira Pinto Gomes
- Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará/ EBSERH Fortaleza, Fortaleza, CE, Brazil
| | | | | | - Virgínia Oliveira Fernandes
- Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará/ EBSERH Fortaleza, Fortaleza, CE, Brazil
- Department of Community Health, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Renan Magalhães Montenegro Júnior
- Department of Clinical Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
- Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará/ EBSERH Fortaleza, Fortaleza, CE, Brazil
- Department of Community Health, Federal University of Ceará, Fortaleza, CE, Brazil
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3
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Mameli C, Triolo TM, Chiarelli F, Rewers M, Zuccotti G, Simmons KM. Lessons and Gaps in the Prediction and Prevention of Type 1 Diabetes. Pharmacol Res 2023; 193:106792. [PMID: 37201589 DOI: 10.1016/j.phrs.2023.106792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/01/2023] [Accepted: 05/08/2023] [Indexed: 05/20/2023]
Abstract
Type 1 diabetes (T1D) is a serious chronic autoimmune condition. Even though the root cause of T1D development has yet to be determined, enough is known about the natural history of T1D pathogenesis to allow study of interventions that may delay or even prevent the onset of hyperglycemia and clinical T1D. Primary prevention aims to prevent the onset of beta cell autoimmunity in asymptomatic people at high genetic risk for T1D. Secondary prevention strategies aim to preserve functional beta cells once autoimmunity is present, and tertiary prevention aims to initiate and extend partial remission of beta cell destruction after the clinical onset of T1D. The approval of teplizumab in the United States to delay the onset of clinical T1D marks an impressive milestone in diabetes care. This treatment opens the door to a paradigm shift in T1D care. People with T1D risk need to be identified early by measuring T1D related islet autoantibodies. Identifying people with T1D before they have symptoms will facilitate better understanding of pre-symptomatic T1D progression and T1D prevention strategies that may be effective.
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Affiliation(s)
- Chiara Mameli
- Department of Pediatrics, V. Buzzi Children's Hospital, Milan, Italy; Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
| | - Taylor M Triolo
- Barbara Davis Center for Diabetes, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045
| | | | - Marian Rewers
- Barbara Davis Center for Diabetes, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045
| | - Gianvincenzo Zuccotti
- Department of Pediatrics, V. Buzzi Children's Hospital, Milan, Italy; Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Kimber M Simmons
- Barbara Davis Center for Diabetes, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045
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Zhang X, Dong Y, Liu D, Yang L, Xu J, Wang Q. Antigen-specific immunotherapies in type 1 diabetes. J Trace Elem Med Biol 2022; 73:127040. [PMID: 35868165 DOI: 10.1016/j.jtemb.2022.127040] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 06/18/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by the destruction of pancreatic beta cells, in which immune system disorder plays an important role. Finding a cure for T1DM and restoring beta cell function has been a long-standing goal. Research has shown that immune regulation with pancreatic islet auto-antigens may be the most specific and safe treatment for T1DM. Immunological intervention using diabetogenic auto-antigens as a target can help identify T1DM in high-risk individuals by early screening of autoantibodies (AAbs) before the loss of pancreatic islet function and thus achieve primary prevention of T1DM. However, induction of self-tolerance in patients with pre-diabetes can also slow down the attack of autoimmunity, and achieve secondary prevention. Antigen-based immune therapy opens up new avenues for the prevention and treatment of T1DM. The zinc transporter 8 (ZnT8) protein, presents in the serum of pre-diabetic and diabetic patients, is immunogenic and can cause T1D autoimmune responses. ZnT8 has become a potential target of humoral autoimmunity; it is of great significance for the early diagnosis of T1D. ZnT8-specific CD8+ T cells can be detected in most T1DM patients, and play a key role in the progression of T1D. As an immunotherapy target, it can improve the dysfunction of beta cells in T1DM and provide new ideas for the treatment of T1D. In this review, we summarize research surrounding antigen-specific immunotherapies (ASI) over the past 10 years and the ZnT8 antigen as an autoimmune target to induce self-tolerance for T1DM.
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Affiliation(s)
- Xuejiao Zhang
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Ying Dong
- Department of Radiation Oncology, Jilin Cancer Hospital, Changchun 130000, China
| | - Dianyuan Liu
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Liu Yang
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Jiayi Xu
- School of Public Health, Jilin University, Changchun 130000, China
| | - Qing Wang
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun 130000, China.
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Pagni PP, Chaplin J, Wijaranakula M, Wesley JD, Granger J, Cracraft J, O'Brien C, Perdue N, Kumar V, Li S, Ratliff SS, Roach A, Misquith A, Chan CL, Coppieters K, von Herrath M. Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes. Diabetes 2021; 71:db210327. [PMID: 34389610 PMCID: PMC8763876 DOI: 10.2337/db21-0327] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/08/2021] [Indexed: 11/13/2022]
Abstract
Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).
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Affiliation(s)
- Philippe P Pagni
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Jay Chaplin
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Michael Wijaranakula
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Johnna D Wesley
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Jaimie Granger
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Justen Cracraft
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Conor O'Brien
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Nikole Perdue
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Vijetha Kumar
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Shangjin Li
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | | | - Allie Roach
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Ayesha Misquith
- Discovery Biologics, Global Research Technologies, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Chung-Leung Chan
- Discovery Biologics, Global Research Technologies, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Ken Coppieters
- Project and Alliance Management, Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - Matthias von Herrath
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark
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Kreiner FF, von Scholten BJ, Coppieters K, von Herrath M. Current state of antigen-specific immunotherapy for type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2021; 28:411-418. [PMID: 34101651 DOI: 10.1097/med.0000000000000647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Update on antigen-specific immunotherapy (ASIT) in type 1 diabetes (T1D) with focus on deoxyribonucleic acid (DNA)-induced immunization and the current obstacles to further research and clinical realization. RECENT FINDINGS In T1D, immune system imbalances together with malfunctioning islet-specific processes cause autoreactive immune cells to destroy beta cells in the islets. ASIT may restore self-tolerance; however, the approach has yet to fully meet its promise and may require co-administration of antigen (preproinsulin) and suitable immune response modifiers. SUMMARY A self-tolerant immune system may be regained using ASIT where T effector cells are repressed and/or T regulatory cells are induced. Administration of exogenous antigens has been safe in T1D. Conversely, adequate and lasting beta cell preservation has yet to be tested in sufficiently large clinical trials in suitable patients and may require targeting of multiple parts of the immunopathophysiology using combination therapies. DNA-based induction of native antigen expression to ensure important posttranscriptional modifications and presentation to the immune system together with tolerance-enhancing immune response modifiers (i.e., cytokines) may be more efficacious than exogenous antigens given alone. Progress is limited mainly by the scarcity of validated biomarkers to track the effects of ASIT in T1D.
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Affiliation(s)
| | | | | | - Matthias von Herrath
- Global Chief Medical Office, Novo Nordisk A/S, Søborg
- Type 1 Diabetes Center, The La Jolla Institute for Immunology, La Jolla, California, USA
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Yao Z, Lin P, Wang C, Wang K, Sun Y. Administration of metrnl delays the onset of diabetes in non-obese diabetic mice. Endocr J 2021; 68:179-188. [PMID: 33162409 DOI: 10.1507/endocrj.ej20-0351] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Type 1 diabetes is a chronic metabolic disease characterized by hyperglycemia due to progressive destruction of pancreatic beta cells via autoimmune attack. Meteorin-like protein (metrnl) is a secreted protein homologous to the neurotrophin metrn and it is induced after exercise in the skeletal muscle. In our paper published previously, we showed that the serum level of metrnl was significantly correlated with the lipid profile, glucose profile and insulin resistance. In this experiment, we asked whether intravenous administration of metrnl could delay the onset of diabetes in non-obese diabetic (NOD) mice. 4-week-old NOD mice were injected intravenously with metrnl. Blood glucose levels were measured weekly. Insulitis scoring, intraperitoneal glucose tolerance test, adoptive T cell transfer, flow cytometry analysis and real-time PCR were performed to investigate the underlying mechanism. The results showed that intravenous administration of metrnl delayed the onset of diabetes in NOD mice. Histology of pancreas showed a decreased infiltration of leukocytes, which was in association with augmentation of regulatory T cells, suppression of autoreactive T cells and altered cytokine secretion. To sum up, the present study showed that intravenous administration of metrnl ameliorated islet lymphocyte infiltration and modulated immune cell responses, raising the possibility that it might be beneficial in improving islet function clinically.
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Affiliation(s)
- Zhina Yao
- Center for Reproductive Medicine, Reproductive Hospital Affiliated with Shandong University, Jinan, 250012, Shandong, PR China
| | - Peng Lin
- Department of Endocrine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Chuan Wang
- Department of Endocrine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Kexin Wang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
| | - Yu Sun
- Department of Endocrine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China
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Falcone M, Fousteri G. Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes. Front Endocrinol (Lausanne) 2020; 11:569. [PMID: 32973682 PMCID: PMC7466754 DOI: 10.3389/fendo.2020.00569] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/13/2020] [Indexed: 12/13/2022] Open
Abstract
The human pancreas, like almost all organs in the human body, is immunologically tolerated despite the presence of innate and adaptive immune cells that promptly mediate protective immune responses against pathogens in situ. The PD-1/PD-L1 inhibitory pathway seems to play a key role in the maintenance of immune tolerance systemically and within the pancreatic tissue. Tissue resident memory T cells (TRM), T regulatory cells (Treg), macrophages and even β cells exhibit PD-1 or PD-L1 expression that contributes in controlling pancreatic immune homeostasis and tolerance. Dysregulation of the PD-1/PD-L1 axis as shown by animal studies and our recent experience with checkpoint inhibitory blockade in humans can lead to immune dysfunctions leading to chronic inflammatory disease and to type 1 diabetes (T1D) in genetically susceptible individuals. In this review, we discuss the role of the PD-1/PD-L1 axis in pancreatic tissue homeostasis and tolerance, speculate how genetic and environmental factors can regulate the PD-1/PD-L1 pathway, and discuss PD-1/PD-L1-based therapeutic approaches for pancreatic islet transplantation and T1D treatment.
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Michels AW, Gottlieb PA. Learning From Past Failures of Oral Insulin Trials. Diabetes 2018; 67:1211-1215. [PMID: 29934364 PMCID: PMC6014551 DOI: 10.2337/dbi17-0043] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 04/06/2018] [Indexed: 02/03/2023]
Abstract
Very recently one of the largest type 1 diabetes prevention trials using daily administration of oral insulin or placebo was completed. After 9 years of study enrollment and follow-up, the randomized controlled trial failed to delay the onset of clinical type 1 diabetes, which was the primary end point. The unfortunate outcome follows the previous large-scale trial, the Diabetes Prevention Trial-Type 1 (DPT-1), which again failed to delay diabetes onset with oral insulin or low-dose subcutaneous insulin injections in a randomized controlled trial with relatives at risk for type 1 diabetes. These sobering results raise the important question, "Where does the type 1 diabetes prevention field move next?" In this Perspective, we advocate for a paradigm shift in which smaller mechanistic trials are conducted to define immune mechanisms and potentially identify treatment responders. The stage is set for these interventions in individuals at risk for type 1 diabetes as Type 1 Diabetes TrialNet has identified thousands of relatives with islet autoantibodies and general population screening for type 1 diabetes risk is under way. Mechanistic trials will allow for better trial design and patient selection based upon molecular markers prior to large randomized controlled trials, moving toward a personalized medicine approach for the prevention of type 1 diabetes.
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Affiliation(s)
- Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Peter A Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
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10
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Abstract
Type 1 diabetes (T1D) results from the immune-mediated destruction of insulin-producing β cells located within the pancreatic islets of Langerhans. The autoimmune process leads to a deficiency in insulin production and resultant hyperglycemia requiring lifelong treatment with insulin administration. T1D continues to dramatically increase in incidence, especially in young children. Substantial knowledge surrounding human disease pathogenesis exists, such that T1D is now predictable with the measurement of antibodies in the peripheral blood directed against insulin and other β cell proteins. With the ability to predict, it naturally follows that T1D should be preventable. As such, over the last two decades, numerous well-controlled clinical trials have been completed attempting to prevent diabetes onset or maintain residual β cell function after clinical onset, all providing relatively disappointing results. Here, we review the T1D prevention efforts, the current landscape of clinical therapies, and end with a discussion regarding the future outlook for preventing T1D.
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Affiliation(s)
- Kimber M Simmons
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Peter A Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
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Joachims ML, Leehan KM, Lawrence C, Pelikan RC, Moore JS, Pan Z, Rasmussen A, Radfar L, Lewis DM, Grundahl KM, Kelly JA, Wiley GB, Shugay M, Chudakov DM, Lessard CJ, Stone DU, Scofield RH, Montgomery CG, Sivils KL, Thompson LF, Farris AD. Single-cell analysis of glandular T cell receptors in Sjögren's syndrome. JCI Insight 2016; 1. [PMID: 27358913 DOI: 10.1172/jci.insight.85609] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
CD4+ T cells predominate in salivary gland (SG) inflammatory lesions in Sjögren's syndrome (SS). However, their antigen specificity, degree of clonal expansion, and relationship to clinical disease features remain unknown. We used multiplex reverse-transcriptase PCR to amplify paired T cell receptor α (TCRα) and β transcripts of single CD4+CD45RA- T cells from SG and peripheral blood (PB) of 10 individuals with primary SS, 9 of whom shared the HLA DR3/DQ2 risk haplotype. TCRα and β sequences were obtained from a median of 91 SG and 107 PB cells per subject. The degree of clonal expansion and frequency of cells expressing two productively rearranged α genes were increased in SG versus PB. Expanded clones from SG exhibited complementary-determining region 3 (CDR3) sequence similarity both within and among subjects, suggesting antigenic selection and shared antigen recognition. CDR3 similarities were shared among expanded clones from individuals discordant for canonical Ro and La autoantibodies, suggesting recognition of alternative SG antigen(s). The extent of SG clonal expansion correlated with reduced saliva production and increased SG fibrosis, linking expanded SG T cells with glandular dysfunction. Knowledge of paired TCRα and β sequences enables further work toward identification of target antigens and development of novel therapies.
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Affiliation(s)
- Michelle L Joachims
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Kerry M Leehan
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA; Department of Pathology, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
| | - Christina Lawrence
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Richard C Pelikan
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Jacen S Moore
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Zijian Pan
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Astrid Rasmussen
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Lida Radfar
- Department of Oral Diagnosis and Radiology, College of Dentistry, OUHSC, Oklahoma City, Oklahoma, USA
| | - David M Lewis
- Department of Oral and Maxillofacial Pathology, College of Dentistry, OUHSC, Oklahoma City, Oklahoma, USA
| | - Kiely M Grundahl
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Jennifer A Kelly
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Graham B Wiley
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Mikhail Shugay
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia; Pirogov Russian National Research Medical University, Moscow, Russia; Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Dmitriy M Chudakov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia; Pirogov Russian National Research Medical University, Moscow, Russia; Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Christopher J Lessard
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA; Department of Pathology, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
| | - Donald U Stone
- Department of Ophthalmology, College of Medicine, OUHSC, Oklahoma City, Oklahoma, USA
| | - R Hal Scofield
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA; Department of Pathology, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA; Section of Endocrinology and Diabetes, College of Medicine, OUHSC, Oklahoma City, Oklahoma, USA
| | - Courtney G Montgomery
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Kathy L Sivils
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA; Department of Pathology, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
| | - Linda F Thompson
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - A Darise Farris
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA; Department of Pathology, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
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12
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Davis IC, Randell J, Davis SN. Immunotherapies currently in development for the treatment of type 1 diabetes. Expert Opin Investig Drugs 2016; 24:1331-41. [PMID: 26364507 DOI: 10.1517/13543784.2015.1075973] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Type I diabetes (T1DM) is an autoimmune disorder that affects the pancreas' ability to produce insulin. While T1DM can be managed using insulin therapy, patients face financial burden, serious complications and premature mortality, from the disease. Efforts have sought to define and ultimately suppress the underlying autoimmune attack that results in T1DM. AREAS COVERED The authors lay out promising immunosuppressive and immunomodulating drugs currently in development for T1DM and outline options for future immune treatment for the disorder. There have been several pharmacological strategies to combat the immune attack which will serve as the organization for this review: antigen-specific therapies; monoclonal antibodies; fusion proteins; alternate Treg affectors. EXPERT OPINION Immunosuppression and immunomodulation studies in T1DM demonstrated differing levels of slowing the progression of the immune attack; however, no single therapeutic approach provides a lasting halt of the immune attack and remission of the disease. The immunosuppressants (teplizumab, rituximab and abatacept) show promise in slowing the T1DM progressions for a specific subpopulation of T1DM patients, but this approach appears temporary and has the potential for unwanted side affects. Combination therapies may have the greatest chance of achieving durable cessation of the T1DM autoimmune attack.
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Affiliation(s)
- Ian C Davis
- a 1 University of Maryland School of Medicine , 3805 Greenway, Baltimore, MD 21218, USA
| | | | - Stephen N Davis
- c 3 University of Maryland School of Medicine , 22 South Greene St. N3W42, Baltimore, MD 21201, USA +1 41 0328 2488 ; +1 41 0328 8688 ;
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Abstract
Type 1 diabetes is a chronic autoimmune disease resulting from T cell-mediated destruction of insulin-producing beta cells within pancreatic islets. Disease incidence has increased significantly in the last two decades, especially in young children. Type 1 diabetes is now predictable in humans with the measurement of serum islet autoantibodies directed against insulin and beta cell proteins. Knowledge regarding the presentation of insulin and islet antigens to T cells has increased dramatically over the last several years. Here, we review the trimolecular complex in diabetes, which consists of a major histocompatibility molecule,self-peptide, and T cell receptor, with a focus on insulin peptide presentation to T cells. With this increased understanding of how antigens are presented to T cells comes the hope for improved therapies for type 1 diabetes prevention.
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Affiliation(s)
- Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Kimberly M Simmons
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.
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Oral administration of PDX1 confers protection against insulitis in the non-obese diabetic (NOD) mice. Biochem Biophys Res Commun 2015; 466:656-63. [PMID: 26403969 DOI: 10.1016/j.bbrc.2015.09.098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 09/17/2015] [Indexed: 12/22/2022]
Abstract
Type 1 diabetes is a T cell-mediated organ-specific autoimmune disease. Antigen-specific immune intervention allows the selective targeting of autoreactive T cell, while leaving the remainder of the immune system intact. However, immune intervention for type 1 diabetes has not yielded perfect results clinically. In our paper published previously, we asked whether pancreatic duodenal home box 1 (PDX1) is a target of anti-islet autoimmunity in type 1 diabetes. In this experiment, we assessed the therapeutic effect of oral administration of PDX1 on diabetes development of 4-week-old non-obese diabetic (NOD) mice. The results indicate that PDX1 immunization is an effective intervention strategy for delaying the onset of diabetes in NOD mice in association with: 1) reduced insulitis; 2) suppression of destructive autoreactive T cells; 3) augmentation of regulatory T cells; 4) a shift in cytokine production. The present observations suggest that immunization with PDX1 modulates immune cell responses in NOD mice, raising the possibility that it is beneficial in ameliorating autoimmune destruction of beta-cells and delaying type 1 diabetes development clinically.
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Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by destruction of insulin-producing β cells in the pancreas. The incidence of T1D is increasing dramatically, and the prevalence has doubled in the last 2 decades, further increasing the morbidity and mortality associated with the disease. T1D is now predictable with the measurement of antibodies directed against β cell proteins. Islet autoantibodies (IAs) are detectable from the peripheral blood months to years before clinical diagnosis. With the presence of two or more antibodies, the risk for developing T1D is nearly 100 % given enough time. Targeted screening for T1D risk has been carried out in first-degree relatives and those with a significant genetic risk. However, more than 85 % of individuals who are diagnosed with T1D do not have a family history. In light of the predictability of T1D and recent advances in IA measurement, general population screening is on the horizon. We provide an overview of the history of general population screening and discuss the rationale for and arguments against screening the general population for T1D risk.
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Affiliation(s)
- Kimber M Simmons
- Pediatric Endocrinology and Diabetes Fellow, Children's Hospital Colorado, Aurora, Colorado, US
| | - Aaron W Michels
- Assistant Professor of Pediatrics & Medicine, Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, US
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Simmons KM, Michels AW. Type 1 diabetes: A predictable disease. World J Diabetes 2015; 6:380-390. [PMID: 25897349 PMCID: PMC4398895 DOI: 10.4239/wjd.v6.i3.380] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 11/26/2014] [Accepted: 01/12/2015] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by loss of insulin producing beta cells and reliance on exogenous insulin for survival. T1D is one of the most common chronic diseases in childhood and the incidence is increasing, especially in children less than 5 years of age. In individuals with a genetic predisposition, an unidentified trigger initiates an abnormal immune response and the development of islet autoantibodies directed against proteins in insulin producing beta cells. There are currently four biochemical islet autoantibodies measured in the serum directed against insulin, glutamic decarboxylase, islet antigen 2, and zinc transporter 8. Development of islet autoantibodies occurs before clinical diagnosis of T1D, making T1D a predictable disease in an individual with 2 or more autoantibodies. Screening for islet autoantibodies is still predominantly done through research studies, but efforts are underway to screen the general population. The benefits of screening for islet autoantibodies include decreasing the incidence of diabetic ketoacidosis that can be life threatening, initiating insulin therapy sooner in the disease process, and evaluating safe and specific therapies in large randomized clinical intervention trials to delay or prevent progression to diabetes onset.
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17
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Askenasy N. Less Is More: The Detrimental Consequences of Immunosuppressive Therapy in the Treatment of Type-1 Diabetes. Int Rev Immunol 2015; 34:523-37. [DOI: 10.3109/08830185.2015.1010723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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18
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Engman C, Wen Y, Meng WS, Bottino R, Trucco M, Giannoukakis N. Generation of antigen-specific Foxp3+ regulatory T-cells in vivo following administration of diabetes-reversing tolerogenic microspheres does not require provision of antigen in the formulation. Clin Immunol 2015; 160:103-23. [PMID: 25773782 DOI: 10.1016/j.clim.2015.03.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 03/05/2015] [Indexed: 11/20/2022]
Abstract
We have developed novel antisense oligonucleotide-formulated microspheres that can reverse hyperglycemia in newly-onset diabetic mice. Dendritic cells taking up the microspheres adopt a restrained co-stimulation ability and migrate to the pancreatic lymph nodes when injected into an abdominal region that is drained by those lymph nodes. Furthermore, we demonstrate that the absolute numbers of antigen-specific Foxp3+ T regulatory cells are increased only in the lymph nodes draining the site of administration and that these T-cells proliferate independently of antigen supply in the microspheres. Taken together, our data add to the emerging model where antigen supply may not be a requirement in "vaccines" for autoimmune disease, but the site of administration - subserved by lymph nodes draining the target organ - is in fact critical to foster the generation of antigen-specific regulatory cells. The implications of these observations on "vaccine" design for autoimmunity are discussed and summarized.
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MESH Headings
- Animals
- B7-1 Antigen/genetics
- B7-2 Antigen/genetics
- Blood Glucose/drug effects
- CD11c Antigen/metabolism
- CD40 Antigens/genetics
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Cells, Cultured
- Dendritic Cells/immunology
- Diabetes Mellitus, Experimental/therapy
- Diabetes Mellitus, Type 1/therapy
- Female
- Forkhead Transcription Factors/analysis
- Gene Knockdown Techniques
- Hyperglycemia/therapy
- Leukocyte Common Antigens/metabolism
- Lymph Nodes/cytology
- Lymph Nodes/immunology
- Lymphocyte Activation/immunology
- Macaca fascicularis
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C3H
- Mice, Inbred NOD
- Mice, Transgenic
- Microspheres
- Oligonucleotides, Antisense/genetics
- Pancreas/immunology
- Receptors, Antigen, T-Cell/genetics
- T-Lymphocytes, Regulatory/cytology
- Vaccines/administration & dosage
- Vaccines/immunology
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Affiliation(s)
- Carl Engman
- Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA, 15212, USA.
| | - Yi Wen
- Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Mellon 413, 600 Forbes Avenue, Pittsburgh, PA 15282, USA
| | - Wilson S Meng
- Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Mellon 413, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
| | - Rita Bottino
- Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA, 15212, USA.
| | - Massimo Trucco
- Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA, 15212, USA.
| | - Nick Giannoukakis
- Institute of Cellular Therapeutics, 11th Floor South Tower, Allegheny Health Network, 320 East North Avenue, Pittsburgh, PA, 15212, USA.
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Lessons from type 1 diabetes for understanding natural history and prevention of autoimmune disease. Rheum Dis Clin North Am 2014; 40:797-811. [PMID: 25437293 DOI: 10.1016/j.rdc.2014.07.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disorder resulting from immune-mediated destruction of insulin-producing beta cells within the pancreatic islets. Prediction of T1D is now possible, as having 2 or more islet autoantibodies confers a 100% risk of diabetes development. With the ability to predict disease development, clinical trials to prevent diabetes onset have been completed and are currently under way. This review focuses on the natural history, prediction, and prevention trials in T1D. We review the lessons learned from these attempts at preventing a chronic autoimmune disease and apply the paradigm from T1D prevention to other autoimmune disorders.
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20
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Involvement of suppressive B-lymphocytes in the mechanism of tolerogenic dendritic cell reversal of type 1 diabetes in NOD mice. PLoS One 2014; 9:e83575. [PMID: 24465383 PMCID: PMC3894962 DOI: 10.1371/journal.pone.0083575] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 11/14/2013] [Indexed: 01/10/2023] Open
Abstract
The objective of the study was to identify immune cell populations, in addition to Foxp3+ T-regulatory cells, that participate in the mechanisms of action of tolerogenic dendritic cells shown to prevent and reverse type 1 diabetes in the Non-Obese Diabetic (NOD) mouse strain. Co-culture experiments using tolerogenic dendritic cells and B-cells from NOD as well as transgenic interleukin-10 promoter-reporter mice along with transfer of tolerogenic dendritic cells and CD19+ B-cells into NOD and transgenic mice, showed that these dendritic cells increased the frequency and numbers of interleukin-10-expressing B-cells in vitro and in vivo. The expansion of these cells was a consequence of both the proliferation of pre-existing interleukin-10-expressing B-lymphocytes and the conversion of CD19+ B-lymphcytes into interleukin-10-expressing cells. The tolerogenic dendritic cells did not affect the suppressive activity of these B-cells. Furthermore, we discovered that the suppressive murine B-lymphocytes expressed receptors for retinoic acid which is produced by the tolerogenic dendritic cells. These data assist in identifying the nature of the B-cell population increased in response to the tolerogenic dendritic cells in a clinical trial and also validate very recent findings demonstrating a mechanistic link between human tolerogenic dendritic cells and immunosuppressive regulatory B-cells.
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21
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Bayer AL, Pugliese A, Malek TR. The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation. Immunol Res 2013; 57:197-209. [PMID: 24214027 PMCID: PMC3990437 DOI: 10.1007/s12026-013-8452-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
IL-2 plays a critical role in the normal function of the immune system. A trophic factor for lymphocytes, IL-2 is required for mounting and sustaining adaptive T cell responses; however, IL-2 is also critical for immune regulation via its effects on regulatory T cells (Treg cells). Over the years, we have contributed to the understanding of the biology of IL-2 and its signaling through the IL-2 receptor and helped define the key role played by IL-2 in Treg development and function. Our data show that Treg cells have a heightened sensitivity to IL-2, which may create a therapeutic window to promote immune regulation by selective stimulation of Treg cells. We are now developing new efforts to translate this knowledge to the clinical arena, through our focused interest in Type 1 diabetes as a prototypic autoimmune disease. Specifically, we aim at developing IL-2-based therapeutic regimens and incorporate means to enhance antigen-specific Treg responses, for improved and more selective regulation of islet autoimmunity. In parallel, we are pursuing studies in preclinical models of autoimmunity and transplantation to define critical factors for successful adoptive Treg therapy and develop clinically applicable therapeutic protocols.
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Affiliation(s)
- Allison L. Bayer
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
| | - Alberto Pugliese
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
| | - Thomas R. Malek
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
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22
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Miskov-Zivanov N, Turner MS, Kane LP, Morel PA, Faeder JR. The duration of T cell stimulation is a critical determinant of cell fate and plasticity. Sci Signal 2013; 6:ra97. [PMID: 24194584 DOI: 10.1126/scisignal.2004217] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Variations in T cell receptor (TCR) signal strength, as indicated by differential activation of downstream signaling pathways, determine the fate of naïve T cells after encounter with antigen. Low-strength signals favor differentiation into regulatory T (T(reg)) cells containing the transcription factor Foxp3, whereas high-strength signals favor generation of interleukin-2-producing T helper (T(H)) cells. We constructed a logic circuit model of TCR signaling pathways, a major feature of which is an incoherent feed-forward loop involving both TCR-dependent activation of Foxp3 and its inhibition by mammalian target of rapamycin (mTOR), leading to the transient appearance of Foxp3(+) cells under T(H) cell-generating conditions. Experiments confirmed this behavior and the prediction that the immunosuppressive cytokine TGF-β (transforming growth factor-β) could generate T(reg) cells even during continued Akt-mTOR signaling. We predicted that sustained mTOR activity could suppress FOXP3 expression upon TGF-β removal, suggesting a possible mechanism for the experimentally observed instability of Foxp3(+) cells. Our model predicted, and experiments confirmed, that transient stimulation of cells with high-dose antigen generated T(H), T(reg), and nonactivated cells in proportions depending on the duration of TCR stimulation. Experimental analysis of cells after antigen removal identified three populations that correlated with these T cell fates. Further analysis of simulations implicated a negative feedback loop involving Foxp3, the phosphatase PTEN, and Akt-mTOR in determining fate. These results suggest that there is a critical time after TCR stimulation during which heterogeneity in the differentiating population of cells leads to increased plasticity of cell fate.
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Affiliation(s)
- Natasa Miskov-Zivanov
- 1Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
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23
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Ramirez L, Hamad ARA. Status of autoimmune diabetes 20-year after generation of BDC2.5-TCR transgenic non-obese diabetic mouse. World J Diabetes 2013; 4:88-91. [PMID: 23961318 PMCID: PMC3746090 DOI: 10.4239/wjd.v4.i4.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 05/22/2013] [Accepted: 06/10/2013] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of insulin-producing β cells by autoreactive T cells, leading to lifelong dependency on insulin therapy and increased risk of long-term cardiovascular complications. Here we take the opportunity of the 20th anniversary of the generation of the BDC2.5 TCR transgenic non-obese diabetic (NOD) mouse model, to provide a brief overview of the significant progress that has been made in understanding the role of T cells in the disease pathogenesis period. This included development of hundreds of reagents that block or even reverse new-onset disease by directly or indirectly controlling T cells. We also reflect on the sobering fact that none of these strategies has shown significant efficacy in clinical trials and discuss potential reasons hindering translation of the preclinical findings into successful therapeutic strategies and potential ways forward.
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24
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Abstract
Type 1a diabetes develops from a chronic autoimmune process leading to absolute insulin deficiency and proneness to ketosis. Prospective studies have clearly shown that intensive insulin therapy (ICT) results in improved quality of life and reduced development of diabetes-associated microvascular and macrovascular complications. The gold standard of therapy in type 1 diabetes is insulin injection with a basal bolus insulin regimen, in which patient daily routine and wishes are considered. The treatment goals should be determined on an individualized basis together with the patient. An HbA(1c) value < 7.0% is considered to be well controlled while values ≤ 6.5% indicate an excellent blood glucose control, as long as there are no episodes of severe hypoglycemia. As many adult patients with type 1 diabetes develop additional cardiovascular risk factors dyslipidemia and hypertension should also be considered and treated according to current treatment guidelines. A multimodal treatment may be the best way to preserve quality of life in patients with type 1 diabetes.
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Affiliation(s)
- I Heukamp
- Medizinische Klinik und Poliklinik IV, Diabeteszentrum, Klinikum der Universität München, Ziemssenstr. 1, 80336, München
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25
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Wan X, Guloglu FB, VanMorlan AM, Rowland LM, Zaghouani S, Cascio JA, Dhakal M, Hoeman CM, Zaghouani H. Recovery from overt type 1 diabetes ensues when immune tolerance and β-cell formation are coupled with regeneration of endothelial cells in the pancreatic islets. Diabetes 2013; 62:2879-89. [PMID: 23715620 PMCID: PMC3717841 DOI: 10.2337/db12-1281] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Immune modulation of pancreatic inflammation induces recovery from type 1 diabetes (T1D), but remission was not durable, perhaps because of an inability to sustain the formation and function of new pancreatic β-cells. We have previously shown that Ig-GAD2, carrying GAD 206-220 peptide, induced in hyperglycemic mice immune modulation that was able to control pancreatic inflammation, stimulate β-cell regeneration, and prevent T1D progression. Herein, we show that the same Ig-GAD2 regimen given to mice with overt T1D was unable to reverse the course of disease despite eradication of Th1 and Th17 cells from the pancreas. However, the regimen was able to sustain recovery from T1D when Ig-GAD2 was accompanied with transfer of bone marrow (BM) cells from healthy donors. Interestingly, alongside immune modulation, there was concomitant formation of new β-cells and endothelial cells (ECs) in the pancreas. The new β-cells were of host origin while the donor BM cells gave rise to the ECs. Moreover, transfer of purified BM endothelial progenitors instead of whole BM cells sustained both β-cell and EC formation and reversal of diabetes. Thus, overcoming T1D requires both immune modulation and repair of the islet vascular niche to preserve newly formed β-cells.
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Affiliation(s)
- Xiaoxiao Wan
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
| | - F. Betul Guloglu
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
| | - Amie M. VanMorlan
- Department of Child Health, University of Missouri School of Medicine, Columbia, Missouri
| | - Linda M. Rowland
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
| | - Sarah Zaghouani
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
| | - Jason A. Cascio
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
| | - Mermagya Dhakal
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
| | - Christine M. Hoeman
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
| | - Habib Zaghouani
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri
- Department of Child Health, University of Missouri School of Medicine, Columbia, Missouri
- Department of Neurology, University of Missouri School of Medicine, Columbia, Missouri
- Corresponding author: Habib Zaghouani,
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26
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Michels AW. Targeting the trimolecular complex: the pathway towards type 1 diabetes prevention. Diabetes Technol Ther 2013; 15 Suppl 2:S2-8-S2-12. [PMID: 23786298 PMCID: PMC3676662 DOI: 10.1089/dia.2013.0114] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
George Eisenbarth devoted his life to understanding the basic immunology of the autoimmune polyglandular syndromes and type 1 diabetes, while providing exceptional clinical care to individuals afflicted with these disorders. Over the last 5 years, I was privileged to know George Eisenbarth as a mentor, colleague, and friend. His enthusiasm for science and specifically understanding the basic immunology of type 1 diabetes was infectious. George was the first to initially hypothesize that type 1 diabetes is a chronic autoimmune disorder. He made diabetes a predictable disease by developing biochemical assays to measure islet autoantibodies and provided this technology worldwide to researchers and the medical community. His work identifying and detecting islet autoantibodies allowed for clinical intervention trials aimed at preventing type 1 diabetes. George worked fervently to prevent the disease. During my time as a fellow in George's laboratory and faculty member at the Barbara Davis Center for Diabetes, we focused our efforts for diabetes prevention at the trimolecular complex (human leukocyte antigen molecule, self-peptide, and T cell receptor), which plays a pivotal role in diabetes pathogenesis. It is our belief that targeting this complex with safe and specific therapies will lead to the prevention of type 1 diabetes and an improved understanding as to why diabetes develops.
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Affiliation(s)
- Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado 80045, USA.
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27
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Li S, Li H, Chen B, Lu D, Deng W, Jiang Y, Zhou Z, Yang Z. Identification of novel HLA-A 0201-restricted cytotoxic T lymphocyte epitopes from Zinc Transporter 8. Vaccine 2013; 31:1610-1615. [PMID: 23246542 DOI: 10.1016/j.vaccine.2012.12.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Revised: 09/29/2012] [Accepted: 12/01/2012] [Indexed: 01/31/2023]
Abstract
Numerous evidences demonstrated that type 1 diabetes (T1D) is due to a loss of immune tolerance to islet antigens, and CD8(+) T cells play an important role in the development of T1D. Zinc Transporter 8 (ZnT8) has emerged in recent years as a target of disease-associated autoreactive T cells in human T1D. However, ZnT8-associated CTL specific-peptides have not been identified. In this study, we predicted and identified HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) epitopes derived from ZnT8, and utilized it to immunize HLA-A2.1/Kb transgenic (Tg) mice. The results demonstrated that peptides of ZnT8 containing residues 107-115, 115-123 and 145-153 could elicit specific CTLs in vitro, and induce diabetes in mice. The results suggest that these specific peptides are novel HLA-A*0201-restricted CTL epitopes, and could have therapeutic potential in preventing of T1D disease.
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Affiliation(s)
- Shufa Li
- Endocrinology Division, Linyi People's Hospital, Linyi 276000, China.
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28
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Abstract
Class II major histocompatibility molecules (MHC) confer disease risk for multiple autoimmune disorders including type 1 diabetes. The interaction between the components of the trimolecular complex (CD4(+) T cell receptors, self-peptide, and MHC class II molecules) plays a pivotal role in autoimmune disease pathogenesis. The development of therapies targeting various components of the trimolecular complex for the prevention of type 1 diabetes is actively being pursued. This review focuses on the components of the anti-insulin trimolecular complex, registers of insulin peptide binding to 'diabetogenic' MHC class II molecules, and therapies targeting each component of the trimolecular complex.
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Affiliation(s)
- Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Court, MS A140, Aurora, CO 80045, USA.
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