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Honap S, Agrinier N, Torres J, Croitoru K, Lee SH, Turpin W, Ungaro RC, Agrawal M, Peter I, Turner D, Dotan I, Hart AL, Netter P, D'Haens G, Rubin DT, Ng SC, Gearry R, Jairath V, Ananthakrishnan AN, Danese S, Colombel JF, Peyrin-Biroulet L. Prevention and interception trials in inflammatory bowel disease: an international taskforce assessment on clinical trial design. Lancet Gastroenterol Hepatol 2025:S2468-1253(24)00439-4. [PMID: 40187359 DOI: 10.1016/s2468-1253(24)00439-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/19/2024] [Accepted: 12/19/2024] [Indexed: 04/07/2025]
Abstract
Therapeutic progress in inflammatory bowel disease (IBD) has hitherto focused on reducing inflammation to minimise long-term complications. However, strategies aimed at preventing IBD and attenuating its disease course are particularly appealing. This concept is derived from accumulating evidence for an "at-risk" preclinical state and the associations linking genetic background and numerous environmental exposures to disease pathogenesis. Trials in rheumatoid arthritis and type 1 diabetes have identified interventions to delay disease onset, modify the subsequent disease course (potentially protecting against irreversible tissue and end organ damage), and prolong normal quality of life. Prevention and interception trials have major challenges compared with therapeutic trials across a number of domains, including ethical considerations, eligibility criteria, sample size, and optimal endpoints. This Review investigates important factors in designing high-quality prevention trials and evaluates the feasibility and current progress of such trials in IBD, aiming to identify therapeutic strategies for populations at risk.
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Affiliation(s)
- Sailish Honap
- School of Immunology and Microbial Sciences, King's College London, London, UK; Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Nelly Agrinier
- CHRU-Nancy, CIC, Epidémiologie Clinique and Inserm, INSPIIRE, Université de Lorraine, Nancy, France
| | - Joana Torres
- Division of Gastroenterology, Hospital da Luz, Lisboa, Portugal; Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal; Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Kenneth Croitoru
- Division of Gastroenterology, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada
| | - Sun-Ho Lee
- Division of Gastroenterology, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada
| | - Williams Turpin
- Division of Gastroenterology, University of Toronto, Mount Sinai Hospital, Toronto, ON, Canada
| | - Ryan C Ungaro
- The Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Manasi Agrawal
- The Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dan Turner
- The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, The Eisenburg R&D Authority, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel and the Faculty of Medicine and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ailsa L Hart
- Department of Gastroenterology, St Mark's Hospital, London, UK
| | - Patrick Netter
- Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA) UMR 7365 CNRS, University of Lorraine, Nancy, France
| | - Geert D'Haens
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - David T Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Siew C Ng
- Microbiota I-Center, Department of Medicine and Therapeutics, LKS Institute of Health Science, State Key Laboratory of Digestive Diseases, New Cornerstone Science Laboratory, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Richard Gearry
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Vipul Jairath
- Department of Medicine, Division of Gastroenterology, Schulich School of Medicine and Dentistry, and Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
| | | | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Jean-Frederic Colombel
- The Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Department of Gastroenterology, CHRU Nancy, INSERM NGERE, Université de Lorraine, Nancy, France.
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Wang SH, Serr I, Digigow R, Metzler B, Surnov A, Gottwick C, Alsamman M, Krzikalla D, Heine M, Zahlten M, Widera A, Mungalpara D, Şeleci M, Fanzutti M, Marques Mesquita LM, Vocaturo AL, Herkel J, Carambia A, Schröter C, Sarko D, Pohlner J, Daniel C, de Min C, Fleischer S. Nanoparticle platform preferentially targeting liver sinusoidal endothelial cells induces tolerance in CD4+ T cell-mediated disease models. Front Immunol 2025; 16:1542380. [PMID: 40165970 PMCID: PMC11955608 DOI: 10.3389/fimmu.2025.1542380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Introduction Treating autoimmune diseases without nonspecific immunosuppression remains challenging. To prevent or treat these conditions through targeted immunotherapy, we developed a clinical-stage nanoparticle platform that leverages the tolerogenic capacity of liver sinusoidal endothelial cells (LSECs) to restore antigen-specific immune tolerance. Methods In vivo efficacy was evaluated in various CD4+ T cell-mediated disease models, including preventive and therapeutic models of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), ovalbumin-sensitized delayed-type hypersensitivity (DTH), and the spontaneous type 1 diabetes model. Nanoparticle-induced antigen-specific immune responses were also analyzed through adoptive transfers of 2D2 transgenic T cells into wild-type mice, followed by nanoparticle administration. Results The peptide-conjugated nanoparticles displayed a uniform size distribution (25-30 nm). Their coupling efficiency for peptides with unfavorable physicochemical properties was significantly enhanced by a proprietary linker technology. Preferential LSEC targeting of nanoparticles coupled with fluorescently labeled peptides was confirmed via intravital microscopy and flow cytometry. Intravenous nanoparticle administration significantly reduced disease severity and demyelination in EAE, independent of prednisone at maintenance doses, and suppressed target tissue inflammation in the DTH model. Furthermore, prophylactic administration of a mixture of nanoparticles coupled with five autoantigenic peptides significantly lowered the hyperglycemia incidence of the non-obese diabetic mice. Mechanistically, the tolerizing effects were associated with the induction of antigen-specific regulatory T cells and T cell anergy, which counteract proinflammatory T cells in the target tissue. Conclusion Our findings demonstrate that peptide-loaded nanoparticles preferentially deliver disease-relevant peptides to LSECs, thereby inducing antigen-specific immune tolerance. This versatile clinical-stage nanoparticle platform holds promise for clinical application across multiple autoimmune diseases.
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Affiliation(s)
- Shu-Hung Wang
- Department of Clinical Development, Topas Therapeutics GmbH, Hamburg, Germany
| | - Isabelle Serr
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Reinaldo Digigow
- Department of Chemistry, Manufacturing & Controls, Topas Therapeutics GmbH, Hamburg, Germany
| | - Barbara Metzler
- Department of Preclinical Development, Topas Therapeutics GmbH, Hamburg, Germany
| | - Alexey Surnov
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Cornelia Gottwick
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Muhammad Alsamman
- Department of Preclinical Development, Topas Therapeutics GmbH, Hamburg, Germany
| | - Daria Krzikalla
- Department of Preclinical Development, Topas Therapeutics GmbH, Hamburg, Germany
| | - Markus Heine
- Department of Biochemistry and Molecular Cell Biology (N30), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Miriam Zahlten
- Department of Preclinical Development, Topas Therapeutics GmbH, Hamburg, Germany
| | - Agata Widera
- Department of Preclinical Development, Topas Therapeutics GmbH, Hamburg, Germany
| | - Disha Mungalpara
- Department of Chemistry, Manufacturing & Controls, Topas Therapeutics GmbH, Hamburg, Germany
| | - Muharrem Şeleci
- Department of Chemistry, Manufacturing & Controls, Topas Therapeutics GmbH, Hamburg, Germany
| | - Marco Fanzutti
- Department of Chemistry, Manufacturing & Controls, Topas Therapeutics GmbH, Hamburg, Germany
| | | | - Anna-Lisa Vocaturo
- Department of Chemistry, Manufacturing & Controls, Topas Therapeutics GmbH, Hamburg, Germany
| | - Johannes Herkel
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Centre for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Antonella Carambia
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Schröter
- Department of Chemistry, Manufacturing & Controls, Topas Therapeutics GmbH, Hamburg, Germany
| | - Dikran Sarko
- Department of Chemistry, Manufacturing & Controls, Topas Therapeutics GmbH, Hamburg, Germany
| | - Johannes Pohlner
- Department of Chemistry, Manufacturing & Controls, Topas Therapeutics GmbH, Hamburg, Germany
| | - Carolin Daniel
- Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Division of Clinical Pharmacology, Department of Medicine IV, Ludwig Maximilian University of Munich, Munich, Germany
| | - Cristina de Min
- Department of Clinical Development, Topas Therapeutics GmbH, Hamburg, Germany
| | - Sabine Fleischer
- Department of Clinical Development, Topas Therapeutics GmbH, Hamburg, Germany
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Yang G, Su R, Bu J, Li Y, Lin X, Jin J, Zhang Y, Zhuang P, Guo H, Yin Q. Emerging role of adaptive immunity in diabetes-induced cognitive impairment: from the periphery to the brain. Metab Brain Dis 2025; 40:102. [PMID: 39821703 DOI: 10.1007/s11011-025-01532-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/09/2025] [Indexed: 01/19/2025]
Abstract
Diabetic cognitive impairment (DCI) is a central nervous system complication induced by peripheral metabolic dysfunction of diabetes mellitus. Cumulative studies have shown that neuro-immune crosstalk is involved in the pathological progression of DCI. However, current studies mostly focus on the interaction between innate immunity cells and neurons, while ignoring the role of adaptive immunity cells in DCI. Notably, recent studies have revealed adaptive immune cells are involved in cognitive development and the progression of neurodegenerative diseases. Equally important, accumulated past studies have also shown that diabetic patients experience imbalanced peripheral adaptive immune homeostasis and disrupted transmission of adaptive immune cells to the central system. Therefore, this review first updated the cognitive mechanism of adaptive immune regulation, and then summarized the contribution of adaptive immunity to DCI from the aspects of peripheral adaptive immune homeostasis, transmission pathways, and brain tissue infiltration. Furthermore, we also summarized the potential of anti-diabetic drugs to regulate adaptive immunity, and looked forward to the potential value of regulatory adaptive immunity in the prevention and treatment of DCI, to provide a new strategy for the prevention and treatment of DCI.
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Affiliation(s)
- Genhui Yang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Runtao Su
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jie Bu
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Ying Li
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xueling Lin
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jiahui Jin
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yanjun Zhang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China
| | - Pengwei Zhuang
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China.
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.
| | - Hong Guo
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China.
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Qingsheng Yin
- National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin, 301617, China.
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
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Mondal S, Pappachan JM. Current perspectives and the future of disease-modifying therapies in type 1 diabetes. World J Diabetes 2025; 16:99496. [PMID: 39817218 PMCID: PMC11718456 DOI: 10.4239/wjd.v16.i1.99496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 10/11/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Use of immunomodulating agents to prevent the progression of autoimmune β-cell damage leading to type 1 diabetes mellitus (T1DM) is an interesting area for research. These include non-specific anti-inflammatory agents, immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines. Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen. Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM. The benefits have been apparent as early as six months to as long as seven years after therapy. It has recently been approved by the Food and Drug Administration to delay the onset of clinical (stage 3) type 1 diabetes in children above 8 years of age. In their recent meta-analysis published in the World Journal of Diabetes, Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use, change in C-peptide response, and better glycemic control compared to the control group with a good safety profile. However, all the included randomized control trials have been conducted in high-income countries. High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.
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Affiliation(s)
- Sunetra Mondal
- Department of Endocrinology, NRS Medical College and Hospital, Kolkata 700014, West Bengal, India
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Department of Endocrinology, Kasturba Medical College, Manipal 576104, India
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Gómez-Peralta F, Pinés-Corrales PJ, Santos E, Cuesta M, González-Albarrán O, Azriel S, Castaño L, Mathieu C. Autoimmune Type 1 Diabetes: An Early Approach Appraisal for Spain by the AGORA Diabetes Collaborative Group. J Clin Med 2025; 14:418. [PMID: 39860426 PMCID: PMC11766439 DOI: 10.3390/jcm14020418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/23/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta-cells, leading to lifelong insulin dependence. This review explores the current understanding of T1D pathogenesis, clinical progression, and emerging therapeutic approaches. We examined the complex interplay between genetic predisposition and environmental factors that could trigger the autoimmune response as well as the immunological mechanisms involved in beta-cell destruction. The clinical phases of T1D are discussed from the preclinical stage through diagnosis and long-term management, highlighting the importance of early detection and intervention. Recent advancements in treatment strategies are presented, including immunomodulatory therapies and potential cell-based treatments aimed at preserving or restoring beta-cell function. Additionally, this review critically evaluates the feasibility and potential benefits of implementing a population-wide screening program for T1D in Spain. The epidemiological, economic, and ethical implications of such an initiative were considered by the national expert panel, focusing on the potential of early diagnosis to improve clinical outcomes in the face of the challenges of large-scale implementation. This comprehensive analysis aims to provide healthcare professionals, researchers, and policymakers with valuable insights into the current landscape of T1D management and prospects for enhanced prevention and treatment strategies in the Spanish context.
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Affiliation(s)
| | - Pedro J. Pinés-Corrales
- Endocrinology and Nutrition Service, Complejo Hospitalario Universitario de Albacete, 02008 Albacete, Spain;
| | - Estefanía Santos
- Endocrinology and Nutrition Service, Complejo Hospitalario de Burgos, 09006 Burgos, Spain;
| | - Martín Cuesta
- Endocrinology and Nutrition Service, Hospital Clínico San Carlos, 28040 Madrid, Spain;
| | | | - Sharona Azriel
- Endocrinology and Nutrition Service, Hospital Universitario Infanta Sofía, 28702 San Sebastián De Los Reyes, Spain;
| | - Luis Castaño
- Biobizkaia Health Research Institute, Pediatric Endocrinology Department, Cruces University Hospital, UPU/EHU, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Endo-ERN, 48903 Barakaldo, Spain;
| | - Chantal Mathieu
- Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, 3000 Leuven, Belgium;
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Eugster A, Lorenc A, Kotrulev M, Kamra Y, Goel M, Steinberg-Bains K, Sabbah S, Dietz S, Bonifacio E, Peakman M, Gomez-Tourino I. Physiological and pathogenic T cell autoreactivity converge in type 1 diabetes. Nat Commun 2024; 15:9204. [PMID: 39472557 PMCID: PMC11522472 DOI: 10.1038/s41467-024-53255-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 10/08/2024] [Indexed: 11/02/2024] Open
Abstract
Autoimmune diseases result from autoantigen-mediated activation of adaptive immunity; intriguingly, autoantigen-specific T cells are also present in healthy donors. An assessment of dynamic changes of this autoreactive repertoire in both health and disease is thus warranted. Here we investigate the physiological versus pathogenic autoreactive processes in the context of Type 1 diabetes (T1D) and one of its landmark autoantigens, glutamic acid decarboxylase 65 (GAD65). Using single cell gene expression profiling and tandem T cell receptor (TCR) sequencing, we find that GAD65-specific true naïve cells are present in both health and disease, with GAD65-specific effector and memory responses showing similar ratios in healthy donors and patients. Deeper assessment of phenotype and TCR repertoire uncover differential features in GAD65-specific TCRs, including lower clonal sizes of healthy donor-derived clonotypes in patients. We thus propose a model whereby physiological autoimmunity against GAD65 is needed during early life, and that alterations of these physiological autoimmune processes in predisposed individuals trigger overt Type 1 diabetes.
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Affiliation(s)
- Anne Eugster
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Anna Lorenc
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, 2nd Floor, Borough Wing, Guy's Hospital, London, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Martin Kotrulev
- Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Santiago de Compostela, Spain
- Health Research Institute of Santiago de Compostela (IDIS), Santiago, Spain
| | - Yogesh Kamra
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, 2nd Floor, Borough Wing, Guy's Hospital, London, UK
| | - Manisha Goel
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Katja Steinberg-Bains
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Shereen Sabbah
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, 2nd Floor, Borough Wing, Guy's Hospital, London, UK
| | - Sevina Dietz
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Ezio Bonifacio
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD), Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden, Faculty of Medicine, Dresden, Germany
| | - Mark Peakman
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, 2nd Floor, Borough Wing, Guy's Hospital, London, UK
| | - Iria Gomez-Tourino
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, 2nd Floor, Borough Wing, Guy's Hospital, London, UK.
- Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Santiago de Compostela, Spain.
- Health Research Institute of Santiago de Compostela (IDIS), Santiago, Spain.
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Zhao LP, Papadopoulos GK, Skyler JS, Parikh HM, Kwok WW, Bondinas GP, Moustakas AK, Wang R, Pyo CW, Nelson WC, Geraghty DE, Lernmark Å. Oral Insulin Delay of Stage 3 Type 1 Diabetes Revisited in HLA DR4-DQ8 Participants in the TrialNet Oral Insulin Prevention Trial (TN07). Diabetes Care 2024; 47:1608-1616. [PMID: 38949847 PMCID: PMC11362107 DOI: 10.2337/dc24-0573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 06/04/2024] [Indexed: 07/02/2024]
Abstract
OBJECTIVE To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As). RESEARCH AND METHODS Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin. RESULTS Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 × 10-6) and negatively associated with the HLA DR7-containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028). CONCLUSIONS These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset.
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Affiliation(s)
- Lue Ping Zhao
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- School of Public Health, University of Washington, Seattle, WA
| | - George K. Papadopoulos
- Laboratory of Biophysics, Biochemistry, Biomaterials and Bioprocessing, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta, Greece
| | - Jay S. Skyler
- Diabetes Research Institute and Division of Endocrinology, Diabetes, and Metabolism, University of Miami Miller School of Medicine, Miami, FL
| | - Hemang M. Parikh
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL
| | | | - George P. Bondinas
- Department of Food Science and Technology, Faculty of Environmental Sciences, Ionian University, Argostoli, Cephalonia, Greece
| | - Antonis K. Moustakas
- Department of Food Science and Technology, Faculty of Environmental Sciences, Ionian University, Argostoli, Cephalonia, Greece
| | - Ruihan Wang
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Chul-Woo Pyo
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Wyatt C. Nelson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Daniel E. Geraghty
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden
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Mănescu M, Mănescu IB, Grama A. A Review of Stage 0 Biomarkers in Type 1 Diabetes: The Holy Grail of Early Detection and Prevention? J Pers Med 2024; 14:878. [PMID: 39202069 PMCID: PMC11355657 DOI: 10.3390/jpm14080878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024] Open
Abstract
Type 1 diabetes mellitus (T1D) is an incurable autoimmune disease characterized by the destruction of pancreatic islet cells, resulting in lifelong dependency on insulin treatment. There is an abundance of review articles addressing the prediction of T1D; however, most focus on the presymptomatic phases, specifically stages 1 and 2. These stages occur after seroconversion, where therapeutic interventions primarily aim to delay the onset of T1D rather than prevent it. This raises a critical question: what happens before stage 1 in individuals who will eventually develop T1D? Is there a "stage 0" of the disease, and if so, how can we detect it to increase our chances of truly preventing T1D? In pursuit of answers to these questions, this narrative review aimed to highlight recent research in the field of early detection and prediction of T1D, specifically focusing on biomarkers that can predict T1D before the onset of islet autoimmunity. Here, we have compiled influential research from the fields of epigenetics, omics, and microbiota. These studies have identified candidate biomarkers capable of predicting seroconversion from very early stages to several months prior, suggesting that the prophylactic window begins at birth. As the therapeutic landscape evolves from treatment to delay, and ideally from delay to prevention, it is crucial to both identify and validate such "stage 0" biomarkers predictive of islet autoimmunity. In the era of precision medicine, this knowledge will enable early intervention with the potential for delaying, modifying, or completely preventing autoimmunity and T1D in at-risk children.
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Affiliation(s)
- Măriuca Mănescu
- Department of Pediatrics, Emergency County Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu, 540136 Targu Mures, Romania;
| | - Ion Bogdan Mănescu
- Department of Laboratory Medicine, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 38 Gheorghe Marinescu, 540142 Targu Mures, Romania;
| | - Alina Grama
- Department of Pediatrics, Emergency County Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu, 540136 Targu Mures, Romania;
- Department of Pediatrics, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 38 Gheorghe Marinescu, 540142 Targu Mures, Romania
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9
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Thomson RL, Oakey H, Haynes A, Craig ME, Harrison LC, Wentworth JM, Anderson A, Ashwood P, Barry S, Brittain B, Brown JD, Colman PG, Davis EA, Hamilton-Williams E, Huynh D, Huynh T, Kim KW, McGorm KJ, Morahan G, Rawlinson W, Sinnott RO, Soldatos G, Tye-Din JA, Vuillermin PJ, Penno MAS, Couper JJ. Environmental Determinants of Islet Autoimmunity (ENDIA) longitudinal prospective pregnancy to childhood cohort study of Australian children at risk of type 1 diabetes: parental demographics and birth information. BMJ Open Diabetes Res Care 2024; 12:e004130. [PMID: 39013632 PMCID: PMC11268074 DOI: 10.1136/bmjdrc-2024-004130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 06/27/2024] [Indexed: 07/18/2024] Open
Abstract
INTRODUCTION The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes. RESEARCH DESIGN AND METHODS Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D. The primary outcome was persistent islet autoimmunity, with children followed until a T1D diagnosis or 10 years of age. Demographic data were collected at enrollment. Lifestyle, clinical and anthropometric data were collected at each visit during pregnancy and clinical pregnancy and birth data were verified against medical case notes. Data were compared between mothers with and without T1D. HLA genotyping was performed on the ENDIA child and all available FDRs. RESULTS The final cohort comprised 1473 infants born to 1214 gestational mothers across 1453 pregnancies, with 80% enrolled during pregnancy. The distribution of familial T1D probands was 62% maternal, 28% paternal and 11% sibling. The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members. Mothers with T1D had higher rates of pregnancy complications and perinatal intervention, and larger babies of shorter gestation. Parent demographics were comparable to the Australian population for age, parity and obesity. A greater percentage of ENDIA parents were Australian born, lived in a major city and had higher socioeconomic advantage and education. CONCLUSIONS This comprehensive profile provides the context for understanding ENDIA's scope, methodology, unique strengths and limitations. Now fully recruited, ENDIA will provide unique insights into the roles of early-life factors in the development of islet autoimmunity and T1D in the Australian environment. TRIAL REGISTRATION NUMBER ACTRN12613000794707.
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Affiliation(s)
- Rebecca L Thomson
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Helena Oakey
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Aveni Haynes
- Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Maria E Craig
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Leonard C Harrison
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - John M Wentworth
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Diabetes and Endocrinology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Amanda Anderson
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Pat Ashwood
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Simon Barry
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Bek Brittain
- Centre for Diabetes Research, Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, Western Australia, Australia
| | - James D Brown
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Peter G Colman
- Department of Diabetes and Endocrinology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Elizabeth A Davis
- Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, Nedlands, Western Australia, Australia
| | | | - Dao Huynh
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Tony Huynh
- Department of Endocrinology and Diabetes, Queensland Children's Hospital, South Brisbane, Queensland, Australia
- Children’s Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia
| | - Ki-Wook Kim
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
- Serology and Virology Division (SaViD), New South Wales Health Pathology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Kelly J McGorm
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Grant Morahan
- Centre for Diabetes Research, Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, Western Australia, Australia
| | - William Rawlinson
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
- Serology and Virology Division (SaViD), New South Wales Health Pathology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Richard O Sinnott
- Melbourne eResearch Group, School of Computing and Information Services, The University of Melbourne, Melbourne, Victoria, Australia
| | - Georgia Soldatos
- School of Public Health and Preventive Medicine and School of Clinical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- Diabetes and Vascular Medicine Unit, Monash Health, Clayton, Victoria, Australia
| | - Jason A Tye-Din
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Peter J Vuillermin
- Faculty of Health, School of Medicine, Deakin University, Geelong, Victoria, Australia
- Child Health Research Unit, Barwon Health, Geelong, Victoria, Australia
| | - Megan A S Penno
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Jennifer J Couper
- Adelaide Medical School, Faculty of Health and Medical Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- Endocrinology and Diabetes Department, Women's and Children's Hospital Adelaide, North Adelaide, South Australia, Australia
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Nabi-Afjadi M, Ostadhadi S, Liaghat M, Pasupulla AP, Masoumi S, Aziziyan F, Zalpoor H, Abkhooie L, Tarhriz V. Revolutionizing type 1 diabetes management: Exploring oral insulin and adjunctive treatments. Biomed Pharmacother 2024; 176:116808. [PMID: 38805967 DOI: 10.1016/j.biopha.2024.116808] [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: 03/14/2024] [Revised: 05/20/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune condition that affects millions of people worldwide. Insulin pumps or injections are the standard treatment options for this condition. This article provides a comprehensive overview of the several type 1 diabetes treatment options, focusing on oral insulin. The article is divided into parts that include immune-focused treatments, antigen vaccination, cell-directed interventions, cytokine-directed interventions, and non-immunomodulatory adjuvant therapy. Under the section on non-immunomodulatory adjunctive treatment, the benefits and drawbacks of medications such as metformin, amylin, sodium-glucose cotransporter inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 Ras), and verapamil are discussed. The article also discusses the advantages of oral insulin, including increased patient compliance and more dependable and regular blood sugar control. However, several variables, including the enzymatic and physical barriers of the digestive system, impair the administration of insulin via the mouth. Researchers have looked at a few ways to get over these challenges, such as changing the structure of the insulin molecule, improving absorption with the use of absorption enhancers or nanoparticles, and taking oral insulin together with other medications. Even with great advancements in the use of these treatment strategies, T1D still needs improvement in the therapeutic difficulties. Future studies in these areas should focus on creating tailored immunological treatments, looking into combination medications, and refining oral insulin formulations in an attempt to better control Type 1 Diabetes. The ultimate objective is to create accurate, customized strategies that will enhance glycemic management and the quality of life for individuals with the condition.
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Affiliation(s)
- Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Samane Ostadhadi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mahsa Liaghat
- Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Islamic Azad University, Kazerun Branch, Kazerun, Iran; Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Ajay Prakash Pasupulla
- Oral and Maxillofacial Pathology, School of Medicine, Colllege of health Sciences, Wachemo University, Hosanna, Ethiopia
| | - Sajjad Masoumi
- Department of Medical Biotechnology, National institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Fatemeh Aziziyan
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran; Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran; Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Leila Abkhooie
- Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran; Department of Medical Biotechnology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Vahideh Tarhriz
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
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11
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Herold KC, Delong T, Perdigoto AL, Biru N, Brusko TM, Walker LSK. The immunology of type 1 diabetes. Nat Rev Immunol 2024; 24:435-451. [PMID: 38308004 PMCID: PMC7616056 DOI: 10.1038/s41577-023-00985-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2023] [Indexed: 02/04/2024]
Abstract
Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.
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Affiliation(s)
- Kevan C Herold
- Department of Immunobiology, Yale University, New Haven, CT, USA.
- Department of Internal Medicine, Yale University, New Haven, CT, USA.
| | - Thomas Delong
- Anschutz Medical Campus, University of Colorado, Denver, CO, USA
| | - Ana Luisa Perdigoto
- Department of Internal Medicine, Yale University, New Haven, CT, USA
- Internal Medicine, VA Connecticut Healthcare System, West Haven, CT, USA
| | - Noah Biru
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Lucy S K Walker
- Institute of Immunity & Transplantation, University College London, London, UK.
- Division of Infection & Immunity, University College London, London, UK.
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12
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Jacobs A, Warnants M, Vollmuth V, Winkler C, Weiss A, Ziegler AG, Lundgren M, Elding Larsson H, Kordonouri O, von dem Berge T, Zielmann ML, Bonifacio E, Hommel A, Ołtarzewski M, Szypowska A, Besser R, Todd JA, Casteels K. Vitamin D insufficiency in infants with increased risk of developing type 1 diabetes: a secondary analysis of the POInT Study. BMJ Paediatr Open 2024; 8:e002212. [PMID: 38216311 PMCID: PMC10806504 DOI: 10.1136/bmjpo-2023-002212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 11/07/2023] [Indexed: 01/14/2024] Open
Abstract
BACKGROUND Vitamin D insufficiency (VDI) may be a factor in the development of type 1 diabetes (T1D). The aim of this study is to investigate the presence and persistence of VDI in a large cohort of infants with increased risk of developing T1D, in light of the differences in local supplementation guidelines. METHODS In the POInT Study, a multicentre primary prevention study between February 2018 and March 2021 in Germany, Poland, Belgium, England and Sweden, including infants aged 4-7 months at high genetic risk of developing β-cell autoantibodies, vitamin D levels were analysed at each study visit from inclusion (4-7 months) until 3 years, with an interval of 2 months (first three visits) or 4-6 months (visits 4-8). The protocol actively promotes vitamin D sufficiency to optimise immune tolerance. VDI was defined as a concentration below 30 ng/mL and was treated according to local guidelines of participating centres. Recovery from VDI was defined as a concentration above or equal to 30 ng/mL on the subsequent visit after VDI. RESULTS 1050 infants were included, of which 5937 vitamin D levels were available for analyses. VDI was observed in 1464 (24.7%) visits and 507 (46.1%) of these were not resolved at the next visit. The risk of having VDI was independently associated with season (higher in winter), weight (higher with increased weight), age (higher with increased age) and country (higher in England). The risk of not recovering from VDI was independently associated with the season of the previously determined VDI, which was higher if VDI was identified in winter. CONCLUSIONS VDI is frequent in infants with increased risk of developing T1D. Treatment guidelines for VDI do not seem effective. Increasing supplementation dosages in this patient population seems warranted, especially during winter, and increasing dosages more aggressively after VDI should be considered.
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Affiliation(s)
- An Jacobs
- Department of Pediatric Endocrinology and Diabetes, KU Leuven University Hospitals Leuven, Leuven, Belgium
| | | | - Veronika Vollmuth
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
| | - Christiane Winkler
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes at Klinikum rechts der Isar, School of Medicine, Technical University Munich, Munich, Germany
| | - Andreas Weiss
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
| | - Anette-Gabriele Ziegler
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Markus Lundgren
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
- Department of Pediatrics, Kristianstad Hospital, Kristianstad, Sweden
| | - Helena Elding Larsson
- Department of Pediatrics, Skåne University Hospital, Malmö, Sweden
- Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
| | | | | | - Marie-Luise Zielmann
- Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ezio Bonifacio
- Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
| | - Angela Hommel
- Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
| | - Mariusz Ołtarzewski
- Department of Screening and Metabolic Diagnostics, Institute of Mother and Child, Warsaw, Poland
| | | | - Rachel Besser
- Department of Paediatrics, University of Oxford, Oxford, UK
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
| | - John A Todd
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Kristina Casteels
- Department of Pediatric Endocrinology and Diabetes, KU Leuven University Hospitals Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
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13
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Mao R, Wang J, Xu Y, Wang Y, Wu M, Mao L, Chen Y, Li D, Zhang T, Diao E, Chi Z, Wang Y, Chang X. Oral delivery of bi-autoantigens by bacterium-like particles (BLPs) against autoimmune diabetes in NOD mice. Drug Deliv 2023; 30:2173339. [PMID: 36719009 PMCID: PMC9891168 DOI: 10.1080/10717544.2023.2173339] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/30/2022] [Accepted: 01/02/2023] [Indexed: 02/01/2023] Open
Abstract
Induction of oral tolerance by vaccination with type 1 diabetes mellitus (T1DM)-associated autoantigens exhibits great potential in preventing and treating this autoimmune disease. However, antigen degradation in the gastrointestinal tract (GIT) limits the delivery efficiency of oral antigens. Previously, bacterium-like particles (BLPs) have been used to deliver a single-chain insulin (SCI-59) analog (BLPs-SCI-59) or the intracellular domain of insulinoma-associated protein 2 (IA-2ic) (BLPs-IA-2ic). Both monovalent BLPs vaccines can suppress T1DM in NOD mice by stimulating the corresponding antigen-specific oral tolerance, respectively. Here, we constructed two bivalent BLPs vaccines which simultaneously deliver SCI-59 and IA-2ic (Bivalent vaccine-mix or Bivalent vaccine-SA), and evaluated whether there is an additive beneficial effect on tolerance induction and suppression of T1DM by treatment with BLPs-delivered bi-autoantigens. Compared to the monovalent BLPs vaccines, oral administration of the Bivalent vaccine-mix could significantly reduce morbidity and mortality in T1DM. Treatment with the bivalent BLPs vaccines (especially Bivalent vaccine-mix) endowed the mice with a stronger ability to regulate blood glucose and protect the integrity and function of pancreatic islets than the monovalent BLPs vaccines treatment. This additive effect of BLPs-delivered bi-autoantigens on T1DM prevention may be related to that SCI-59- and IA-2-specific Th2-like immune responses could be induced, which was more beneficial for the correction of Th1/Th2 imbalance. In addition, more CD4+CD25+Foxp3+ regulatory T cells (Tregs) were induced by treatment with the bivalent BLPs vaccines than did the monovalent BLPs vaccines. Therefore, multiple autoantigens delivered by BLPs maybe a promising strategy to prevent T1DM by efficiently inducing antigen-specific immune tolerance.
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Affiliation(s)
- Ruifeng Mao
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Jin Wang
- Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing211200, China
| | - Ying Xu
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Yuqi Wang
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Mengmeng Wu
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Lixia Mao
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Yingying Chen
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Dengchao Li
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Tong Zhang
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Enjie Diao
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai’an223300, China
| | - Zhenjing Chi
- Huai’an First People’s Hospital, Nanjing Medical University, Huai’an223300, China
| | - Yefu Wang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan430072, China
| | - Xin Chang
- Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing211200, China
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14
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Simmons KM, Sims EK. Screening and Prevention of Type 1 Diabetes: Where Are We? J Clin Endocrinol Metab 2023; 108:3067-3079. [PMID: 37290044 PMCID: PMC11491628 DOI: 10.1210/clinem/dgad328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/10/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023]
Abstract
A diagnosis of type 1 diabetes (T1D) and the subsequent requirement for exogenous insulin treatment is associated with considerable acute and chronic morbidity and a substantial effect on patient quality of life. Importantly, a large body of work suggests that early identification of presymptomatic T1D can accurately predict clinical disease, and when paired with education and monitoring, can yield improved health outcomes. Furthermore, a growing cadre of effective disease-modifying therapies provides the potential to alter the natural history of early stages of T1D. In this mini review, we highlight prior work that has led to the current landscape of T1D screening and prevention, as well as challenges and next steps moving into the future of these rapidly evolving areas of patient care.
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Affiliation(s)
- Kimber M Simmons
- Barbara Davis Center for Diabetes, Division of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Emily K Sims
- Division of Pediatric Endocrinology and Diabetology, Herman B Wells Center for Pediatric Research; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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15
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Pande AK, Dutta D, Singla R. Prevention of Type 1 Diabetes: Current Perspective. Indian J Endocrinol Metab 2023; 27:277-285. [PMID: 37867976 PMCID: PMC10586562 DOI: 10.4103/ijem.ijem_78_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/17/2023] [Accepted: 05/16/2023] [Indexed: 10/24/2023] Open
Abstract
People living with type 1 Diabetes (T1D) and their families have poor perception of health related quality of life. Therapies for T1D are becoming better with time, but they still involve a lot of effort. Prevention of T1D, if successful, has potential to change lives of millions of families across the globe. Type 1 diabetes is an autoimmune disease with underlying genetic predisposition for autoimmunity against beta cell antigens upon exposure to an environmental trigger. Identifying underlying primary antigen responsible for initiating autoimmune cascade, avoiding environmental trigger and modifying immunity has all been used as strategies for preventing or delaying onset of type 1 diabetes. Primary prevention for type 1 diabetes is hindered by difficulty in identifying at-risk population and also due to lack of effective preventive strategy. Secondary prevention, in children with presence of autoimmunity, has recently received a boost with approval of Teplizumab, an immunity modifying drug by its Anti-CD3 action. Application of preventive strategies would also change based on country specific incidence, prevalence and availability of health resources. In current review, an update on preventive strategies for type 1 diabetes is being discussed as well as their applicability in Indian context.
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Affiliation(s)
- Arun K Pande
- Consultant Endocrinologist, Lucknow Endocrine Diabetes and Thyroid Clinic, Lucknow, Uttar Pradesh, India
| | - Deep Dutta
- Consultant Endocrinologist, CEDAR Superspeciality Healthcare, Dwarka, New Delhi, India
| | - Rajiv Singla
- Consultant Endocrinologist, Kalpavriksh Healthcare, Dwarka, Delhi, India
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Krishnamurthy B, Lacorcia M, Kay TWH, Thomas HE, Mannering SI. Monitoring immunomodulation strategies in type 1 diabetes. Front Immunol 2023; 14:1206874. [PMID: 37346035 PMCID: PMC10279879 DOI: 10.3389/fimmu.2023.1206874] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 05/26/2023] [Indexed: 06/23/2023] Open
Abstract
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease. Short-term treatment with agents targeting T cells, B cells and inflammatory cytokines to modify the disease course resulted in a short-term pause in disease activity. Lessons learnt from these trials will be discussed in this review. It is expected that effective disease-modifying agents will become available for use in earlier stages of T1D. Progress has been made to analyze antigen-specific T cells with standardization of T cell assay and discovery of antigen epitopes but there are many challenges. High-dimensional profiling of gene, protein and TCR expression at single cell level with innovative computational tools should lead to novel biomarker discovery. With this, assays to detect, quantify and characterize the phenotype and function of antigen-specific T cells will continuously evolve. An improved understanding of T cell responses will help researchers and clinicians to better predict disease onset, and progression, and the therapeutic efficacy of interventions to prevent or arrest T1D.
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Affiliation(s)
- Balasubramanian Krishnamurthy
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Matthew Lacorcia
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
| | - Thomas W. H. Kay
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Helen E. Thomas
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Stuart I. Mannering
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia
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17
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Arif S, Domingo-Vila C, Pollock E, Christakou E, Williams E, Tree TIM. Monitoring islet specific immune responses in type 1 diabetes clinical immunotherapy trials. Front Immunol 2023; 14:1183909. [PMID: 37283770 PMCID: PMC10240960 DOI: 10.3389/fimmu.2023.1183909] [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: 03/10/2023] [Accepted: 05/02/2023] [Indexed: 06/08/2023] Open
Abstract
The number of immunotherapeutic clinical trials in type 1 diabetes currently being conducted is expanding, and thus there is a need for robust immune-monitoring assays which are capable of detecting and characterizing islet specific immune responses in peripheral blood. Islet- specific T cells can serve as biomarkers and as such can guide drug selection, dosing regimens and immunological efficacy. Furthermore, these biomarkers can be utilized in patient stratification which can then benchmark suitability for participation in future clinical trials. This review focusses on the commonly used immune-monitoring techniques including multimer and antigen induced marker assays and the potential to combine these with single cell transcriptional profiling which may provide a greater understanding of the mechanisms underlying immuno-intervention. Although challenges remain around some key areas such as the need for harmonizing assays, technological advances mean that multiparametric information derived from a single sample can be used in coordinated efforts to harmonize biomarker discovery and validation. Moreover, the technologies discussed here have the potential to provide a unique insight on the effect of therapies on key players in the pathogenesis of T1D that cannot be obtained using antigen agnostic approaches.
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18
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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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19
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Zala A, Thomas R. Antigen-specific immunotherapy to restore antigen-specific tolerance in Type 1 diabetes and Graves' disease. Clin Exp Immunol 2023; 211:164-175. [PMID: 36545825 PMCID: PMC10019129 DOI: 10.1093/cei/uxac115] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 10/23/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Type 1 diabetes and Graves' disease are chronic autoimmune conditions, characterized by a dysregulated immune response. In Type 1 diabetes, there is beta cell destruction and subsequent insulin deficiency whereas in Graves' disease, there is unregulated excessive thyroid hormone production. Both diseases result in significant psychosocial, physiological, and emotional burden. There are associated risks of diabetic ketoacidosis and hypoglycaemia in Type 1 diabetes and risks of thyrotoxicosis and orbitopathy in Graves' disease. Advances in the understanding of the immunopathogenesis and response to immunotherapy in Type 1 diabetes and Graves' disease have facilitated the introduction of targeted therapies to induce self-tolerance, and subsequently, the potential to induce long-term remission if effective. We explore current research surrounding the use of antigen-specific immunotherapies, with a focus on human studies, in Type 1 diabetes and Graves' disease including protein-based, peptide-based, dendritic-cell-based, and nanoparticle-based immunotherapies, including discussion of factors to be considered when translating immunotherapies to clinical practice.
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Affiliation(s)
- Aakansha Zala
- Frazer Institute, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Ranjeny Thomas
- Correspondence: Ranjeny Thomas, Frazer Institute, The University of Queensland.
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20
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Ackun-Farmmer MA, Jewell CM. Delivery route considerations for designing antigen-specific biomaterial strategies to combat autoimmunity. ADVANCED NANOBIOMED RESEARCH 2023; 3:2200135. [PMID: 36938103 PMCID: PMC10019031 DOI: 10.1002/anbr.202200135] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Disease modifying drugs and biologics used to treat autoimmune diseases, although promising, are non-curative. As the field moves towards development of new approaches to treat autoimmune disease, antigen-specific therapies immunotherapies (ASITs) have emerged. Despite clinical approval of ASITs for allergies, clinical trials using soluble ASITs for autoimmunity have been largely unsuccessful. A major effort to address this shortcoming is the use of biomaterials to harness the features unique to specific delivery routes. This review focuses on biomaterials being developed for delivery route-specific strategies to induce antigen-specific responses in autoimmune diseases such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and celiac disease. We first discuss the delivery strategies used in ongoing and completed clinical trials in autoimmune ASITs. Next, we highlight pre-clinical biomaterial approaches from the most recent 3 years in the context of these same delivery route considerations. Lastly, we provide discussion on the gaps remaining in biomaterials development and comment on the need to consider delivery routes in the process of designing biomaterials for ASITs.
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Affiliation(s)
- Marian A Ackun-Farmmer
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
| | - Christopher M Jewell
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
- US Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, 21201, USA
- Robert E. Fischell Institute for Biomedical Devices, College Park, MD, 20742, USA
- Department of Microbiology and Immunology, University of Maryland Medical School, Baltimore, MD, 21201, USA
- Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, 21201, USA
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21
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Bertolini TB, Herzog RW, Kumar SRP, Sherman A, Rana J, Kaczmarek R, Yamada K, Arisa S, Lillicrap D, Terhorst C, Daniell H, Biswas M. Suppression of anti-drug antibody formation against coagulation factor VIII by oral delivery of anti-CD3 monoclonal antibody in hemophilia A mice. Cell Immunol 2023; 385:104675. [PMID: 36746071 PMCID: PMC9993859 DOI: 10.1016/j.cellimm.2023.104675] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 12/26/2022] [Accepted: 01/27/2023] [Indexed: 01/31/2023]
Abstract
Active tolerance to ingested dietary antigens forms the basis for oral immunotherapy to food allergens or autoimmune self-antigens. Alternatively, oral administration of anti-CD3 monoclonal antibody can be effective in modulating systemic immune responses without T cell depletion. Here we assessed the efficacy of full length and the F(ab')2 fragment of oral anti-CD3 to prevent anti-drug antibody (ADA) formation to clotting factor VIII (FVIII) protein replacement therapy in hemophilia A mice. A short course of low dose oral anti-CD3 F(ab')2 reduced the production of neutralizing ADAs, and suppression was significantly enhanced when oral anti-CD3 was timed concurrently with FVIII administration. Tolerance was accompanied by the early induction of FoxP3+LAP-, FoxP3+LAP+, and FoxP3-LAP+ populations of CD4+ T cells in the spleen and mesenteric lymph nodes. FoxP3+LAP+ Tregs expressing CD69, CTLA-4, and PD1 persisted in spleens of treated mice, but did not produce IL-10. Finally, we attempted to combine the anti-CD3 approach with oral intake of FVIII antigen (using our previously established method of using lettuce plant cells transgenic for FVIII antigen fused to cholera toxin B (CTB) subunit, which suppresses ADAs in part through induction of IL-10 producing FoxP3-LAP+ Treg). However, combining these two approaches failed to improve suppression of ADAs. We conclude that oral anti-CD3 treatment is a promising approach to prevention of ADA formation in systemic protein replacement therapy, albeit via mechanisms distinct from and not synergistic with oral intake of bioencapsulated antigen.
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Affiliation(s)
- Thais B Bertolini
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Roland W Herzog
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - Sandeep R P Kumar
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Alexandra Sherman
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jyoti Rana
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Radoslaw Kaczmarek
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kentaro Yamada
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sreevani Arisa
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - David Lillicrap
- Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA
| | - Cox Terhorst
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada
| | - Henry Daniell
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
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22
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Dolgin E. How a pioneering diabetes drug offers hope for preventing autoimmune disorders. Nature 2023; 614:404-406. [PMID: 36792744 DOI: 10.1038/d41586-023-00400-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
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23
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Roep BO. The need and benefit of immune monitoring to define patient and disease heterogeneity, mechanisms of therapeutic action and efficacy of intervention therapy for precision medicine in type 1 diabetes. Front Immunol 2023; 14:1112858. [PMID: 36733487 PMCID: PMC9887285 DOI: 10.3389/fimmu.2023.1112858] [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: 11/30/2022] [Accepted: 01/04/2023] [Indexed: 01/18/2023] Open
Abstract
The current standard of care for type 1 diabetes patients is limited to treatment of the symptoms of the disease, insulin insufficiency and its complications, not its cause. Given the autoimmune nature of type 1 diabetes, immunology is critical to understand the mechanism of disease progression, patient and disease heterogeneity and therapeutic action. Immune monitoring offers the key to all this essential knowledge and is therefore indispensable, despite the challenges and costs associated. In this perspective, I attempt to make this case by providing evidence from the past to create a perspective for future trials and patient selection.
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24
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Prozorova TM, Zhulkevych IV, Andreychyn SM, Korylchuk NI, Hanberher II, Riabokon SS, Kamyshnyi AM. EXPERIMENTAL GESTATIONAL DIABETES DISRUPTS THE FORMATION OF IMMUNE TOLERANCE IN OFFSPRING. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2023; 76:115-121. [PMID: 36883499 DOI: 10.36740/wlek202301116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
OBJECTIVE The aim: To analyze the mRNA gene expression level of Aire, Deaf1, Foxp3, Ctla4, Il10, Nlrp3 and distribution of NLRP3+-cells in mesenteric lymph nodes (MLNs) of the offspring of rats with GD, both untreated and treated with glibenclamide and in conditions of insulin oral tolerance formation. PATIENTS AND METHODS Materials and methods: The study involves 160 male rats, one- or six-month-old. The mRNA genes expression was studied by real time quantitative poly¬merase chain reaction. Structure of Nlrp3+ -cells population was studied by histological sections of MLNs. RESULTS Results: We observed AIRE gene repression, reduced mRNA levels of Deaf1 and the transcription factor Foxp3 in offspring of rats with GD. This was accompanied by inhibition of IL-10 gene expression and negative costimulatory molecules Ctla4. The development of the experimental GD was accompanied by transcrip¬tional induction of the Nlrp3 gene in MLNs of descendants. The administration of glibenclamide to pregnant female rats with GD inhibited the transcription of the Nlrp3 gene only in one-month-old offspring (5.3-fold) and did not change it in six-month-old animals. In offspring of rats with GD, the density of the NLRP3+-lymphocyte population in the MLNs increased, more pronounced in one-month-old animals. The administration of glibenclamide to pregnant rats with GD reduced the number of NLRP3+ -lymphocytes only in one-month-old offspring (by 33.0 %), whereas this index in six month-old offspring even increased. CONCLUSION Conclusions: Experimental prenatal hyperglycemia leads to increased proinflammatory signaling and violation of peripheral immunological tolerance formation more pronounced at one month of life.
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Affiliation(s)
| | - Igor V Zhulkevych
- I. HORBACHEVSKY TERNOPIL NATIONAL MEDICAL UNIVERSITY, TERNOPIL, UKRAINE
| | | | | | - Irina I Hanberher
- I. HORBACHEVSKY TERNOPIL NATIONAL MEDICAL UNIVERSITY, TERNOPIL, UKRAINE
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25
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Besser REJ, Bell KJ, Couper JJ, Ziegler AG, Wherrett DK, Knip M, Speake C, Casteels K, Driscoll KA, Jacobsen L, Craig ME, Haller MJ. ISPAD Clinical Practice Consensus Guidelines 2022: Stages of type 1 diabetes in children and adolescents. Pediatr Diabetes 2022; 23:1175-1187. [PMID: 36177823 DOI: 10.1111/pedi.13410] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 12/29/2022] Open
Affiliation(s)
- Rachel E J Besser
- Wellcome Centre for Human Genetics, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Kirstine J Bell
- Charles Perkins Centre and Faculty Medicine and Health, University of Sydney, Sydney, Australia
| | - Jenny J Couper
- Department of Pediatrics, University of Adelaide, South Australia, Australia.,Robinson Research Institute, University of Adelaide, Adelaide, Australia
| | - Anette-G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Diane K Wherrett
- Division of Endocrinology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Mikael Knip
- Children's Hospital, University of Helsinki, Helsinki, Finland
| | - Cate Speake
- Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - Kristina Casteels
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.,Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Kimberly A Driscoll
- Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, USA
| | - Laura Jacobsen
- Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, Florida, USA
| | - Maria E Craig
- Department of Pediatrics, The Children's Hospital at Westmead, University of Sydney, Sydney, Australia
| | - Michael J Haller
- Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, Florida, USA
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26
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Warncke K, Weiss A, Achenbach P, von dem Berge T, Berner R, Casteels K, Groele L, Hatzikotoulas K, Hommel A, Kordonouri O, Elding Larsson H, Lundgren M, Marcus BA, Snape MD, Szypowska A, Todd JA, Bonifacio E, Ziegler AG. Elevations in blood glucose before and after the appearance of islet autoantibodies in children. J Clin Invest 2022; 132:e162123. [PMID: 36250461 PMCID: PMC9566912 DOI: 10.1172/jci162123] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/16/2022] [Indexed: 01/07/2023] Open
Abstract
The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.
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Affiliation(s)
- Katharina Warncke
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Department of Pediatrics, Kinderklinik München Schwabing, School of Medicine, Technical University Munich, Munich, Germany
| | - Andreas Weiss
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes, School of Medicine, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
- Forschergruppe Diabetes e.V. at Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | | | - Reinhard Berner
- Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Kristina Casteels
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Lidia Groele
- Department of Paediatrics, The Children’s Clinical Hospital Józef Polikarp Brudziński, Warsaw, Poland
| | - Konstantinos Hatzikotoulas
- Institute of Translational Genomics, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Angela Hommel
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Germany
| | - Olga Kordonouri
- Kinder- und Jugendkrankenhaus auf der Bult, Hannover, Germany
| | - Helena Elding Larsson
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
- Department of Paediatrics, Skåne University Hospital, Malmö, Sweden
| | - Markus Lundgren
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
- Department of Pediatrics, Kristianstad Hospital, Kristianstad, Sweden
| | - Benjamin A. Marcus
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes, School of Medicine, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
| | - Matthew D. Snape
- Oxford Vaccine Group, University of Oxford Department of Paediatrics, and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | | | - John A. Todd
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Ezio Bonifacio
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Germany
| | - Anette-G. Ziegler
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes, School of Medicine, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
- Forschergruppe Diabetes e.V. at Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
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27
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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: 6] [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: 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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28
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Wesley JD, Pagni PP, Bergholdt R, Kreiner FF, von Herrath M. Induction of antigenic immune tolerance to delay type 1 diabetes - challenges for clinical translation. Curr Opin Endocrinol Diabetes Obes 2022; 29:379-385. [PMID: 35776831 DOI: 10.1097/med.0000000000000742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Dissect the field of antigen-specific immunotherapy (ASIT) in type 1 diabetes (T1D), highlighting the major barriers currently blocking clinical translation. RECENT FINDINGS ASIT remains a promising approach in T1D to re-establish the proper balance in the immune system to avoid the autoimmune-mediated attack or destruction of beta-cells in the pancreas. Despite some encouraging preclinical results, ASIT has not yet successfully translated into clinical utility, predominantly due to the lack of validated and clinically useful biomarkers. SUMMARY To restore immune tolerance towards self-antigens, ASIT aims to establish a favourable balance between T effector cells and T regulatory cells. Whilst most ASITs, including systemic or oral administration of relevant antigens, have appeared safe in T1D, meaningful and durable preservation of functional beta-cell mass has not been proven clinically. Development, including clinical translation, remains negatively impacted by lack of predictive biomarkers with confirmed correlation between assay readout and clinical outcomes. To be able to address the high unmet medical need in T1D, we propose continued reinforced research to identify such biomarkers, as well efforts to ensure alignment in terms of trial design and conduct.
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Affiliation(s)
- Johnna D Wesley
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, Washington, USA
| | - Philippe P Pagni
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, Washington, USA
| | - Regine Bergholdt
- Type 1 Diabetes & Functional Insulins, Clinical Drug Development
| | | | - Matthias von Herrath
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark
- Type 1 Diabetes Center, The La Jolla Institute for Immunology, La Jolla, California, USA
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Personalized Immunotherapies for Type 1 Diabetes: Who, What, When, and How? J Pers Med 2022; 12:jpm12040542. [PMID: 35455658 PMCID: PMC9031881 DOI: 10.3390/jpm12040542] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/18/2022] [Accepted: 03/23/2022] [Indexed: 02/06/2023] Open
Abstract
Our understanding of the immunopathological features of type 1 diabetes (T1D) has greatly improved over the past two decades and has shed light on disease heterogeneity dictated by multiple immune, metabolic, and clinical parameters. This may explain the limited effects of immunotherapies tested so far to durably revert or prevent T1D, for which life-long insulin replacement remains the only therapeutic option. In the era of omics and precision medicine, offering personalized treatment could contribute to turning this tide. Here, we discuss how to structure the selection of the right patient at the right time for the right treatment. This individualized therapeutic approach involves enrolling patients at a defined disease stage depending on the target and mode of action of the selected drug, and better stratifying patients based on their T1D endotype, reflecting intrinsic disease aggressiveness and immune context. To this end, biomarker screening will be critical, not only to help stratify patients and disease stage, but also to select the best predicted responders ahead of treatment and at early time points during clinical trials. This strategy could contribute to increase therapeutic efficacy, notably through the selection of drugs with complementary effects, and to further develop precision multi-hit medicine.
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30
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Mao R, Yang M, Yang R, Chen Y, Diao E, Zhang T, Li D, Chang X, Chi Z, Wang Y. Oral delivery of the intracellular domain of the insulinoma-associated protein 2 (IA-2ic) by bacterium-like particles (BLPs) prevents type 1 diabetes mellitus in NOD mice. Drug Deliv 2022; 29:925-936. [PMID: 35311607 PMCID: PMC8942491 DOI: 10.1080/10717544.2022.2053760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Antigen-specific immune tolerance, which possesses great potential in preventing or curing type 1 diabetes mellitus (T1DM), can be induced by oral vaccination with T1DM-related autoantigens. However, direct administration of autoantigens via oral route exhibits a low tolerance-inducing effect as a result of the digestion of protein antigens in the gastrointestinal tract (GIT) and therefore, a large dosage of autoantigens may be needed. In this study, bacterium-like particles (BLPs) made from food-grade lactic acid bacteria were used to deliver the intracellular domain of the insulinoma-associated protein 2 (IA-2ic). For this purpose, BLPs-IA-2ic vaccine in which IA-2ic bound to the surface of BLPs was constructed. BLPs enhanced the stability of the delivered IA-2ic based on the stability analysis in vitro. Oral administration of BLPs-IA-2ic significantly reduced T1DM incidence in NOD mice. The mice fed BLPs-IA-2ic exhibited a significant reduction in insulitis and preserved the ability to secrete insulin. Immunologic analysis showed that oral vaccination with BLPs-IA-2ic induced antigen-specific T cell tolerance. The results revealed that the successful induction of immune tolerance was dependent on the immune deviation (in favor of T helper 2 responses) and CD4+CD25+FoxP3+ regulatory T cells. Hence, oral vaccination with BLPs-IA-2ic shows potential for application in preventing T1DM.
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Affiliation(s)
- Ruifeng Mao
- School of Life Sciences, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huai'an, China
| | - Menglan Yang
- School of Life Sciences, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huai'an, China
| | - Rui Yang
- School of Life Sciences, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huai'an, China
| | - Yingying Chen
- School of Life Sciences, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huai'an, China
| | - Enjie Diao
- School of Life Sciences, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huai'an, China
| | - Tong Zhang
- School of Life Sciences, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huai'an, China
| | - Dengchao Li
- School of Life Sciences, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huai'an, China
| | - Xin Chang
- Nanjing Lishui People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
| | - Zhenjing Chi
- Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China
| | - Yefu Wang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
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31
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Mitchell AM, Michels AW. Self-Antigens Targeted by Regulatory T Cells in Type 1 Diabetes. Int J Mol Sci 2022; 23:3155. [PMID: 35328581 PMCID: PMC8954990 DOI: 10.3390/ijms23063155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/03/2022] [Accepted: 03/12/2022] [Indexed: 12/15/2022] Open
Abstract
While progress has been made toward understanding mechanisms that lead to the development of autoimmunity, there is less knowledge regarding protective mechanisms from developing such diseases. For example, in type 1 diabetes (T1D), the immune-mediated form of diabetes, the role of pathogenic T cells in the destruction of pancreatic islets is well characterized, but immune-mediated mechanisms that contribute to T1D protection have not been fully elucidated. One potential protective mechanism includes the suppression of immune responses by regulatory CD4 T cells (Tregs) that recognize self-peptides from islets presented by human leukocyte antigen (HLA) class II molecules. In this review, we summarize what is known about the antigenic self-peptides recognized by Tregs in the context of T1D.
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Affiliation(s)
| | - Aaron W. Michels
- Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO 80045, USA;
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Martens PJ, Ellis D, Bruggeman Y, Viaene M, Laureys J, Teyton L, Mathieu C, Gysemans C. Preventing type 1 diabetes in late-stage pre-diabetic NOD mice with insulin: A central role for alum as adjuvant. Front Endocrinol (Lausanne) 2022; 13:1023264. [PMID: 36339431 PMCID: PMC9630573 DOI: 10.3389/fendo.2022.1023264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/04/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Restoration of immune tolerance to disease-relevant antigens is an appealing approach to prevent or arrest an organ-specific autoimmune disease like type 1 diabetes (T1D). Numerous studies have identified insulin as a key antigen of interest to use in such strategies, but to date, the success of these interventions in humans has been inconsistent. The efficacy of antigen-specific immunotherapy may be enhanced by optimising the dose, timing, and route of administration, and perhaps by the inclusion of adjuvants like alum. The aim of our study was to evaluate the effect of an insulin peptide vaccine formulated with alum to prevent T1D development in female non-obese diabetic (NOD) mice when administered during late-stage pre-diabetes. METHODS Starting at 10 weeks of age, female NOD mice received four weekly subcutaneous injections of an insulin B:8-24 (InsB:8-24) peptide with (Ins+alum) or without Imject® alum (Ins) as adjuvant. Diabetes incidence was assessed for up to 30 weeks of age. Insulin autoantibodies and C-peptide concentrations were measured in plasma and flow cytometric analysis was performed on pancreatic-draining lymph nodes (PLN) and pancreas using an InsB:12-20-reactive tetramer. RESULTS InsB:8-24 peptide formulated in alum reduced diabetes incidence (39%), compared to mice receiving the InsB:8-24 peptide without alum (71%, P < 0.05), mice receiving alum alone (76%, P < 0.01), or mice left untreated (70%, P < 0.01). This was accompanied by reduced insulitis severity, and preservation of C-peptide. Ins+alum was associated with reduced frequencies of pathogenic effector memory CD4+ and CD8+ T cells in the pancreas and increased frequencies of insulin-reactive FoxP3+ Tregs in the PLN. Of interest, insulin-reactive Tregs were enriched amongst populations of Tregs expressing markers indicative of stable FoxP3 expression and enhanced suppressive function. CONCLUSION An InsB:8-24 peptide vaccine prevented the onset of T1D in late-stage pre-diabetic NOD mice, but only when formulated in alum. These findings support the use of alum as adjuvant to optimise the efficacy of antigen-specific immunotherapy in future trials.
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Affiliation(s)
- Pieter-Jan Martens
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Darcy Ellis
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Ylke Bruggeman
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Marijke Viaene
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Jos Laureys
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Luc Teyton
- Scripps Research Institute, Department of Immunology and Microbiology, La Jolla, CA, United States
| | - Chantal Mathieu
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Conny Gysemans
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
- *Correspondence: Conny Gysemans,
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Anderson AM, Landry LG, Alkanani AA, Pyle L, Powers AC, Atkinson MA, Mathews CE, Roep BO, Michels AW, Nakayama M. Human islet T cells are highly reactive to preproinsulin in type 1 diabetes. Proc Natl Acad Sci U S A 2021; 118:e2107208118. [PMID: 34611019 PMCID: PMC8521679 DOI: 10.1073/pnas.2107208118] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2021] [Indexed: 01/29/2023] Open
Abstract
Cytotoxic CD8 T lymphocytes play a central role in the tissue destruction of many autoimmune disorders. In type 1 diabetes (T1D), insulin and its precursor preproinsulin are major self-antigens targeted by T cells. We comprehensively examined preproinsulin specificity of CD8 T cells obtained from pancreatic islets of organ donors with and without T1D and identified epitopes throughout the entire preproinsulin protein and defective ribosomal products derived from preproinsulin messenger RNA. The frequency of preproinsulin-reactive T cells was significantly higher in T1D donors than nondiabetic donors and also differed by individual T1D donor, ranging from 3 to over 40%, with higher frequencies in T1D organ donors with HLA-A*02:01. Only T cells reactive to preproinsulin-related peptides isolated from T1D donors demonstrated potent autoreactivity. Reactivity to similar regions of preproinsulin was also observed in peripheral blood of a separate cohort of new-onset T1D patients. These findings have important implications for designing antigen-specific immunotherapies and identifying individuals that may benefit from such interventions.
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Affiliation(s)
- Amanda M Anderson
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
| | - Laurie G Landry
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
| | - Aimon A Alkanani
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
| | - Laura Pyle
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
- Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, CO 80045
| | - Alvin C Powers
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
- Medical Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Mark A Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Clayton E Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Bart O Roep
- Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA 91010
- Department of Internal Medicine, Leiden University Medical Center, 2300RC Leiden, The Netherlands
| | - Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045
| | - Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045;
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045
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Ziegler AG, Danne T, Daniel C, Bonifacio E. 100 Years of Insulin: Lifesaver, immune target, and potential remedy for prevention. MED 2021; 2:1120-1137. [PMID: 34993499 PMCID: PMC8730368 DOI: 10.1016/j.medj.2021.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
In this review, we bring our personal experiences to showcase insulin from its breakthrough discovery as a life-saving drug 100 years ago to its uncovering as the autoantigen and potential cause of type 1 diabetes and eventually as an opportunity to prevent autoimmune diabetes. The work covers the birth of insulin to treat patients, which is now 100 years ago, the development of human insulin, insulin analogues, devices, and the way into automated insulin delivery, the realization that insulin is the primary autoimmune target of type 1 diabetes in children, novel approaches of immunotherapy using insulin for immune tolerance induction, the possible limitations of insulin immunotherapy, and an outlook how modern vaccines could remove the need for another 100 years of insulin therapy.
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Affiliation(s)
- Anette-Gabriele Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- German Center for Diabetes Research (DZD), Munich, Germany
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany
- Lead Contact
| | - Thomas Danne
- Diabetes Centre for Children and Adolescents, Kinder- und Jugendkrankenhaus AUF DER BULT, 30173 Hannover, Germany
| | - Carolin Daniel
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- German Center for Diabetes Research (DZD), Munich, Germany
- Division of Clinical Pharmacology, Department of Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Ezio Bonifacio
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, Germany
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35
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Biologia Futura: Emerging antigen-specific therapies for autoimmune diseases. Biol Futur 2021; 72:15-24. [PMID: 34554499 DOI: 10.1007/s42977-021-00074-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/16/2021] [Indexed: 02/05/2023]
Abstract
Autoimmune diseases are caused by breaking the central and/or peripheral tolerance against self, leading to uncontrolled immune response to autoantigens. The incidences of autoimmune diseases have increased significantly worldwide over the last decades; nearly 5% of the world's population is affected. The current treatments aim to reduce pain and inflammation to prevent organ damage and have a general immunosuppressive effect, but they cannot cure the disease. There is a huge unmet need for autoantigen-specific therapy, without affecting the immune response against pathogens. This goal can be achieved by targeting autoantigen-specific T or B cells and by restoring self-tolerance by inducing tolerogenic antigen-presenting cells (APC) and the development of regulatory T (Treg) cells, for example, by using autoantigenic peptides bound to nanoparticles. Transferring in vitro manipulated autologous tolerogenic APC or autologous autoantigen-specific Treg cells to patients is the promising approach to develop cellular therapeutics. Most recently, chimeric autoantibody receptor T cells have been designed to specifically deplete autoreactive B cells. Limitations of these novel autoantigen-specific therapies will also be discussed.
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36
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Corcos N, Culina S, Deligne C, Lavaud C, You S, Mallone R. Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes. Front Immunol 2021; 12:616215. [PMID: 34447366 PMCID: PMC8382691 DOI: 10.3389/fimmu.2021.616215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 07/27/2021] [Indexed: 11/30/2022] Open
Abstract
Tolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the initiating antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy employs an oral administration of PPI-Fc, i.e. PPI fused with an IgG Fc to bind the intestinal neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring during breastfeeding. Neonatal oral PPI-Fc vaccination did not prevent diabetes development in PPI T-cell receptor-transgenic G9C8.NOD mice. However, PPI-Fc was efficiently transferred through the intestinal epithelium in an Fc- and FcRn-dependent manner, was taken up by antigen presenting cells, and reached the spleen and thymus. Although not statistically significant, neonatal oral PPI-Fc vaccination delayed diabetes onset in polyclonal Ins2-/-.NOD mice that spontaneously develop accelerated diabetes. Thus, this strategy shows promise in terms of systemic and thymic antigen delivery via the intestinal FcRn pathway, but the current PPI-Fc formulation/regimen requires further improvements to achieve diabetes prevention.
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Affiliation(s)
- Noémie Corcos
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Slobodan Culina
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Claire Deligne
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Cassandra Lavaud
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Sylvaine You
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Roberto Mallone
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France.,Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Cochin Hospital, Service de Diabétologie et Immunologie Clinique, Paris, France
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Kordonouri O, Danne T, Lange K. Neue Wege zur Prävention des Typ-1-Diabetes bei Kindern. Monatsschr Kinderheilkd 2021. [DOI: 10.1007/s00112-021-01274-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Abstract
PURPOSE OF REVIEW Loss of tolerance to insulin likely contributes to the immunopathogenesis of type 1 diabetes (T1D). Several large clinical trials and smaller mechanistic studies have failed to demonstrate the efficacy of insulin antigen therapy. The growing awareness of the heterogeneity of T1D likely affects the response to various immune therapies including insulin. Identification of biomarkers of clinical response will provide further insight into mechanisms leading to the disease and classify responders in the quest for personalized therapy. RECENT FINDINGS Several biomarkers have identified subpopulations in posthoc analyses that showed benefit from oral insulin even though the placebo-controlled study was as a whole unsuccessful. High insulin autoantibody titer, low first phase insulin response, and high Diabetes Prevention Trial-Type 1 Risk Score identify at-risk relatives more likely to benefit from oral insulin. Future incorporation of human leukocyte antigen and the variable number of tandem repeats polymorphism located in the insulin gene promoter (INS VNTR) is of interest for both primary and secondary prevention studies. SUMMARY Although primary and secondary prevention trials using oral insulin are ongoing, those completed have been largely unsuccessful. However, we believe that oral insulin should be considered in future trials as part of combination therapies as prerandomization biomarker testing is refined.
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Affiliation(s)
- Laura M. Jacobsen
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Desmond A. Schatz
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
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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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40
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Serr I, Drost F, Schubert B, Daniel C. Antigen-Specific Treg Therapy in Type 1 Diabetes - Challenges and Opportunities. Front Immunol 2021; 12:712870. [PMID: 34367177 PMCID: PMC8341764 DOI: 10.3389/fimmu.2021.712870] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/06/2021] [Indexed: 01/16/2023] Open
Abstract
Regulatory T cells (Tregs) are key mediators of peripheral self-tolerance and alterations in their frequencies, stability, and function have been linked to autoimmunity. The antigen-specific induction of Tregs is a long-envisioned goal for the treatment of autoimmune diseases given reduced side effects compared to general immunosuppressive therapies. However, the translation of antigen-specific Treg inducing therapies for the treatment or prevention of autoimmune diseases into the clinic remains challenging. In this mini review, we will discuss promising results for antigen-specific Treg therapies in allergy and specific challenges for such therapies in autoimmune diseases, with a focus on type 1 diabetes (T1D). We will furthermore discuss opportunities for antigen-specific Treg therapies in T1D, including combinatorial strategies and tissue-specific Treg targeting. Specifically, we will highlight recent advances in miRNA-targeting as a means to foster Tregs in autoimmunity. Additionally, we will discuss advances and perspectives of computational strategies for the detailed analysis of tissue-specific Tregs on the single-cell level.
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Affiliation(s)
- Isabelle Serr
- Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, Institute of Diabetes Research, Munich, Germany
- Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany
| | - Felix Drost
- School of Life Sciences Weihenstephan, Technische Universität München, Garching bei München, Germany
| | - Benjamin Schubert
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Mathematics, Technische Universität München, Garching bei München, Germany
| | - Carolin Daniel
- Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, Institute of Diabetes Research, Munich, Germany
- Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany
- Division of Clinical Pharmacology, Department of Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany
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Frontino G, Guercio Nuzio S, Scaramuzza AE, D'Annunzio G, Toni S, Citriniti F, Bonfanti R. Prevention of type 1 diabetes: where we are and where we are going. Minerva Pediatr (Torino) 2021; 73:486-503. [PMID: 34286946 DOI: 10.23736/s2724-5276.21.06529-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
T1D (T1D) is one of the most frequent chronic disease in children and is associated to the risk of severe acute and chronic complications. There are about 550000 children with T1D in the world and about 86000 children are diagnosed with T1D every year and its incidence is ever increasing. In this narrative review we will discuss current and future perspectives in T1D prevention strategies as well as their pitfalls. It is important to remember that for the first time one drug, in particular Teplizumab (antibody anti CD3) is going to be accepted for treatment in stage 2 of type 1 diabetes mellitus: this represent the onset of a new era.
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Affiliation(s)
- Giulio Frontino
- Diabetes Research Institute, Department of Pediatrics, IRCCS San Raffaele Scientific Institute, Milano, Italy
| | - Salvatore Guercio Nuzio
- Division of Pediatric, Santa Maria della Speranza Hospital, Battipaglia, ASL Salerno, Salerno, Italy
| | | | - Giuseppe D'Annunzio
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Sonia Toni
- Diabetology and Endocrinology Unit, Meyer Children Hospital, Firenze, Italy
| | - Felice Citriniti
- Department of Pediatrics, Pugliese-Ciaccio Hospital, Catanzaro, Italy
| | - Riccardo Bonfanti
- Diabetes Research Institute, Department of Pediatrics, IRCCS San Raffaele Scientific Institute, Milano, Italy - .,Università Vita-Salute San Raffaele, Milan, Italy
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42
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Ramzy A, Kieffer TJ. Altered islet prohormone processing: A cause or consequence of diabetes? Physiol Rev 2021; 102:155-208. [PMID: 34280055 DOI: 10.1152/physrev.00008.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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43
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The dark side of insulin: A primary autoantigen and instrument of self-destruction in type 1 diabetes. Mol Metab 2021; 52:101288. [PMID: 34242821 PMCID: PMC8513143 DOI: 10.1016/j.molmet.2021.101288] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/27/2021] [Accepted: 07/02/2021] [Indexed: 12/12/2022] Open
Abstract
Background Since its discovery 100 years ago, insulin, as the ‘cure’ for type 1 diabetes, has rescued the lives of countless individuals. As the century unfolded and the autoimmune nature of type 1 diabetes was recognised, a darker side of insulin emerged. Autoimmunity to insulin was found to be an early marker of risk for type 1 diabetes in young children. In humans, it remains unclear if autoimmunity to insulin is primarily due to a defect in the beta cell itself or to dysregulated immune activation. Conversely, it may be secondary to beta-cell damage from an environmental agent (e.g., virus). Nevertheless, direct, interventional studies in non-obese diabetic (NOD) mouse models of type 1 diabetes point to a critical role for (pro)insulin as a primary autoantigen that drives beta cell pathology. Scope of review Modelled on Koch's postulates for the pathogenicity of an infectious agent, evidence for a pathogenic role of (pro)insulin as an autoantigen in type 1 diabetes, particularly applicable to the NOD mouse model, is reviewed. Evidence in humans remains circumstantial. Additionally, as (pro)insulin is a target of autoimmunity in type 1 diabetes, its application as a therapeutic tool to elicit antigen-specific immune tolerance is assessed. Major conclusions Paradoxically, insulin is both a ‘cure’ and a potential ‘cause’ of type 1 diabetes, actively participating as an autoantigen to drive autoimmune destruction of beta cells - the instrument of its own destruction.
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Selck C, Dominguez-Villar M. Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation. Front Immunol 2021; 12:661875. [PMID: 34054826 PMCID: PMC8160309 DOI: 10.3389/fimmu.2021.661875] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/27/2021] [Indexed: 12/30/2022] Open
Abstract
Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cells in vitro or in vivo are currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as the in vivo stability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.
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Affiliation(s)
- Claudia Selck
- Faculty of Medicine, Imperial College London, London, United Kingdom
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45
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Aktuelle Entwicklungen in der Prävention des Typ-1-Diabetes. DIABETOLOGE 2021. [DOI: 10.1007/s11428-021-00759-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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46
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von Scholten BJ, Kreiner FF, Gough SCL, von Herrath M. Current and future therapies for type 1 diabetes. Diabetologia 2021; 64:1037-1048. [PMID: 33595677 PMCID: PMC8012324 DOI: 10.1007/s00125-021-05398-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/22/2020] [Indexed: 12/14/2022]
Abstract
In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia. Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction. Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists. Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential. In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes.
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Affiliation(s)
| | | | | | - Matthias von Herrath
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark.
- Type 1 Diabetes Center, The La Jolla Institute for Immunology, La Jolla, CA, USA.
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47
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Assfalg R, Knoop J, Hoffman KL, Pfirrmann M, Zapardiel-Gonzalo JM, Hofelich A, Eugster A, Weigelt M, Matzke C, Reinhardt J, Fuchs Y, Bunk M, Weiss A, Hippich M, Halfter K, Hauck SM, Hasford J, Petrosino JF, Achenbach P, Bonifacio E, Ziegler AG. Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial. Diabetologia 2021; 64:1079-1092. [PMID: 33515070 PMCID: PMC8012335 DOI: 10.1007/s00125-020-05376-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome. METHODS A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. RESULTS Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. CONCLUSIONS/INTERPRETATION The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. TRIAL REGISTRATION Clinicaltrials.gov NCT02547519 FUNDING: The main funding source was the German Center for Diabetes Research (DZD e.V.).
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Affiliation(s)
- Robin Assfalg
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany
- German Center for Diabetes Research (DZD), Munich, Germany
| | - Jan Knoop
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Kristi L Hoffman
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Markus Pfirrmann
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jose Maria Zapardiel-Gonzalo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Anna Hofelich
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany
| | - Anne Eugster
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Marc Weigelt
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Claudia Matzke
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Julia Reinhardt
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Yannick Fuchs
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Melanie Bunk
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Andreas Weiss
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Markus Hippich
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Kathrin Halfter
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Jörg Hasford
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Joseph F Petrosino
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany
- German Center for Diabetes Research (DZD), Munich, Germany
| | - Ezio Bonifacio
- German Center for Diabetes Research (DZD), Munich, Germany
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, Dresden, Germany
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Munich-Neuherberg, Germany
| | - Anette-Gabriele Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany.
- German Center for Diabetes Research (DZD), Munich, Germany.
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48
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Chen XY, Du GS, Sun X. Targeting Lymphoid Tissues to Promote Immune Tolerance. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202100056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Xiao Yan Chen
- Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University No.17, Block 3, Southern Renmin Road Chengdu 610041 China
| | - Guang Sheng Du
- Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University No.17, Block 3, Southern Renmin Road Chengdu 610041 China
| | - Xun Sun
- Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University No.17, Block 3, Southern Renmin Road Chengdu 610041 China
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49
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Marfil-Garza BA, Hefler J, Bermudez De Leon M, Pawlick R, Dadheech N, Shapiro AMJ. Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation. Endocr Rev 2021; 42:198-218. [PMID: 33247733 DOI: 10.1210/endrev/bnaa028] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Tregs) have become highly relevant in the pathophysiology and treatment of autoimmune diseases, such as type 1 diabetes (T1D). As these cells are known to be defective in T1D, recent efforts have explored ex vivo and in vivo Treg expansion and enhancement as a means for restoring self-tolerance in this disease. Given their capacity to also modulate alloimmune responses, studies using Treg-based therapies have recently been undertaken in transplantation. Islet transplantation provides a unique opportunity to study the critical immunological crossroads between auto- and alloimmunity. This procedure has advanced greatly in recent years, and reports of complete abrogation of severe hypoglycemia and long-term insulin independence have become increasingly reported. It is clear that cellular transplantation has the potential to be a true cure in T1D, provided the remaining barriers of cell supply and abrogated need for immune suppression can be overcome. However, the role that Tregs play in islet transplantation remains to be defined. Herein, we synthesize the progress and current state of Treg-based therapies in T1D and islet transplantation. We provide an extensive, but concise, background to understand the physiology and function of these cells and discuss the clinical evidence supporting potency and potential Treg-based therapies in the context of T1D and islet transplantation. Finally, we discuss some areas of opportunity and potential research avenues to guide effective future clinical application. This review provides a basic framework of knowledge for clinicians and researchers involved in the care of patients with T1D and islet transplantation.
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Affiliation(s)
| | - Joshua Hefler
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Mario Bermudez De Leon
- Department of Molecular Biology, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, Nuevo Leon, Mexico
| | - Rena Pawlick
- Department of Surgery, University of Alberta, Edmonton, Canada
| | | | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, Canada.,Clinical Islet Transplant Program, University of Alberta, Edmonton, Canada
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50
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Rodriguez-Fernandez S, Almenara-Fuentes L, Perna-Barrull D, Barneda B, Vives-Pi M. A century later, still fighting back: antigen-specific immunotherapies for type 1 diabetes. Immunol Cell Biol 2021; 99:461-474. [PMID: 33483995 DOI: 10.1111/imcb.12439] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/11/2020] [Accepted: 01/20/2021] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes (T1D) is a chronic metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. Ever since the 1920s, the fate of patients suffering from T1D was dramatically improved owing to the isolation and production of insulin, and the scientific field has largely progressed as a result of the evidence gathered about its underpinnings and mechanisms. The last years have seen this knowledge transformed into actual antigen-specific immunotherapies with potential to restore selectively the breach of tolerance to β-cell autoantigens and halt the autoimmune aggression. However, so far, the results of both prevention and reversion trials in T1D have been rather discouraging, so there is still an urgent need to optimize those immunotherapies and their associated factors, for example, posology and administration patterns, route and timing. In this review, we look back on what has been achieved in the last century and identify the main autoantigens driving the autoimmune attack in T1D. Then, we take a deep dive into the numerous antigen-specific immunotherapies trialed and the ones still at a preclinical phase, ranging from peptides, proteins and agent combinations to gene transfer, nanoparticles, cell-based strategies and novel approaches exploiting naturally occurring tolerogenic processes. Finally, we provide insight into the several features to be considered in a T1D clinical trial, the ideal time point for intervention and the biomarkers needed for monitoring the successful regulatory effect of the antigen-specific immunotherapy. Although further research and optimization remain imperative, the development of a therapeutic armamentarium against T1D autoimmunity is certainly advancing with a confident step.
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Affiliation(s)
- Silvia Rodriguez-Fernandez
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.,Ahead Therapeutics SL, Barcelona, Spain
| | - Lidia Almenara-Fuentes
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.,Ahead Therapeutics SL, Barcelona, Spain
| | - David Perna-Barrull
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
| | | | - Marta Vives-Pi
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.,Ahead Therapeutics SL, Barcelona, Spain
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