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Mauvais FX, van Endert PM. Type 1 Diabetes: A Guide to Autoimmune Mechanisms for Clinicians. Diabetes Obes Metab 2025. [PMID: 40375390 DOI: 10.1111/dom.16460] [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: 03/19/2025] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/18/2025]
Abstract
Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells by autoreactive T lymphocytes, leading to insulin deficiency and lifelong insulin dependence. It develops in genetically predisposed individuals, triggered by environmental or immunological factors. Although the exact causes of T1D remain unknown, the autoimmune pathogenesis of the disease is clearly indicated by the genetic risk conferred by allelic human leukocyte antigens (HLA), the almost obligatory presence of islet cell autoantibodies (AAbs) and immune cell infiltration of pancreatic islets from patients. At the same time, epidemiological data point to a role of environmental factors, notably enteroviral infections, in the disease, although precise causative links between specific pathogens and T1D have been difficult to establish. Studies of human pancreas organs from patients made available through repositories and the advent of high-dimensional high-throughput technologies for genomic and proteomic studies have significantly elucidated our understanding of the disease in recent years and provided mechanistic insights that can be exploited for innovative targeted therapeutic approaches. This short overview will summarise current salient knowledge on immune cell and beta cell dysfunction in T1D pathogenesis. PLAIN LANGUAGE SUMMARY: Type 1 diabetes (T1D) is a chronic disease where the body's own immune system attacks and destroys the insulin-producing beta cells in the pancreas. This leads to a lack of insulin, a hormone essential for regulating blood sugar, which means people with T1D need insulin for life. The disease can develop at any age but is most diagnosed in children and young adults. Despite advances in treatment, T1D still significantly reduces life expectancy, especially in countries with fewer healthcare resources. T1D develops in people with a genetic predisposition, often triggered by environmental factors such as viral infections or changes in the gut microbiome. The disease progresses silently through three stages: Stage 1: Autoantibodies to beta cell components appear, signalling the immune system is reacting against the pancreas, but there are no symptoms; Stage 2: Beta cell function starts to decline, but fasting blood sugar is still normal; Stage 3: Enough beta cells are destroyed that fasting blood sugar rises, and symptoms of diabetes appear. The risk of progressing from stage 1 to full-blown diabetes is about 35-50% within five years, and even higher from stage 2. Over 60 genes are linked to T1D risk, most of which affect how the immune system works. The strongest genetic risk comes from specific versions of histocompatibility genes, which help the immune system distinguish between the body's own cells and invaders. Some types of these genes make it easier for the immune system to mistakenly attack beta cells. However, 90% of people diagnosed with T1D have no family member with T1D, showing that genetics is only part of the story. Environmental factors also play a big role. For example, certain viral infections, especially with viruses infecting the intestine, are associated with a higher risk of developing T1D. The gut microbiome - the community of bacteria living in our intestines - also influences risk, with healthier, more diverse microbiomes appearing to offer some protection. In T1D, immune cells - especially so-called T lymphocytes - mistake beta cells in the pancreas for threats and destroy them. This process is called autoimmunity. The attack is often reflected by the presence of autoantibodies against proteins found in beta cells. Over time, as more beta cells are lost, the body can no longer produce enough insulin, leading to the symptoms of diabetes. Interestingly, not all people with T1D have the same pattern of disease. For example, children diagnosed before age 7 often have more aggressive disease, more autoantibodies, and stronger genetic risk factors than those diagnosed later. Much of our understanding of T1D has come from studying animal models, but new technologies now allow researchers to study human pancreas tissue and blood immune cells in greater detail. Scientists are also exploring how the gut microbiome, diet, and environmental exposures contribute to T1D risk and progression. Treatment currently focuses on replacing insulin, but researchers are working on therapies that target the immune system or aim to protect or replace beta cells. Strategies include immunotherapy, gene therapy, and even modifying the gut microbiome. The goal is to prevent or reverse the disease, not just manage its symptoms. In summary, T1D is a complex autoimmune disease influenced by both genes and the environment. It progresses silently before symptoms appear, and while insulin therapy is life-saving, new research is paving the way for treatments that could one day halt or even prevent the disease.
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Affiliation(s)
- François-Xavier Mauvais
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France
- Service de Physiologie - Explorations Fonctionnelles Pédiatriques, AP-HP, Hôpital Universitaire Robert Debré, Paris, France
| | - Peter M van Endert
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France
- Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker - Enfants Malades, Paris, France
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2
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Islam MZ, Zimmerman S, Lindahl A, Weidanz J, Ordovas-Montanes J, Kostic A, Luber J, Robben M. Single-cell RNA-seq reveals disease-specific CD8+ T cell clonal expansion and a high frequency of transcriptionally distinct double-negative T cells in diabetic NOD mice. PLoS One 2025; 20:e0317987. [PMID: 40106422 PMCID: PMC11922263 DOI: 10.1371/journal.pone.0317987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/08/2025] [Indexed: 03/22/2025] Open
Abstract
T cells primarily drive the autoimmune destruction of pancreatic beta cells in Type 1 diabetes (T1D). However, the profound yet uncharacterized diversity of the T cell populations in vivo has hindered obtaining a clear picture of the T cell changes that occur longitudinally during T1D onset. This study aimed to identify T cell clonal expansion and distinct transcriptomic signatures associated with T1D progression in Non-Obese Diabetic (NOD) mice. Here we profiled the transcriptome and T cell receptor (TCR) repertoire of T cells at single-cell resolution from longitudinally collected peripheral blood and pancreatic islets of NOD mice using single-cell RNA sequencing technology. We detected disease dependent development of infiltrating CD8 + T cells with altered cytotoxic and inflammatory effector states. In addition, we discovered a high frequency of transcriptionally distinct double negative (DN) T cells that fluctuate throughout T1D pathogenesis. This study identifies potential disease relevant TCR sequences and potential disease biomarkers that can be further characterized through future research.
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Affiliation(s)
- Md Zohorul Islam
- Section on Pathophysiology and Molecular Pharmacology, Joslin Diabetes Center, Boston, Massachusetts, United States of America
- Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
- CSIRO Health & Biosecurity, Australian Centre for Disease Preparedness, Geelong, Victoria, Australia
| | - Sam Zimmerman
- Section on Pathophysiology and Molecular Pharmacology, Joslin Diabetes Center, Boston, Massachusetts, United States of America
- Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Alexis Lindahl
- Department of Animal Science, University of Illinois, Urbana-Champaign, Illinois, United States of America
| | - Jon Weidanz
- Department of Kinesiology, The University of Texas at Arlington, Texas, United States of America
- Department of Bioengineering, The University of Texas at Arlington, Texas, United States of America
| | - Jose Ordovas-Montanes
- Division of Gastroenterology, Boston Children’s Hospital, Boston, Massachusetts, United States of America
- Harvard Stem Cell Institute, Harvard University, Boston, Massachusetts, United States of America
| | - Aleksandar Kostic
- Section on Pathophysiology and Molecular Pharmacology, Joslin Diabetes Center, Boston, Massachusetts, United States of America
- Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Jacob Luber
- Department of Computer Science and Engineering, The University of Texas at Arlington, United States of America
| | - Michael Robben
- Department of Animal Science, University of Illinois, Urbana-Champaign, Illinois, United States of America
- Department of Computer Science and Engineering, The University of Texas at Arlington, United States of America
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Schaaf C, Sussel L. A Cure for Type 1 Diabetes: Are We There Yet? Diabetes Technol Ther 2025. [PMID: 39911033 DOI: 10.1089/dia.2024.0498] [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] [Indexed: 02/07/2025]
Abstract
Type 1 diabetes (T1D) affects over 2 million people in the United States and has no known cure. The discovery and first use of insulin in humans 102 years ago marked a revolutionary course of treatment for the disease, and although the formulations and delivery systems have advanced, insulin administration remains the standard of care today. While improved treatment options represent notable progress in T1D management, finding a functional cure for the disease remains the ultimate goal. Approaches to curing T1D have historically focused on blunting the autoimmune response, although sustained effects of immune modulation have proven elusive. Islet transplant therapies have also proven effective, although a lack of available donor tissue and the need for immunosuppression to prevent both host-graft rejection and the autoimmune response have reserved such treatments for those who already require immunosuppressive regimens for other reasons or undergo severe hypoglycemic events in conjunction with hypoglycemic unawareness. With the advent of human stem cell research, the focus has shifted toward generating an abundance of allogeneic, functional beta-like cells that can be transplanted into the patients. Immunoisolation devices have also shown some promise as a method of preventing immune rejection and the autoimmune destruction of transplanted cells. Finally, advances in new immune therapies, if used in the early stages of T1D progression, have proven to delay the onset of diabetes. Stem cell-based therapies are a promising approach to curing T1D. The ongoing clinical trials show some success, although they currently require immunosuppressant agents. Encapsulation devices provide a method of immunoisolation that does not require immunosuppression; however, the devices tested thus far eventually lead to cell death and fibrotic tissue growth. Substantial research efforts are underway to develop new approaches to protect the stem cell-derived beta cells upon transplantation.
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Affiliation(s)
- Christopher Schaaf
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Center, Denver, Colorado, USA
| | - Lori Sussel
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Center, Denver, Colorado, USA
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Rosell-Mases E, Santiago A, Corral-Pujol M, Yáñez F, Varela E, Egia-Mendikute L, Arpa B, Cosovanu C, Panosa A, Serrano-Gómez G, Mora C, Verdaguer J, Manichanh C. Mutual modulation of gut microbiota and the immune system in type 1 diabetes models. Nat Commun 2023; 14:7770. [PMID: 38012160 PMCID: PMC10682479 DOI: 10.1038/s41467-023-43652-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 11/15/2023] [Indexed: 11/29/2023] Open
Abstract
The transgenic 116C-NOD mouse strain exhibits a prevalent Th17 phenotype, and reduced type 1 diabetes (T1D) compared to non-obese diabetic (NOD) mice. A cohousing experiment between both models revealed lower T1D incidence in NOD mice cohoused with 116C-NOD, associated with gut microbiota changes, reduced intestinal permeability, shifts in T and B cell subsets, and a transition from Th1 to Th17 responses. Distinct gut bacterial signatures were linked to T1D in each group. Using a RAG-2-/- genetic background, we found that T cell alterations promoted segmented filamentous bacteria proliferation in young NOD and 116C-NOD, as well as in immunodeficient NOD.RAG-2-/- and 116C-NOD.RAG-2-/- mice across all ages. Bifidobacterium colonization depended on lymphocytes and thrived in a non-diabetogenic environment. Additionally, 116C-NOD B cells in 116C-NOD.RAG-2-/- mice enriched the gut microbiota in Adlercreutzia and reduced intestinal permeability. Collectively, these results indicate reciprocal modulation between gut microbiota and the immune system in rodent T1D models.
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Affiliation(s)
- Estela Rosell-Mases
- Immunology and Immunopathology Group, Department of Experimental Medicine, Faculty of Medicine, Universitat de Lleida (UdL) and Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198, Lleida, Spain
| | - Alba Santiago
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain
| | - Marta Corral-Pujol
- Immunology and Immunopathology Group, Department of Experimental Medicine, Faculty of Medicine, Universitat de Lleida (UdL) and Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198, Lleida, Spain
| | - Francisca Yáñez
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain
| | - Encarna Varela
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain
| | - Leire Egia-Mendikute
- Immunology and Immunopathology Group, Department of Experimental Medicine, Faculty of Medicine, Universitat de Lleida (UdL) and Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198, Lleida, Spain
| | - Berta Arpa
- Immunology and Immunopathology Group, Department of Experimental Medicine, Faculty of Medicine, Universitat de Lleida (UdL) and Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198, Lleida, Spain
| | - Catalina Cosovanu
- Immunology and Immunopathology Group, Department of Experimental Medicine, Faculty of Medicine, Universitat de Lleida (UdL) and Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198, Lleida, Spain
| | - Anaïs Panosa
- Flow Cytometry Facility, Universitat de Lleida (UdL) and Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198, Lleida, Spain
| | - Gerard Serrano-Gómez
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain
| | - Conchi Mora
- Immunology and Immunopathology Group, Department of Experimental Medicine, Faculty of Medicine, Universitat de Lleida (UdL) and Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198, Lleida, Spain
| | - Joan Verdaguer
- Immunology and Immunopathology Group, Department of Experimental Medicine, Faculty of Medicine, Universitat de Lleida (UdL) and Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198, Lleida, Spain.
- CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
| | - Chaysavanh Manichanh
- Microbiome Lab, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain.
- CIBER of Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
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Stadinski BD, Cleveland SB, Brehm MA, Greiner DL, Huseby PG, Huseby ES. I-A g7 β56/57 polymorphisms regulate non-cognate negative selection to CD4 + T cell orchestrators of type 1 diabetes. Nat Immunol 2023; 24:652-663. [PMID: 36807641 PMCID: PMC10623581 DOI: 10.1038/s41590-023-01441-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 01/20/2023] [Indexed: 02/22/2023]
Abstract
Genetic susceptibility to type 1 diabetes is associated with homozygous expression of major histocompatibility complex class II alleles that carry specific beta chain polymorphisms. Why heterozygous expression of these major histocompatibility complex class II alleles does not confer a similar predisposition is unresolved. Using a nonobese diabetic mouse model, here we show that heterozygous expression of the type 1 diabetes-protective allele I-Ag7 β56P/57D induces negative selection to the I-Ag7-restricted T cell repertoire, including beta-islet-specific CD4+ T cells. Surprisingly, negative selection occurs despite I-Ag7 β56P/57D having a reduced ability to present beta-islet antigens to CD4+ T cells. Peripheral manifestations of non-cognate negative selection include a near complete loss of beta-islet-specific CXCR6+ CD4+ T cells, an inability to cross-prime islet-specific glucose-6-phosphatase catalytic subunit-related protein and insulin-specific CD8+ T cells and disease arrest at the insulitis stage. These data reveal that negative selection on non-cognate self-antigens in the thymus can promote T cell tolerance and protection from autoimmunity.
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Affiliation(s)
- Brian D Stadinski
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Sarah B Cleveland
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Michael A Brehm
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
| | - Dale L Greiner
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
| | - Priya G Huseby
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Eric S Huseby
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
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Ferris ST, Liu T, Chen J, Ohara RA, Ou F, Wu R, Kim S, Murphy TL, Murphy KM. WDFY4 deficiency in NOD mice ameliorates autoimmune diabetes and insulitis. Proc Natl Acad Sci U S A 2023; 120:e2219956120. [PMID: 36940342 PMCID: PMC10068798 DOI: 10.1073/pnas.2219956120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/13/2023] [Indexed: 03/22/2023] Open
Abstract
The events that initiate autoimmune diabetes in nonobese diabetic (NOD) mice remain poorly understood. CD4+ and CD8+ T cells are both required to develop disease, but their relative roles in initiating disease are unclear. To test whether CD4+ T cell infiltration into islets requires damage to β cells induced by autoreactive CD8+ T cells, we inactivated Wdfy4 in nonobese diabetic (NOD) mice (NOD.Wdfy4-/--) using CRISPR/Cas9 targeting to eliminate cross-presentation by type 1 conventional dendritic cells (cDC1s). Similar to C57BL/6 Wdfy4-/- mice, cDC1 in NOD.Wdfy4-/- mice are unable to cross-present cell-associated antigens to prime CD8+ T cells, while cDC1 from heterozygous NOD.Wdfy4+/- mice cross-present normally. Further, NOD.Wdfy4-/- mice fail to develop diabetes while heterozygous NOD.Wdfy4+/- mice develop diabetes similarly to wild-type NOD mice. NOD.Wdfy4-/- mice remain capable of processing and presenting major histocompatibility complex class II (MHC-II)-restricted autoantigens and can activate β cell-specific CD4+ T cells in lymph nodes. However, disease in these mice does not progress beyond peri-islet inflammation. These results indicate that the priming of autoreactive CD8+ T cells in NOD mice requires cross-presentation by cDC1. Further, autoreactive CD8+ T cells appear to be required not only to develop diabetes, but to recruit autoreactive CD4+ T cells into islets of NOD mice, perhaps in response to progressive β cell damage.
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Affiliation(s)
- Stephen T. Ferris
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
| | - Tiantian Liu
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
| | - Jing Chen
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
| | - Ray A. Ohara
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
| | - Feiya Ou
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
| | - Renee Wu
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
| | - Sunkyung Kim
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
| | - Theresa L. Murphy
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
| | - Kenneth M. Murphy
- Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO63110
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7
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Pham VT, Ciccaglione M, Ramirez DG, Benninger RKP. Ultrasound Imaging of Pancreatic Perfusion Dynamics Predicts Therapeutic Prevention of Diabetes in Preclinical Models of Type 1 Diabetes. ULTRASOUND IN MEDICINE & BIOLOGY 2022; 48:1336-1347. [PMID: 35473669 PMCID: PMC9149043 DOI: 10.1016/j.ultrasmedbio.2022.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/07/2022] [Accepted: 03/18/2022] [Indexed: 06/14/2023]
Abstract
In type 1 diabetes (T1D), immune-cell infiltration into islets of Langerhans (insulitis) and β-cell decline occur years before diabetes presents. There is a lack of validated clinical approaches for detecting insulitis and β-cell decline, to diagnose eventual diabetes and monitor the efficacy of therapeutic interventions. We previously determined that contrast-enhanced ultrasound measurements of pancreas perfusion dynamics predict disease progression in T1D pre-clinical models. Here, we test whether these measurements predict therapeutic prevention of T1D. We performed destruction-reperfusion measurements with size-isolated microbubbles in non-obese diabetic (NOD)-severe combined immunodeficiency (SCID) mice receiving an adoptive transfer of diabetogenic splenocytes. Mice received vehicle control or the following treatments: (i) anti-CD3 to block T-cell activation; (ii) anti-CD4 to deplete CD4+ T cells; (iii) verapamil to reduce β-cell apoptosis; or (iv) tauroursodeoxycholic acid (TUDCA) to reduce β-cell endoplasmic reticulum stress. We compared measurements of pancreas perfusion dynamics with subsequent progression to diabetes. Anti-CD3, anti-CD4, and verapamil delayed diabetes development. Blood flow dynamics was significantly altered in treated mice with delayed/absent diabetes development compared with untreated mice. Conversely, blood flow dynamics in treated mice with unchanged diabetes development was similar to that in untreated mice. Thus, measurement of pancreas perfusion dynamics predicts the successful prevention of diabetes. This strategy may provide a clinically deployable predictive marker for therapeutic prevention in asymptomatic T1D.
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Affiliation(s)
- Vinh T Pham
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Mark Ciccaglione
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - David G Ramirez
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Richard K P Benninger
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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8
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De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes. Proc Natl Acad Sci U S A 2021; 118:2112032118. [PMID: 34782469 DOI: 10.1073/pnas.2112032118] [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] [Accepted: 09/28/2021] [Indexed: 01/22/2023] Open
Abstract
Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.
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Amdare N, Purcell AW, DiLorenzo TP. Noncontiguous T cell epitopes in autoimmune diabetes: From mice to men and back again. J Biol Chem 2021; 297:100827. [PMID: 34044020 PMCID: PMC8233151 DOI: 10.1016/j.jbc.2021.100827] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/18/2021] [Accepted: 05/21/2021] [Indexed: 11/30/2022] Open
Abstract
Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that affects the insulin-producing beta cells of the pancreatic islets. The nonobese diabetic mouse is a widely studied spontaneous model of the disease that has contributed greatly to our understanding of T1D pathogenesis. This is especially true in the case of antigen discovery. Upon review of existing knowledge concerning the antigens and peptide epitopes that are recognized by T cells in this model, good concordance is observed between mouse and human antigens. A fascinating recent illustration of the contribution of the nonobese diabetic mouse in the area of epitope identification is the discovery of noncontiguous CD4+ T cell epitopes. This novel epitope class is characterized by the linkage of an insulin-derived peptide to, most commonly, a fragment of a natural cleavage product of another beta cell secretory granule constituent. These so-called hybrid insulin peptides are also recognized by T cells in patients with T1D, although the precise mechanism for their generation has yet to be defined and is the subject of active investigation. Although evidence from the tumor immunology arena documented the existence of noncontiguous CD8+ T cell epitopes, generated by proteasome-mediated peptide splicing involving transpeptidation, such CD8+ T cell epitopes were thought to be a rare immunological curiosity. However, recent advances in bioinformatics and mass spectrometry have challenged this view. These developments, coupled with the discovery of hybrid insulin peptides, have spurred a search for noncontiguous CD8+ T cell epitopes in T1D, an exciting frontier area still in its infancy.
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Affiliation(s)
- Nitin Amdare
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Anthony W Purcell
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Teresa P DiLorenzo
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA; Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA; The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, New York, USA.
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10
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Carré A, Richardson SJ, Larger E, Mallone R. Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset? Diabetologia 2021; 64:15-25. [PMID: 33084970 PMCID: PMC7717061 DOI: 10.1007/s00125-020-05298-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 08/20/2020] [Indexed: 12/31/2022]
Abstract
Available evidence provides arguments both for and against a primary pathogenic role for T cells in human type 1 diabetes. Genetic susceptibility linked to HLA Class II lends strong support. Histopathology documents HLA Class I hyperexpression and islet infiltrates dominated by CD8+ T cells. While both hallmarks are near absent in autoantibody-positive donors, the variable insulitis and residual beta cells of recent-onset donors suggests the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells. Functional arguments from ex vivo and in vitro human studies and in vivo 'humanised' mouse models are instead neutral or against a T cell role. Clinical support is provided by the appearance of islet autoantibodies before disease onset. The faster C-peptide loss and superior benefits of immunotherapies in individuals with younger-onset type 1 diabetes reinforce the view of age-related endotypes. Clarifying the relative role of T cells will require technical advances in the identification of their target antigens, in their detection and phenotyping in the blood and pancreas, and in the study of the T cell/beta cell crosstalk. Critical steps toward this goal include the understanding of the link with environmental triggers, the description of T cell changes along the natural history of disease, and their relationship with age and the 'benign' islet autoimmunity of healthy individuals. Graphical abstract.
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Affiliation(s)
- Alexia Carré
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Sarah J Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
| | - Etienne Larger
- 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
| | - 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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11
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Oulghazi S, Wegner SK, Spohn G, Müller N, Harenkamp S, Stenzinger A, Papayannopoulou T, Bonig H. Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4-Integrin Deficient NOD Mouse. Cells 2020; 9:cells9122597. [PMID: 33291571 PMCID: PMC7761835 DOI: 10.3390/cells9122597] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022] Open
Abstract
Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. Results: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. Conclusion: α4 is a potential target for primary or secondary prevention of T1D.
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Affiliation(s)
- Salim Oulghazi
- Institute for Transfusion Medicine and Immunohematology, School of Medicine, Goethe University, Sandhofstraße 1, 60528 Frankfurt, Germany or (S.O.); (S.K.W.)
| | - Sarah K. Wegner
- Institute for Transfusion Medicine and Immunohematology, School of Medicine, Goethe University, Sandhofstraße 1, 60528 Frankfurt, Germany or (S.O.); (S.K.W.)
| | - Gabriele Spohn
- Institute Frankfurt, German Red Cross Blood Service BaWüHe, Sandhofstraße 1, 60528 Frankfurt, Germany; (G.S.); (N.M.); (S.H.)
| | - Nina Müller
- Institute Frankfurt, German Red Cross Blood Service BaWüHe, Sandhofstraße 1, 60528 Frankfurt, Germany; (G.S.); (N.M.); (S.H.)
| | - Sabine Harenkamp
- Institute Frankfurt, German Red Cross Blood Service BaWüHe, Sandhofstraße 1, 60528 Frankfurt, Germany; (G.S.); (N.M.); (S.H.)
| | - Albrecht Stenzinger
- Institute for Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany;
| | - Thalia Papayannopoulou
- Department of Medicine/Division of Hematology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA;
| | - Halvard Bonig
- Institute for Transfusion Medicine and Immunohematology, School of Medicine, Goethe University, Sandhofstraße 1, 60528 Frankfurt, Germany or (S.O.); (S.K.W.)
- Institute Frankfurt, German Red Cross Blood Service BaWüHe, Sandhofstraße 1, 60528 Frankfurt, Germany; (G.S.); (N.M.); (S.H.)
- Department of Medicine/Division of Hematology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA;
- Correspondence: ; Tel.: +49-69-6782177
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12
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Cytocidal macrophages in symbiosis with CD4 and CD8 T cells cause acute diabetes following checkpoint blockade of PD-1 in NOD mice. Proc Natl Acad Sci U S A 2020; 117:31319-31330. [PMID: 33229539 DOI: 10.1073/pnas.2019743117] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Autoimmune diabetes is one of the complications resulting from checkpoint blockade immunotherapy in cancer patients, yet the underlying mechanisms for such an adverse effect are not well understood. Leveraging the diabetes-susceptible nonobese diabetic (NOD) mouse model, we phenocopy the diabetes progression induced by programmed death 1 (PD-1)/PD-L1 blockade and identify a cascade of highly interdependent cellular interactions involving diabetogenic CD4 and CD8 T cells and macrophages. We demonstrate that exhausted CD8 T cells are the major cells that respond to PD-1 blockade producing high levels of IFN-γ. Most importantly, the activated T cells lead to the recruitment of monocyte-derived macrophages that become highly activated when responding to IFN-γ. These macrophages acquire cytocidal activity against β-cells via nitric oxide and induce autoimmune diabetes. Collectively, the data in this study reveal a critical role of macrophages in the PD-1 blockade-induced diabetogenesis, providing new insights for the understanding of checkpoint blockade immunotherapy in cancer and infectious diseases.
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13
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Honkanen J, Vuorela A, Muthas D, Orivuori L, Luopajärvi K, Tejesvi MVG, Lavrinienko A, Pirttilä AM, Fogarty CL, Härkönen T, Ilonen J, Ruohtula T, Knip M, Koskimäki JJ, Vaarala O. Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity. Front Immunol 2020; 11:468. [PMID: 32265922 PMCID: PMC7103650 DOI: 10.3389/fimmu.2020.00468] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 02/28/2020] [Indexed: 01/01/2023] Open
Abstract
Although gut bacterial dysbiosis is recognized as a regulator of beta-cell autoimmunity, no data is available on fungal dysbiosis in the children at the risk of type 1 diabetes (T1D). We hypothesized that the co-occurrence of fungal and bacterial dysbiosis contributes to the intestinal inflammation and autoimmune destruction of insulin-producing beta-cells in T1D. Fecal and blood samples were collected from 26 children tested positive for at least one diabetes-associated autoantibody (IAA, GADA, IA-2A or ICA) and matched autoantibody-negative children with HLA-conferred susceptibility to T1D (matched for HLA-DQB1 haplotype, age, gender and early childhood nutrition). Bacterial 16S and fungal ITS2 sequencing, and analyses of the markers of intestinal inflammation, namely fecal human beta-defensin-2 (HBD2), calprotectin and secretory total IgA, were performed. Anti-Saccharomyces cerevisiae antibodies (ASCA) and circulating cytokines, IFNG, IL-17 and IL-22, were studied. After these analyses, the children were followed for development of clinical T1D (median 8 years and 8 months). Nine autoantibody positive children were diagnosed with T1D, whereas none of the autoantibody negative children developed T1D during the follow-up. Fungal dysbiosis, characterized by high abundance of fecal Saccharomyces and Candida, was found in the progressors, i.e., children with beta-cell autoimmunity who during the follow-up progressed to clinical T1D. These children showed also bacterial dysbiosis, i.e., increased Bacteroidales and Clostridiales ratio, which was, however, found also in the non-progressors, and is thus a common nominator in the children with beta-cell autoimmunity. Furthermore, the progressors showed markers of intestinal inflammation detected as increased levels of fecal HBD2 and ASCA IgG to fungal antigens. We conclude that the fungal and bacterial dysbiosis, and intestinal inflammation are associated with the development of T1D in children with beta-cell autoimmunity.
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Affiliation(s)
- Jarno Honkanen
- Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Arja Vuorela
- Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Daniel Muthas
- Translational & Experimental Medicine, Early Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Laura Orivuori
- Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Kristiina Luopajärvi
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | | | - Anton Lavrinienko
- Ecology and Genetics Research Unit, University of Oulu, Oulu, Finland.,Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
| | | | | | - Taina Härkönen
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, University of Turku, Turku, Finland
| | - Terhi Ruohtula
- Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mikael Knip
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Janne J Koskimäki
- Ecology and Genetics Research Unit, University of Oulu, Oulu, Finland
| | - Outi Vaarala
- Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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14
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Ma H, Lu Y, Lowe K, van der Meijden-Erkelens L, Wasserfall C, Atkinson MA, Song S. Regulated hAAT Expression from a Novel rAAV Vector and Its Application in the Prevention of Type 1 Diabetes. J Clin Med 2019; 8:jcm8091321. [PMID: 31466263 PMCID: PMC6780368 DOI: 10.3390/jcm8091321] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/14/2019] [Accepted: 08/20/2019] [Indexed: 12/26/2022] Open
Abstract
We, and others, have previously achieved high and sustained levels of transgene expression from viral vectors, such as recombinant adeno-associated virus (rAAV). However, regulatable transgene expression may be preferred in gene therapy for diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis (RA), in which the timing and dosing of the therapeutic gene product play critical roles. In the present study, we generated a positive feedback regulation system for human alpha 1 antitrypsin (hAAT) expression in the rAAV vector. We performed quantitative kinetics studies in vitro and in vivo demonstrating that this vector system can mediate high levels of inducible transgene expression. Transgene induction could be tailored to occur rapidly or gradually, depending on the dose of the inducing drug, doxycycline (Dox). Conversely, after withdrawal of Dox, the silencing of transgene expression occurred slowly over the course of several weeks. Importantly, rAAV delivery of inducible hAAT significantly prevented T1D development in non-obese diabetic (NOD) mice. These results indicate that this Dox-inducible vector system may facilitate the fine-tuning of transgene expression, particularly for hAAT treatment of human autoimmune diseases, including T1D.
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Affiliation(s)
- Hongxia Ma
- College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
- Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA
| | - Yuanqing Lu
- Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA
| | - Keith Lowe
- Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA
| | | | - Clive Wasserfall
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Sihong Song
- Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA.
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15
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Tahvili S, Törngren M, Holmberg D, Leanderson T, Ivars F. Paquinimod prevents development of diabetes in the non-obese diabetic (NOD) mouse. PLoS One 2018; 13:e0196598. [PMID: 29742113 PMCID: PMC5942776 DOI: 10.1371/journal.pone.0196598] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 04/16/2018] [Indexed: 12/12/2022] Open
Abstract
Quinoline-3-carboxamides (Q compounds) are immunomodulatory compounds that have shown efficacy both in autoimmune disease and cancer. We have in here investigated the impact of one such compound, paquinimod, on the development of diabetes in the NOD mouse model for type I diabetes (T1D). In cohorts of NOD mice treated with paquinimod between weeks 10 to 20 of age and followed up until 40 weeks of age, we observed dose-dependent reduction in incidence of disease as well as delayed onset of disease. Further, in contrast to untreated controls, the majority of NOD mice treated from 15 weeks of age did not develop diabetes at 30 weeks of age. Importantly, these mice displayed significantly less insulitis, which correlated with selectively reduced number of splenic macrophages and splenic Ly6Chi inflammatory monocytes at end point as compared to untreated controls. Collectively, these results demonstrate that paquinimod treatment can significantly inhibit progression of insulitis to T1D in the NOD mouse. We propose that the effect of paquinimod on disease progression may be related to the reduced number of these myeloid cell populations. Our finding also indicates that this compound could be a candidate for clinical development towards diabetes therapy in humans.
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Affiliation(s)
- Sahar Tahvili
- Immunology group, Section for Immunology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | | | - Dan Holmberg
- Immunology group, Section for Immunology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Tomas Leanderson
- Immunology group, Section for Immunology, Department of Experimental Medical Science, Lund University, Lund, Sweden
- Active Biotech AB, Lund, Sweden
| | - Fredrik Ivars
- Immunology group, Section for Immunology, Department of Experimental Medical Science, Lund University, Lund, Sweden
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16
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Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models. Nat Commun 2018; 9:1742. [PMID: 29717116 PMCID: PMC5931596 DOI: 10.1038/s41467-018-03953-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 03/23/2018] [Indexed: 12/13/2022] Open
Abstract
In type 1 diabetes (T1D), immune-cell infiltration into the islets of Langerhans (insulitis) and β-cell decline occurs many years before diabetes clinically presents. Non-invasively detecting insulitis and β-cell decline would allow the diagnosis of eventual diabetes, and provide a means to monitor therapeutic intervention. However, there is a lack of validated clinical approaches for specifically and non-invasively imaging disease progression leading to T1D. Islets have a denser microvasculature that reorganizes during diabetes. Here we apply contrast-enhanced ultrasound measurements of pancreatic blood-flow dynamics to non-invasively and predictively assess disease progression in T1D pre-clinical models. STZ-treated mice, NOD mice, and adoptive-transfer mice demonstrate altered islet blood-flow dynamics prior to diabetes onset, consistent with islet microvasculature reorganization. These assessments predict both time to diabetes onset and future responders to antiCD4-mediated disease prevention. Thus contrast-enhanced ultrasound measurements of pancreas blood-flow dynamics may provide a clinically deployable predictive marker for disease progression in pre-symptomatic T1D and therapeutic reversal.
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17
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Abstract
CD4+CD25highFoxP3+ T regulatory cells (Tregs) are immunodominant suppressors in the immune system. Tregs use various mechanisms to control immune responses. Preclinical data from animal models have confirmed the huge therapeutic potential of Tregs in many immune-mediated diseases. Hence, these cells are now on the road to translation to cell therapy in the clinic as the first clinical trials are accomplished. To date, clinical research has involved mainly hematopoietic stem cell transplantations, solid organ transplantations, and autoimmunity. Despite difficulties with legislation and technical issues, treatment is constantly evolving and may soon represent a valid alternative for patients with diseases that are currently incurable. This review focuses on the basic and clinical experience with Tregs with adoptive transfer of these cells, primarily from clinical trials, as well as on perspectives on clinical use and technical problems with implementing the therapy.
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18
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T Cell Repertoire Diversity Is Decreased in Type 1 Diabetes Patients. GENOMICS PROTEOMICS & BIOINFORMATICS 2016; 14:338-348. [PMID: 28024918 PMCID: PMC5200939 DOI: 10.1016/j.gpb.2016.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 10/13/2016] [Accepted: 10/25/2016] [Indexed: 02/01/2023]
Abstract
Type 1 diabetes mellitus (T1D) is an immune-mediated disease. The autoreactive T cells in T1D patients attack and destroy their own pancreatic cells. In order to systematically investigate the potential autoreactive T cell receptors (TCRs), we used a high-throughput immune repertoire sequencing technique to profile the spectrum of TCRs in individual T1D patients and controls. We sequenced the T cell repertoire of nine T1D patients, four type 2 diabetes (T2D) patients, and six nondiabetic controls. The diversity of the T cell repertoire in T1D patients was significantly decreased in comparison with T2D patients (P=7.0E-08 for CD4+ T cells, P=1.4E-04 for CD8+ T cells) and nondiabetic controls (P=2.7E-09 for CD4+ T cells, P=7.6E-06 for CD8+ T cells). Moreover, T1D patients had significantly more highly-expanded T cell clones than T2D patients (P=5.2E-06 for CD4+ T cells, P=1.9E-07 for CD8+ T cells) and nondiabetic controls (P=1.7E-07 for CD4+ T cells, P=3.3E-03 for CD8+ T cells). Furthermore, we identified a group of highly-expanded T cell receptor clones that are shared by more than two T1D patients. Although further validation in larger cohorts is needed, our data suggest that T cell receptor diversity measurements may become a valuable tool in investigating diabetes, such as using the diversity as an index to distinguish different types of diabetes.
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19
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Chabot S, Alvarez F, Amrani A, Djilali-Saiah I. Novel model of double transgenic mouse results in autoimmune diabetes in males. Autoimmunity 2016; 49:397-404. [PMID: 27683954 DOI: 10.1080/08916934.2016.1203907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Identifying the type of diabetogenic CD8+ T cells that initiate autoimmune diabetes (AID) is a critical step in designing appropriate strategies for the early detection of beta cell-directed autoimmunity and its progression to diabetes. We generated a novel double transgenic (Tg) mouse model on the naturally diabetes resistant C57Bl/6 background, co-expressing two transgenes including a specific TCR anti-lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) carried by CD8+ T cells and LCMV-NP (as neo-self antigen) expressed by pancreatic beta cells. The resulting double Tg mouse showed partial thymic deletion of the NP-specific CD8+ T cells. The escaping autoreactive NP-specific CD8+ T cells joining the periphery were activated and gained effector functions. Both male and female mice mounted anti-NP antibodies, but only one-fourth adult males spontaneously developed AID. Significant upregulation of the CD44 and CD122 markers as compared to healthy male and female mice characterized the phenotype of diabetogenic CD8+ T cells in diabetic male mice. We also show that only 10% of these CD8+ T cells expressed programmed death 1 receptor (PD-1). Together, these results suggest that in our double Tg mouse model, Ag-specific effector CD44+CD122+PD-1-CD8+ T cell subpopulation is associated with the pathogenesis of AID.
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Affiliation(s)
- Sylvie Chabot
- a Gastroenterology, Hepatology and Nutrition Division, CHU Sainte-Justine , Montreal , QC , Canada.,b Department of Microbiology , Infectiology and Immunology, University of Montreal , Montreal , QC , Canada
| | - Fernando Alvarez
- a Gastroenterology, Hepatology and Nutrition Division, CHU Sainte-Justine , Montreal , QC , Canada.,b Department of Microbiology , Infectiology and Immunology, University of Montreal , Montreal , QC , Canada.,c Department of Pediatrics , University of Montreal , Montreal , QC , Canada , and
| | - Abdelaziz Amrani
- d Immunology Division, Department of Pediatrics, University of Sherbrooke , Sherbrooke , QC , Canada
| | - Idriss Djilali-Saiah
- a Gastroenterology, Hepatology and Nutrition Division, CHU Sainte-Justine , Montreal , QC , Canada
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20
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Nikoopour E, Krougly O, Lee-Chan E, Haeryfar SM, Singh B. Detection of vasostatin-1-specific CD8(+) T cells in non-obese diabetic mice that contribute to diabetes pathogenesis. Clin Exp Immunol 2016; 185:292-300. [PMID: 27185276 DOI: 10.1111/cei.12811] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/04/2016] [Accepted: 05/12/2016] [Indexed: 11/29/2022] Open
Abstract
Chromogranin A (ChgA) is an antigenic target of pathogenic CD4(+) T cells in a non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Vasostatin-1 is a naturally processed fragment of ChgA. We have now identified a novel H2-K(d) -restricted epitope of vasostatin-1, ChgA 36-44, which elicits CD8(+) T cell responses in NOD mice. By using ChgA 36-44/K(d) tetramers we have determined the frequency of vasostatin-1-specific CD8(+) T cells in pancreatic islets and draining lymph nodes of NOD mice. We also demonstrate that vasostatin-1-specific CD4(+) and CD8(+) T cells constitute a significant fraction of islet-infiltrating T cells in diabetic NOD mice. Adoptive transfer of T cells from ChgA 36-44 peptide-primed NOD mice into NOD/severe combined immunodeficiency (SCID) mice led to T1D development. These findings indicate that vasostatin-1-specific CD8(+) T cells contribute to the pathogenesis of type 1 diabetes in NOD mice.
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Affiliation(s)
- E Nikoopour
- Department of Microbiology and Immunology, Centre for Human Immunology
| | - O Krougly
- Department of Microbiology and Immunology, Centre for Human Immunology
| | - E Lee-Chan
- Department of Microbiology and Immunology, Centre for Human Immunology
| | - S M Haeryfar
- Department of Microbiology and Immunology, Centre for Human Immunology
| | - B Singh
- Department of Microbiology and Immunology, Centre for Human Immunology.,Robarts Research Institute, University of Western Ontario, London, ON, Canada
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21
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Abstract
Type 1 diabetes (T1D) results from a chronic and selective destruction of insulin-secreting β-cells within the islets of Langerhans of the pancreas by autoreactive CD4(+) and CD8(+) T lymphocytes. The use of animal models of T1D was instrumental for deciphering the steps of the autoimmune process leading to T1D. The non-obese diabetic (NOD) mouse and the bio-breeding (BB) rat spontaneously develop the disease similar to the human pathology in terms of the immune responses triggering autoimmune diabetes and of the genetic and environmental factors influencing disease susceptibility. The generation of genetically modified models allowed refining our understanding of the etiology and the pathogenesis of the disease. In the present review, we provide an overview of the experimental models generated and used to gain knowledge on the molecular and cellular mechanisms underlying the breakdown of self-tolerance in T1D and the progression of the autoimmune response. Immunotherapeutic interventions designed in these animal models and translated into the clinical arena in T1D patients will also be discussed.
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22
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Barrie ES, Lodder M, Weinreb PH, Buss J, Rajab A, Adin C, Mi QS, Hadley GA. Role of ITGAE in the development of autoimmune diabetes in non-obese diabetic mice. J Endocrinol 2015; 224:235-43. [PMID: 25525188 DOI: 10.1530/joe-14-0396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
There is compelling evidence that autoreactive CD8(+)T cells play a central role in precipitating the development of autoimmune diabetes in non-obese diabetic (NOD) mice, but the underlying mechanisms remain unclear. Given that ITGAE (CD103) recognizes an islet-restricted ligand (E-cadherin), we postulated that its expression is required for initiation of disease. We herein use a mouse model of autoimmune diabetes (NOD/ShiLt mice) to test this hypothesis. We demonstrate that ITGAE is expressed by a discrete subset of CD8(+)T cells that infiltrate pancreatic islets before the development of diabetes. Moreover, we demonstrate that development of diabetes in Itgae-deficient NOD mice is significantly delayed at early but not late time points, indicating that ITGAE is preferentially involved in early diabetes development. To rule out a potential contribution by closely linked loci to this delay, we treated WT NOD mice beginning at 2 weeks of age through 5 weeks of age with a depleting anti-ITGAE mAb and found a decreased incidence of diabetes following anti-ITGAE mAb treatment compared with mice that received isotype control mAbs or non-depleting mAbs to ITGAE. Moreover, a histological examination of the pancreas of treated mice revealed that NOD mice treated with a depleting mAb were resistant to immune destruction. These results indicate that ITGAE(+) cells play a key role in the development of autoimmune diabetes and are consistent with the hypothesis that ITGAE(+)CD8(+)T effectors initiate the disease process.
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Affiliation(s)
- Elizabeth S Barrie
- The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA
| | - Mels Lodder
- The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA
| | - Paul H Weinreb
- The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA
| | - Jill Buss
- The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA
| | - Amer Rajab
- The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA
| | - Christopher Adin
- The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA
| | - Qing-Sheng Mi
- The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA
| | - Gregg A Hadley
- The Ohio State University Wexner Medical CenterRoom 216 Tzagournis Medical Research Facility, 420 W 12th Avenue, Columbus, Ohio 43201, USABiogen IdecCambridge, Massachusetts 02142, USACollege of Veterinary MedicineColumbus, Ohio 43201 USAHenry Ford HospitalDetroit, Michigan 48202, USA
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Brozzi F, Gerlo S, Grieco FA, Nardelli TR, Lievens S, Gysemans C, Marselli L, Marchetti P, Mathieu C, Tavernier J, Eizirik DL. A combined "omics" approach identifies N-Myc interactor as a novel cytokine-induced regulator of IRE1 protein and c-Jun N-terminal kinase in pancreatic beta cells. J Biol Chem 2015; 289:20677-93. [PMID: 24936061 DOI: 10.1074/jbc.m114.568808] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Type 1 diabetes is an autoimmune disease with a strong inflammatory component. The cytokines interleukin-1β and interferon-γ contribute to beta cell apoptosis in type 1 diabetes. These cytokines induce endoplasmic reticulum stress and the unfolded protein response (UPR), contributing to the loss of beta cells. IRE1α, one of the UPR mediators, triggers insulin degradation and inflammation in beta cells and is critical for the transition from "physiological" to "pathological" UPR. The mechanisms regulating inositol-requiring protein 1α (IRE1α) activation and its signaling for beta cell "adaptation," "stress response," or "apoptosis" remain to be clarified. To address these questions, we combined mammalian protein-protein interaction trap-based IRE1α interactome and functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines to identify novel cytokine-induced regulators of IRE1α. Based on this approach, we identified N-Myc interactor (NMI) as an IRE1α-interacting/modulator protein in rodent and human pancreatic beta cells. An increased expression of NMI was detected in islets from nonobese diabetic mice with insulitis and in rodent or human beta cells exposed in vitro to the pro-inflammatory cytokines interleukin-1β and interferon-γ. Detailed mechanistic studies demonstrated that NMI negatively modulates IRE1α-dependent activation of JNK and apoptosis in rodent and human pancreatic beta cells. In conclusion, by using a combined omics approach, we identified NMI induction as a novel negative feedback mechanism that decreases IRE1α-dependent activation of JNK and apoptosis in cytokine-exposed beta cells
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24
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Ferris ST, Carrero JA, Mohan JF, Calderon B, Murphy KM, Unanue ER. A minor subset of Batf3-dependent antigen-presenting cells in islets of Langerhans is essential for the development of autoimmune diabetes. Immunity 2015; 41:657-69. [PMID: 25367577 DOI: 10.1016/j.immuni.2014.09.012] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 09/26/2014] [Indexed: 10/24/2022]
Abstract
Autoimmune diabetes is characterized by inflammatory infiltration; however, the initiating events are poorly understood. We found that the islets of Langerhans in young nonobese diabetic (NOD) mice contained two antigen-presenting cell (APC) populations: a major macrophage and a minor CD103(+) dendritic cell (DC) population. By 4 weeks of age, CD4(+) T cells entered islets coincident with an increase in CD103(+) DCs. In order to examine the role of the CD103(+) DCs in diabetes, we examined Batf3-deficient NOD mice that lacked the CD103(+) DCs in islets and pancreatic lymph nodes. This led to a lack of autoreactive T cells in islets and, importantly, no incidence of diabetes. Additional examination revealed that presentation of major histocompatibility complex (MHC) class I epitopes in the pancreatic lymph nodes was absent with a partial impairment of MHC class II presentation. Altogether, this study reveals that CD103(+) DCs are essential for autoimmune diabetes development.
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Affiliation(s)
- Stephen T Ferris
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Javier A Carrero
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - James F Mohan
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Boris Calderon
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kenneth M Murphy
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Emil R Unanue
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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25
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Arndt B, Witkowski L, Ellwart J, Seissler J. CD8+ CD122+ PD-1- effector cells promote the development of diabetes in NOD mice. J Leukoc Biol 2014; 97:111-20. [PMID: 25387835 DOI: 10.1189/jlb.3a0613-344rr] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
It is well established that CD4 and CD8 T cells are required for the initiation of autoimmune diabetes in NOD mice. However, different subsets of CD4 or CD8 cells may play different roles in the initiation of insulitis. In this study, we evaluated the role of the previously described CD8(+) CD122(+) in this process. We found that prediabetic NOD mice have an almost 50% reduction of CD8(+) CD122(+) T cells in their secondary lymphoid organs compared with BL/6 or Balb/c mouse strains. This reduction is explained by the lack of the regulatory CD8(+) CD122(+) PD-1(+) cell population in the NOD mice, as we found that all CD8(+) CD122(+) T cells from prediabetic NOD mice lack PD-1 expression and regulatory function. Depletion of CD8(+) CD122(+) PD-1(-) cells through injection of anti-CD122 mAb in prediabetic female NOD mice reduced the infiltration of mononuclear cells into the Langerhans islets and delayed the onset and decreased the incidence of overt diabetes. In addition, we found that transfer of highly purified and activated CD8(+) CD122(+) PD-1(-) cells, together with diabetogenic splenocytes from NOD donors to NOD SCID recipients, accelerates the diabetes development in these mice. Together, these results demonstrate that CD8(+) CD122(+) PD-1(-) T cells from NOD mice are effector cells that are involved in the pathogenesis of autoimmune diabetes.
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Affiliation(s)
- Börge Arndt
- *Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; Medizinische Klinik und Poliklinik III, Campus Grosshadern, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; and Helmholtz Zentrum München, Institute of Molecular Immunology (Hämatologikum), Munich, Germany
| | - Lukas Witkowski
- *Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; Medizinische Klinik und Poliklinik III, Campus Grosshadern, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; and Helmholtz Zentrum München, Institute of Molecular Immunology (Hämatologikum), Munich, Germany
| | - Joachim Ellwart
- *Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; Medizinische Klinik und Poliklinik III, Campus Grosshadern, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; and Helmholtz Zentrum München, Institute of Molecular Immunology (Hämatologikum), Munich, Germany
| | - Jochen Seissler
- *Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; Medizinische Klinik und Poliklinik III, Campus Grosshadern, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany; and Helmholtz Zentrum München, Institute of Molecular Immunology (Hämatologikum), Munich, Germany
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26
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Abstract
This paper reviews the presentation of peptides by major histocompatibility complex (MHC) class II molecules in the autoimmune diabetes of the nonobese diabetic (NOD) mouse. Islets of Langerhans contain antigen-presenting cells that capture the proteins and peptides of the beta cells' secretory granules. Peptides bound to I-A(g7), the unique MHC class II molecule of NOD mice, are presented in islets and in pancreatic lymph nodes. The various beta cell-derived peptides interact with selected CD4 T cells to cause inflammation and beta cell demise. Many autoreactive T cells are found in NOD mice, but not all have a major role in the initiation of the autoimmune process. I emphasize here the evidence pointing to insulin autoreactivity as a seminal component in the diabetogenic process.
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Affiliation(s)
- Emil R Unanue
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110;
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27
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Nair-Gupta P, Blander JM. An updated view of the intracellular mechanisms regulating cross-presentation. Front Immunol 2013; 4:401. [PMID: 24319447 PMCID: PMC3837292 DOI: 10.3389/fimmu.2013.00401] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 11/08/2013] [Indexed: 02/05/2023] Open
Abstract
Cross-presentation involves the presentation of peptides derived from internalized cargo on major histocompatibility complex class I molecules by dendritic cells, a process critical for tolerance and immunity. Detailed studies of the pathways mediating cross-presentation have revealed that this process takes place in a specialized subcellular compartment with a unique set of proteins. In this review, we focus on the recently appreciated role for intracellular vesicular traffic, which serves to equip compartments such as endosomes and phagosomes with the necessary apparatus for conducting the various steps of cross-presentation. We also consider how these pathways may integrate with inflammatory signals particularly from pattern recognition receptors that detect the presence of microbial components during infection. We discuss the consequences of such signals on initiating cross-presentation to stimulate adaptive CD8 T cell responses.
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Affiliation(s)
- Priyanka Nair-Gupta
- Department of Medicine, Immunology Institute, Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY , USA
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28
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Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse. Clin Sci (Lond) 2013; 126:1-18. [PMID: 24020444 DOI: 10.1042/cs20120627] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
T1D (Type 1 diabetes) is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Studies in T1D patients have been limited by the availability of pancreatic samples, a protracted pre-diabetic phase and limitations in markers that reflect β-cell mass and function. The NOD (non-obese diabetic) mouse is currently the best available animal model of T1D, since it develops disease spontaneously and shares many genetic and immunopathogenic features with human T1D. Consequently, the NOD mouse has been extensively studied and has made a tremendous contribution to our understanding of human T1D. The present review summarizes the key lessons from NOD mouse studies concerning the genetic susceptibility, aetiology and immunopathogenic mechanisms that contribute to autoimmune destruction of β-cells. Finally, we summarize the potential and limitations of immunotherapeutic strategies, successful in NOD mice, now being trialled in T1D patients and individuals at risk of developing T1D.
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T-lymphocyte recognition of beta cells in type 1 diabetes: clinical perspectives. DIABETES & METABOLISM 2013; 39:459-66. [PMID: 24139825 DOI: 10.1016/j.diabet.2013.08.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 08/14/2013] [Indexed: 11/23/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the activation of lymphocytes against pancreatic β cells. Landmarks in the history of T1D were the description of insulitis and of islet cell autoantibodies, and report an association between T1D and a limited number of HLA alleles. Another step was the study of T-lymphocytes, now known to be central to the disease process of T1D whether in mice or men. In humans, T-lymphocytes, and especially CD8⁺ T-cells, are predominant in insulitis. The characterization of antigenic fragments--peptides--recognized by T-cells paves the way towards new assays for predicting T1D and its prevention using antigen- or peptide-specific immunotherapy, while avoiding side effects that may counteract the limited efficacy of immunosuppression and immunomodulation in preserving β-cells from autoimmune destruction in recent-onset T1D patients. The current need for new preclinical models for testing strategies of antigen-specific immune tolerance is also highlighted.
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30
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Marrero I, Hamm DE, Davies JD. High-throughput sequencing of islet-infiltrating memory CD4+ T cells reveals a similar pattern of TCR Vβ usage in prediabetic and diabetic NOD mice. PLoS One 2013; 8:e76546. [PMID: 24146886 PMCID: PMC3798422 DOI: 10.1371/journal.pone.0076546] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 08/25/2013] [Indexed: 12/29/2022] Open
Abstract
Autoreactive memory CD4+ T cells play a critical role in the development of type 1 diabetes, but it is not yet known how the clonotypic composition and TCRβ repertoire of the memory CD4+ T cell compartment changes during the transition from prediabetes to diabetes. In this study, we used high-throughput sequencing to analyze the TCRβ repertoire of sorted islet-infiltrating memory CD4+CD44high T cells in 10-week-old prediabetic and recently diabetic NOD mice. We show that most clonotypes of islet-infiltrating CD4+CD44high T cells were rare, but high-frequency clonotypes were significantly more common in diabetic than in prediabetic mice. Moreover, although the CD4+CD44high TCRβ repertoires were highly diverse at both stages of disease development, dominant use of TRBV1 (Vβ2), TRBV13-3 (Vβ8.1), and TRBV19 (Vβ6) was evident in both prediabetic and diabetic mice. Our findings strongly suggest that therapeutic targeting of cells specifically expressing the dominant TCRβ might reduce pancreatic infiltration in prediabetic mice and attenuate the progression to diabetes.
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Affiliation(s)
- Idania Marrero
- Torrey Pines Institute for Molecular Studies, San Diego, California, United States of America
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31
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Ramirez L, Hamad ARA. Status of autoimmune diabetes 20-year after generation of BDC2.5-TCR transgenic non-obese diabetic mouse. World J Diabetes 2013; 4:88-91. [PMID: 23961318 PMCID: PMC3746090 DOI: 10.4239/wjd.v4.i4.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 05/22/2013] [Accepted: 06/10/2013] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of insulin-producing β cells by autoreactive T cells, leading to lifelong dependency on insulin therapy and increased risk of long-term cardiovascular complications. Here we take the opportunity of the 20th anniversary of the generation of the BDC2.5 TCR transgenic non-obese diabetic (NOD) mouse model, to provide a brief overview of the significant progress that has been made in understanding the role of T cells in the disease pathogenesis period. This included development of hundreds of reagents that block or even reverse new-onset disease by directly or indirectly controlling T cells. We also reflect on the sobering fact that none of these strategies has shown significant efficacy in clinical trials and discuss potential reasons hindering translation of the preclinical findings into successful therapeutic strategies and potential ways forward.
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32
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Yang T, Hohenstein AC, Lee CE, Hutton JC, Davidson HW. Mapping I-A(g7) restricted epitopes in murine G6PC2. Immunol Res 2013; 55:91-9. [PMID: 22983906 DOI: 10.1007/s12026-012-8368-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
G6PC2, also known as islet-specific glucose 6-phosphatase catalytic subunit-related protein (IGRP), is a major target of autoreactive CD8(+) T cells in both diabetic human subjects and the non-obese diabetic (NOD) mouse. However, in contrast to the abundant literature regarding the CD8(+) response to this antigen, much less is known about the potential involvement of IGRP-reactive CD4(+) T cells in diabetogenesis. The single previous study that examined this question in NOD mice was based upon a candidate epitope approach and identified three I-A(g7)-restricted epitopes that each elicited spontaneous responses in these animals. However, given the known inaccuracies of MHC class II epitope prediction algorithms, we hypothesized that additional specificities might also be targeted. To address this issue, we immunized NOD mice with membranes from insect cells overexpressing full-length recombinant mouse IGRP and measured recall responses of purified CD4(+) T cells using a library of overlapping peptides encompassing the entire 355-aa primary sequence. Nine peptides representing 8 epitopes gave recall responses, only 1 of which corresponded to any of the previously reported sequences. In each case proliferation was blocked by a monoclonal antibody to I-A(g7), but not the appropriate isotype control. Consistent with a role in diabetogenesis, proliferative responses to 4 of the 9 peptides (3 epitopes) were also detected in CD4(+) T cells purified from the pancreatic draining lymph nodes of pre-diabetic female animals, but not from peripheral lymph nodes or spleens of the same animals. Intriguingly, one of the newly identified spontaneously reactive epitopes (P8 [IGRP(55-72)]) is highly conserved between mice and man, suggesting that it might also be a target of HLA-DQ8-restricted T cells in diabetic human subjects, an hypothesis that we are currently testing.
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Affiliation(s)
- Tao Yang
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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33
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Brooks-Worrell B, Palmer JP. Prevention versus intervention of type 1 diabetes. Clin Immunol 2013; 149:332-8. [PMID: 23803322 DOI: 10.1016/j.clim.2013.05.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2013] [Revised: 05/29/2013] [Accepted: 05/30/2013] [Indexed: 01/10/2023]
Abstract
Type 1 diabetes (T1D) is a cell-mediated autoimmune disease. New cases of T1D are on the increase and exogenous insulin therapy is the only intervention regularly initiated for T1D patients. Though tremendous strides have been made in prediction of T1D, prevention and intervention strategies have not experienced the same success. In this review, we will discuss some possible reasons why new intervention therapies for T1D have not been implemented into the mainstream treatment regimen for T1D patients. We will also discuss potential caveats for why prevention and intervention trials in T1D may not have experienced the same success as prediction trials.
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Affiliation(s)
- Barbara Brooks-Worrell
- Department of Medicine, University of Washington, Seattle, WA 98108, USA; Department of Medicine, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
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34
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Berry G, Waldner H. Accelerated type 1 diabetes induction in mice by adoptive transfer of diabetogenic CD4+ T cells. J Vis Exp 2013:e50389. [PMID: 23685789 DOI: 10.3791/50389] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes after 12 weeks of age and is the most extensively studied animal model of human Type 1 diabetes (T1D). Cell transfer studies in irradiated recipient mice have established that T cells are pivotal in T1D pathogenesis in this model. We describe herein a simple method to rapidly induce T1D by adoptive transfer of purified, primary CD4+ T cells from pre-diabetic NOD mice transgenic for the islet-specific T cell receptor (TCR) BDC2.5 into NOD.SCID recipient mice. The major advantages of this technique are that isolation and adoptive transfer of diabetogenic T cells can be completed within the same day, irradiation of the recipients is not required, and a high incidence of T1D is elicited within 2 weeks after T cell transfer. Thus, studies of pathogenesis and therapeutic interventions in T1D can proceed at a faster rate than with methods that rely on heterogenous T cell populations or clones derived from diabetic NOD mice.
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Affiliation(s)
- Gregory Berry
- Department of Microbiology & Immunology, Pennsylvania State University College of Medicine, USA
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35
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Yang J, James EA, Sanda S, Greenbaum C, Kwok WW. CD4+ T cells recognize diverse epitopes within GAD65: implications for repertoire development and diabetes monitoring. Immunology 2013; 138:269-79. [PMID: 23228173 DOI: 10.1111/imm.12034] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Revised: 09/17/2012] [Accepted: 10/24/2012] [Indexed: 12/25/2022] Open
Abstract
Type 1 diabetes is associated with T-cell responses to β-cell antigens such as GAD65. Single T-cell epitopes have been investigated for immune monitoring with some success, but multiple epitopes may be required to fully characterize responses in all subjects. We used a systematic approach to examine the diversity of the GAD65-specific T-cell repertoire in subjects with DRB1*04:01 haplotypes. Using class II tetramers, we observed responses to 15 GAD65 epitopes, including five novel epitopes. The majority were confirmed to be processed and presented. Upon stimulation with peptides, GAD-specific responses were equally broad in subjects with diabetes and healthy controls in the presence or absence of CD25(+) T cells, suggesting that a susceptible HLA is sufficient to generate a potentially autoreactive repertoire. Without depleting CD25(+) cells, GAD(113-132) and GAD(265-284) responses were significantly stronger in subjects with diabetes. Although nearly every individual responded to at least one GAD65 epitope, most were seen in less than half of the subjects tested, suggesting that multiple epitopes are recommended for immune monitoring.
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Affiliation(s)
- Junbao Yang
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
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36
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Tang DQ, Shun L, Koya V, Sun Y, Wang Q, Wang H, Li SW, Sun Y, Purich DL, Zhang C, Hansen B, Qian K, Atkinson M, Phillips MI, Yang LJ. Genetically reprogrammed, liver-derived insulin-producing cells are glucose-responsive, but susceptible to autoimmune destruction in settings of murine model of type 1 diabetes. Am J Transl Res 2013; 5:184-199. [PMID: 23573363 PMCID: PMC3612514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 03/08/2013] [Indexed: 06/02/2023]
Abstract
Many previous studies demonstrate that hepatocytes can be reprogrammed into insulin-producing cells (IPCs) utilizing viral vector-mediated delivery of pancreatic transcription factors (PTFs). However, whether these liver-derived IPCs are susceptible to autoimmune attack in animal models of type 1 diabetes remains unclear, in part due to the immunogenicity of the viral vectors used to introduce PTF genes. Adeno-associated virus serotype 2 vector-expressing Pdx1-VP16 (Pdx1) and Ngn3 were prepared and injected into the portal vein of streptozotocin (Stz)/diabetic NOD/SCID mice. The presence of glucose-responsive liver-IPCs and their susceptibility to anti-beta cell autoimmunity were assessed by blood glucose levels, insulin content, IPC cell distribution, and intraperitoneal glucose tolerance test following subtotal pancreatectomy (Px) and passive transfer of diabetogenic splenocytes isolated from diabetic female NOD mice. A combination of two PTF genes (Pdx1/Ngn3) effectively reprogrammed liver cells into glucose-responsive IPCs. These IPCs corrected hyperglycemia in Stz/diabetic NOD/SCID mice and maintained normoglycemia following subtotal Px, indicating that liver-derived IPCs could maintain glucose homeostasis. Importantly, we also demonstrated that the glucose-responsive liver-derived IPCs were susceptible to autoimmune destruction by diabetogenic splenocytes, as indicated by progressive elevation in blood glucose levels as well as mixed T-, and B-lymphocytic infiltrates surrounding liver-IPCs 2~3 weeks following transferring of diabetogenic splenocytes into NOD/SCID mice, and confirmed by immunohistochemical studies. In conclusion, genetically reprogrammed liver-IPCs, like pancreatic islet beta-cells, are susceptible to autoimmune attack, suggesting that for cell-replacement therapy of treating type 1 diabetes, beta-cell surrogates may require concomitant immunotherapy to avoid autoimmune destruction.
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Affiliation(s)
- Dong-Qi Tang
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Lu Shun
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Vijay Koya
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Yuping Sun
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Qiwei Wang
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Hai Wang
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Shi-Wu Li
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Yu Sun
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Daniel L Purich
- Department of Biochemistry & Molecular Biology, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - Clare Zhang
- Obesity, Diabetes and Aging Research Center and Departments of Internal Medicine and Pediatrics, College of Medicine, University of South FloridaTampa, FL 33612, USA
| | - Barbara Hansen
- Obesity, Diabetes and Aging Research Center and Departments of Internal Medicine and Pediatrics, College of Medicine, University of South FloridaTampa, FL 33612, USA
| | - Keping Qian
- Center for Rare Disease Therapies, Keck Graduate InstituteClaremont, California, 91711, USA
| | - Mark Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
| | - M Ian Phillips
- Center for Rare Disease Therapies, Keck Graduate InstituteClaremont, California, 91711, USA
| | - Li-Jun Yang
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of MedicineGainesville, Florida 32610, USA
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Alkhamis T, Barbic J, Crnogorac-Jurcevic T, Greenlaw RE, Peakman M, Jurcevic S. Antibody combination therapy targeting CD25, CD70 and CD8 reduces islet inflammation and improves glycaemia in diabetic mice. Clin Exp Immunol 2013; 170:139-48. [PMID: 23039884 DOI: 10.1111/j.1365-2249.2012.04651.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Destruction of pancreatic islets in type 1 diabetes is caused by infiltrating, primed and activated T cells. In a clinical setting this autoimmune process is already in an advanced stage before intervention therapy can be administered. Therefore, an effective intervention needs to reduce islet inflammation and preserve any remaining islet function. In this study we have investigated the role of targeting activated T cells in reversing autoimmune diabetes. A combination therapy consisting of CD25-, CD70- and CD8-specific monoclonal antibodies was administered to non-obese diabetic (NOD) mice with either new-onset diabetes or with advanced diabetes. In NOD mice with new-onset diabetes antibody combination treatment reversed hyperglycaemia and achieved long-term protection from diabetes (blood glucose <13·9 mmol/l) in >50% of mice. In contrast, in the control, untreated group blood glucose levels continued to increase and none of the mice were protected from diabetes (P < 0·0001). Starting therapy early when hyperglycaemia was relatively mild proved critical, as the mice with advanced diabetes showed less efficient control of blood glucose and shorter life span. Histological analysis (insulitis score) showed islet preservation and reduced immune infiltration in all treated groups, compared to their controls. In conclusion, antibody combination therapy that targets CD25, CD70 and CD8 results in decreased islet infiltration and improved blood glucose levels in NOD mice with established diabetes.
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Affiliation(s)
- T Alkhamis
- Medical Research Council (MRC) Centre for Transplantation, King's Health Partners Department of Immunobiology, King's College London, Guy's Hospital Barts Cancer Institute, Queen Mary, University of London, London, UK
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Green-Mitchell SM, Tersey SA, Cole BK, Ma K, Kuhn NS, Cunningham TD, Maybee NA, Chakrabarti SK, McDuffie M, Taylor-Fishwick DA, Mirmira RG, Nadler JL, Morris MA. Deletion of 12/15-lipoxygenase alters macrophage and islet function in NOD-Alox15(null) mice, leading to protection against type 1 diabetes development. PLoS One 2013; 8:e56763. [PMID: 23437231 PMCID: PMC3578926 DOI: 10.1371/journal.pone.0056763] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Accepted: 01/16/2013] [Indexed: 11/19/2022] Open
Abstract
AIMS Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. We showed previously that deletion of the 12/15-lipoxygenase enzyme (12/15-LO, Alox15 gene) in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D. METHODS 12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD-Alox15(null) macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass. RESULTS 12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15(null) mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass. CONCLUSIONS These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass.
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Affiliation(s)
- Shamina M. Green-Mitchell
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
| | - Sarah A. Tersey
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Banumathi K. Cole
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
| | - Kaiwen Ma
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
| | - Norine S. Kuhn
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
| | - Tina Duong Cunningham
- Graduate Program in Public Health, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
| | - Nelly A. Maybee
- Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America
| | - Swarup K. Chakrabarti
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
| | - Marcia McDuffie
- Department of Microbiology, University of Virginia, Charlottesville, Virginia, United States of America
- Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America
| | - David A. Taylor-Fishwick
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
| | - Raghavendra G. Mirmira
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Jerry L. Nadler
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
- Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America
| | - Margaret A. Morris
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America
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Abstract
Insulin is the hormone produced by pancreatic β-cells, with a central role in carbohydrate and fat metabolism. Together with its precursors preproinsulin and proinsulin, insulin is also a key target antigen (Ag) of the autoimmune islet destruction leading to type 1 diabetes. Being recognized by both autoantibodies (aAbs) and autoreactive T cells, insulin plays a triggering role, at least in rodent models, in diabetes pathogenesis. It is expressed not only by β-cells but also in the thymus, where it plays a major role in central tolerance mechanisms. We will summarize current knowledge concerning insulin, its role in β-cell autoimmunity as initial target Ag, its recognition by aAbs and autoreactive T cells, and the detection of these immune responses to provide biomarkers for clinical trials employing insulin as an immune modulatory agent.
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Affiliation(s)
- Sloboda Culina
- INSERM, U986, DeAR Lab Avenir, Saint Vincent de Paul Hospital, 82 Avenue Denfert Rochereau, 75674 Paris Cedex 14, France
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Chabot S, Fakhfakh A, Béland K, Lamarre A, Oldstone MBA, Alvarez F, Djilali-Saiah I. Mouse liver-specific CD8(+) T-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes. J Autoimmun 2012; 42:19-28. [PMID: 23137675 DOI: 10.1016/j.jaut.2012.10.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 10/13/2012] [Indexed: 12/30/2022]
Abstract
CD8(+) T-cell immune response to liver antigens is often functionally diminished or absent. This may occur via deletion of these autoaggressive T-cells, through the acquisition of an anergic phenotype, or via active suppression mediated by other cell populations. We generated a double transgenic model in which mice express CD8(+) T-cells specific for the lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) and LCMV-NP as a hepatic neo-autoantigen, to study the immunological response of potentially liver antigen autoaggressive CD8(+) T-cells. Autoreactive transgenic CD8(+) T-cells were analyzed for functionality and cytotoxic effector status. Despite severe peripheral deletion of liver-specific CD8(+) T-cells, a fraction of autoreactive NP-specific CD8(+) T-cells accumulate in liver, resulting in hepatocyte injury and production of auto-antibodies in both male and female mice. NP-specific intrahepatic T-cells showed capacity to proliferate, produce cytokines and up-regulate activation markers. These data provide in vivo evidence that autoreactive CD8(+) T-cells are activated in the liver and developed an inflammatory process, but require additional factors to cause severe autoimmune destruction of hepatocytes. Our new model will provide a valuable tool for further exploration of the immunological response involved in inflammatory liver diseases, including autoimmune hepatitis.
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Affiliation(s)
- Sylvie Chabot
- Gastroenterology, Hepatology and Nutrition Division, CHU Sainte-Justine, Montreal, Quebec, Canada
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Nieminen JK, Vakkila J, Salo HM, Ekström N, Härkönen T, Ilonen J, Knip M, Vaarala O. Altered phenotype of peripheral blood dendritic cells in pediatric type 1 diabetes. Diabetes Care 2012; 35:2303-10. [PMID: 22787171 PMCID: PMC3476907 DOI: 10.2337/dc11-2460] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Dendritic cells (DCs) are largely responsible for the activation and fine-tuning of T-cell responses. Altered numbers of blood DCs have been reported in type 1 diabetes (T1D). We aimed at characterizing the less well-known phenotypic properties of DCs in T1D. RESEARCH DESIGN AND METHODS In a case-control setting, samples from a total of 90 children were studied by flow cytometry or by quantitative real-time PCR (qPCR). RESULTS We found decreased numbers of myeloid DCs (mDCs) (8.97 vs. 13.4 cells/μL, P = 0.009, n = 31) and plasmacytoid DCs (pDCs) (9.47 vs. 14.6 cells/μL, P = 0.018, n = 30) in recent-onset T1D. Using a panel of antibodies against functionally important DC markers, we detected a decreased expression of CC chemokine receptor 2 (CCR2) on mDCs (percentage above negative control, P = 0.002, n = 29) and pDCs (median intensity, P = 0.003, n = 30) from T1D patients. In an independent series of children, the reduced expression of CCR2 was confirmed by qPCR in isolated mDCs (P = 0.043, n = 20). Serum concentrations of CCR2 ligands monocyte chemotactic protein-1 and -3 did not differ between the groups. A trend for an enhanced responsiveness of the nuclear factor-κB pathway (P = 0.063, n = 39) was seen in mDCs from children with β-cell autoantibodies, which is possibly related to the reduced CCR2 expression, since CCR2 on mDCs was downregulated by nuclear factor-κB-activating agents. CONCLUSIONS Given the role of CCR2 in DC chemotaxis and in DC-elicited Th1 differentiation, our results may indicate a functionally important DC abnormality in T1D affecting the initiation and quality of immune responses.
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Affiliation(s)
- Janne K Nieminen
- Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland.
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42
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Varanasi V, Avanesyan L, Schumann DM, Chervonsky AV. Cytotoxic mechanisms employed by mouse T cells to destroy pancreatic β-cells. Diabetes 2012; 61:2862-70. [PMID: 22773667 PMCID: PMC3478530 DOI: 10.2337/db11-1784] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 05/01/2012] [Indexed: 12/21/2022]
Abstract
Several cytotoxic mechanisms have been attributed to T cells participating in β-cell death in type 1 diabetes. However, sensitivity of β-cells to these mechanisms in vitro and in vivo is likely to be different. Moreover, CD4⁺ and CD8⁺ T cells may use distinct mechanisms to cause β-cell demise that possibly involve activation of third-party cytotoxic cells. We used the transfer of genetically modified diabetogenic T cells into normal, mutant, and bone marrow chimeric recipients to test the contribution of major cytotoxic mechanisms in β-cell death. We found that 1) the killing of β-cells by CD4⁺ T cells required activation of the recipient's own cytotoxic cells via tumor necrosis factor-α (TNF-α); 2) CD8⁺ T-cell cytotoxic mechanisms destroying β-cells were limited to perforin and Fas ligand, as double knockouts of these molecules abrogated the ability of T cells to cause diabetes; and 3) individual CD8⁺ T-cell clones chose their cytotoxic weaponry by a yet unknown mechanism and destroyed their targets via either Fas-independent or Fas-dependent (~40% of clones) pathways. Fas-dependent destruction was assisted by TNF-α.
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MESH Headings
- Adoptive Transfer
- Animals
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/pathology
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/pathology
- Cells, Cultured
- Clone Cells
- Cytotoxicity, Immunologic
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Fas Ligand Protein/genetics
- Fas Ligand Protein/metabolism
- Gene Expression Regulation
- Insulin-Secreting Cells/immunology
- Lymphocyte Activation
- Mice
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Mice, Transgenic
- Pore Forming Cytotoxic Proteins/genetics
- Pore Forming Cytotoxic Proteins/metabolism
- RNA, Messenger/metabolism
- Signal Transduction
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
- T-Lymphocytes, Cytotoxic/pathology
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- Vineeth Varanasi
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Lia Avanesyan
- Department of Pathology, University of Chicago, Chicago, Illinois
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44
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Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, Wujtewicz MA, Witkowski P, Mlynarski W, Balcerska A, Mysliwska J, Trzonkowski P. Administration of CD4+CD25highCD127- regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes Care 2012; 35:1817-20. [PMID: 22723342 PMCID: PMC3425004 DOI: 10.2337/dc12-0038] [Citation(s) in RCA: 341] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Type 1 diabetes is a condition in which pancreatic islets are destroyed by self-reactive T cells. The process is facilitated by deficits in the number and suppressive activity of regulatory T cells (Tregs). Here, we show for the first time that the infusion of autologous Tregs prolongs remission in recently diagnosed type 1 diabetes in children. RESEARCH DESIGN AND METHODS We have administered Tregs in 10 type 1 diabetic children (aged 8-16 years) within 2 months since diagnosis. In total, 4 patients received 10 × 10(6) Tregs/kg body wt, and the remaining 6 patients received 20 × 10(6) Tregs/kg body wt. The preparation consisted of sorted autologous CD3(+)CD4(+)CD25(high)CD127(-) Tregs expanded under good manufacturing practice conditions. RESULTS No toxicity of the therapy was noted. A significant increase in the percentage of Tregs in the peripheral blood has been observed since the day of infusion. These patients were followed along with matched type 1 diabetic patients not treated with Tregs. Half a year after type 1 diabetes onset (4-5 months after Tregs infusion), 8 patients treated with Tregs still required <0.5 UI/kg body wt of insulin daily, with 2 patients out of insulin completely, whereas the remission was over in the nontreated group. In addition, plasma C-peptide levels were significantly higher in the treated group as compared with those not treated. CONCLUSIONS This study shows that the administration of Tregs is safe and tolerable in children with recent-onset type 1 diabetes.
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45
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Klarenbeek PL, de Hair MJH, Doorenspleet ME, van Schaik BDC, Esveldt REE, van de Sande MGH, Cantaert T, Gerlag DM, Baeten D, van Kampen AHC, Baas F, Tak PP, de Vries N. Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease. Ann Rheum Dis 2012; 71:1088-93. [PMID: 22294635 DOI: 10.1136/annrheumdis-2011-200612] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE To profile quantitatively the T-cell repertoire in multiple joints and peripheral blood of patients with recent onset (early) or established rheumatoid arthritis (RA) using a novel next-generation sequencing protocol to identify potential autoreactive clones. METHODS Synovium of patients with recent onset (early) RA (<6 months) (n=6) or established RA (>18 months) (n=6) was screened for T-cell clones by sequencing over 10 000 T-cell receptors (TCR) per sample. T cells from paired blood samples were analysed for comparison. From two patients synovial T cells were obtained from multiple inflamed joints. The degree of expansion of each individual clone was based on its unique CDR3 sequence frequency within a sample. Clones with a frequency of over 0.5% were considered to be highly expanded clones (HEC). RESULTS In early RA synovium, the T-cell repertoire was dominated by 35 HEC (median, range 2-70) accounting for 56% of the TCR sequenced. The clonal dominance in the synovium was patient specific and significantly greater than in established RA (median of 11 HEC (range 5-24) in established RA synovium accounting for 9.8% of T cells; p<0.01). 34% (range 28-40%) of the most expanded T-cell clones were shared between different joints in the same patients, compared with only 4% (range 0-8%) between synovium and blood (p=0.01). CONCLUSIONS In RA, a systemic autoimmune disease, the inflamed synovium forms a niche for specific expanded T-cell clones, especially in early disease. This suggests that, at least in RA, autoreactive T cells should be addressed specifically in the inflamed tissue, preferably in the early phase of the disease.
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Affiliation(s)
- P L Klarenbeek
- Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands
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Brooks-Worrell B, Palmer JP. Immunology in the Clinic Review Series; focus on metabolic diseases: development of islet autoimmune disease in type 2 diabetes patients: potential sequelae of chronic inflammation. Clin Exp Immunol 2012; 167:40-6. [PMID: 22132883 DOI: 10.1111/j.1365-2249.2011.04501.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Historically, the development of type 2 diabetes has been considered not to have an autoimmune component, in contrast to the autoimmune pathogenesis of type 1 diabetes. In this review we will discuss the accumulating data supporting the concept that islet autoreactivity and inflammation is present in type 2 diabetes pathogenesis, and the islet autoimmunity appears to be one of the factors associated with the progressive nature of the type 2 diabetes disease process.
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Affiliation(s)
- B Brooks-Worrell
- Department of Medicine, University of Washington, Seattle, WA, USA.
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47
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Li CR, Baaten BJG, Bradley LM. Harnessing memory adaptive regulatory T cells to control autoimmunity in type 1 diabetes. J Mol Cell Biol 2011; 4:38-47. [PMID: 22116888 DOI: 10.1093/jmcb/mjr040] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing β-cells in the pancreatic islets. There is an immediate need to restore both β-cell function and immune tolerance to control disease progression and ultimately cure T1D. Currently, there is no effective treatment strategy to restore glucose regulation in patients with T1D. FoxP3-expressing CD4(+) regulatory T cells (Tregs) are potential candidates to control autoimmunity because they play a central role in maintaining self-tolerance. However, deficiencies in either naturally occurring Tregs (nTregs) themselves and/or their ability to control pathogenic effector T cells have been associated with T1D. Here, we hypothesize that nTregs can be replaced by FoxP3(+) adaptive Tregs (aTregs), which are uniquely equipped to combat autoreactivity in T1D. Unlike nTregs, aTregs are stable and provide long-lived protection. In this review, we summarize the current understanding of aTregs and their potential for use as an immunological intervention to treat T1D.
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Affiliation(s)
- Cheng-Rui Li
- Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA
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48
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Brooks-Worrell B, Tree T, Mannering SI, Durinovic-Bello I, James E, Gottlieb P, Wong S, Zhou Z, Yang L, Cilio CM, Reichow J, Menart B, Rutter R, Schreiner R, Pham M, Petrich de Marquesini L, Lou O, Scotto M, Mallone R, Schloot NC. Comparison of cryopreservation methods on T-cell responses to islet and control antigens from type 1 diabetic patients and controls. Diabetes Metab Res Rev 2011; 27:737-45. [PMID: 22069253 DOI: 10.1002/dmrr.1245] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Type 1 diabetes (T1D) is a cell-mediated autoimmune disease characterized by destruction of the pancreatic islet cells. The use of cryopreserved cells is preferable to the use of freshly isolated cells to monitor clinical trials to decrease assay and laboratory variability. METHODS The T-Cell Workshop Committee of the Immunology of Diabetes Society compared two widely accepted T-cell freezing protocols (warm and cold) to freshly isolated peripheral blood mononuclear cells from patients with T1D and controls in terms of recovery, viability, cell subset composition, and performance in functional assays currently in use in T1D-related research. Nine laboratories participated in the study with four different functional assays included. RESULTS The cold freezing method yielded higher recovery and viability compared with the warm freezing method. Irrespective of freezing protocol, B cells and CD8+ T cells were enriched, monocyte fraction decreased, and islet antigen-reactive responses were lower in frozen versus fresh cells. However, these results need to take in to account that the overall response to islet autoantigens was low in some assays. CONCLUSIONS In the current study, none of the tested T-cell functional assays performed well using frozen samples. More research is required to identify a freezing method and a T-cell functional assay that will produce responses in patients with T1D comparable to responses using fresh peripheral blood mononuclear cells.
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Affiliation(s)
- B Brooks-Worrell
- University of Washington, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
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Brezar V, Carel JC, Boitard C, Mallone R. Beyond the hormone: insulin as an autoimmune target in type 1 diabetes. Endocr Rev 2011; 32:623-69. [PMID: 21700723 DOI: 10.1210/er.2011-0010] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Insulin is not only the hormone produced by pancreatic β-cells but also a key target antigen of the autoimmune islet destruction leading to type 1 diabetes. Despite cultural biases between the fields of endocrinology and immunology, these two facets should not be regarded separately, but rather harmonized in a unifying picture of diabetes pathogenesis. There is increasing evidence suggesting that metabolic factors (β-cell dysfunction, insulin resistance) and immunological components (inflammation and β-cell-directed adaptive immune responses) may synergize toward islet destruction, with insulin standing at the crossroad of these pathways. This concept further calls for a revision of the classical dichotomy between type 1 and type 2 diabetes because metabolic and immune mechanisms may both contribute to different extents to the development of different forms of diabetes. After providing a background on the mechanisms of β-cell autoimmunity, we will explain the role of insulin and its precursors as target antigens expressed not only by β-cells but also in the thymus. Available knowledge on the autoimmune antibody and T-cell responses against insulin will be summarized. A unifying scheme will be proposed to show how different aspects of insulin biology may lead to β-cell destruction and may be therapeutically exploited. We will argue about possible reasons why insulin remains the mainstay of metabolic control in type 1 diabetes but has so far failed to prevent or halt β-cell autoimmunity as an immune modulatory reagent.
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Affiliation(s)
- Vedran Brezar
- Institut National de la Santé et de la Recherche Médicale, Unité 986, DeAR Lab Avenir, Saint Vincent de Paul Hospital, and Paris Descartes University, 82 avenue Denfert Rochereau, 75674 Paris Cedex 14, France
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50
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Chee J, Angstetra E, Mariana L, Graham KL, Carrington EM, Bluethmann H, Santamaria P, Allison J, Kay TWH, Krishnamurthy B, Thomas HE. TNF receptor 1 deficiency increases regulatory T cell function in nonobese diabetic mice. THE JOURNAL OF IMMUNOLOGY 2011; 187:1702-12. [PMID: 21734073 DOI: 10.4049/jimmunol.1100511] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
TNF has been implicated in the pathogenesis of type 1 diabetes. When administered early in life, TNF accelerates and increases diabetes in NOD mice. However, when administered late, TNF decreases diabetes incidence and delays onset. TNFR1-deficient NOD mice were fully protected from diabetes and only showed mild peri-insulitis. To further dissect how TNFR1 deficiency affects type 1 diabetes, these mice were crossed to β cell-specific, highly diabetogenic TCR transgenic I-A(g7)-restricted NOD4.1 mice and Kd-restricted NOD8.3 mice. TNFR1-deficient NOD4.1 and NOD8.3 mice were protected from diabetes and had significantly less insulitis compared with wild type NOD4.1 and NOD8.3 controls. Diabetic NOD4.1 mice rejected TNFR1-deficient islet grafts as efficiently as control islets, confirming that TNFR1 signaling is not directly required for β cell destruction. Flow cytometric analysis showed a significant increase in the number of CD4(+)CD25(+)Foxp3(+) T regulatory cells in TNFR1-deficient mice. TNFR1-deficient T regulatory cells were functionally better at suppressing effector cells than were wild type T regulatory cells both in vitro and in vivo. This study suggests that blocking TNF signaling may be beneficial in increasing the function of T regulatory cells and suppression of type 1 diabetes.
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Affiliation(s)
- Jonathan Chee
- St. Vincent's Institute, Fitzroy, Victoria 3065, Australia
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