Glutamic acid decarboxylase T lymphocyte responses associated with susceptibility or resistance to type I diabetes: analysis in disease discordant human twins, non-obese diabetic mice and HLA-DQ transgenic mice.

Boyton, Rosemary J.; Lohmann, Tobias; Londei, Marco; Kalbacher, Hubert; Halder, Thomas; Frater, A J; Douek, Daniel C.; Leslie, D G; Flavell, R.A.; Altmann, Daniel M.

doi:10.1093/intimm/10.12.1765

Cited by 38 publications

(22 citation statements)

References 48 publications

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“…The amount of IL-10 produced by G206 T cells was Ϸ200 pg͞ml, much lower than that produced by Th2 cells (28, 29). The concomitant production of low-level IFN-␥ and IL-10 was also observed with G286 T cells (18) and in other systems, including the GAD65 epitope p521-535-specific T cell response in NOD mice (30)(31)(32). These studies have not yet resolved whether IFN-␥ and IL-10 are produced by the same T cells or by different subsets of T cells of the same antigen specificity.…”

Section: Antigen-specific Proliferation and Cytokine Production By G2mentioning

confidence: 97%

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Kim

Tarbell

Sanna

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Glutamic acid decarboxylase (GAD) 65 is one of the major pancreatic antigens targeted by self-reactive T cells in type I diabetes mellitus. T cells specific for GAD65 are among the first to enter inflamed islets and may be important for the initiation of autoimmune diabetes. However, we previously reported that nonobese diabetic (NOD) mice transgenic for a T cell antigen receptor (TCR) specific for one of the immunodominant epitopes of GAD65, peptide 286-300 (G286), are protected from insulitis and diabetes. To examine whether other GAD65-reactive T cells share this phenotype, we have generated TCR transgenic NOD mice for a second immunodominant epitope of GAD65, peptide 206-220 (G206). As in G286 mice, G206 mice do not develop islet inflammation or diabetes. When adoptively transferred along with diabetogenic T cells, activated G206 T cells significantly delayed the onset of diabetes in NOD.scid recipients. Both G206 and G286 T cells produce immunoregulatory cytokines IFN-␥ and IL-10 at low levels when activated by cognate antigens. These data suggest that GAD65-specific T cells may play a protective role in diabetes pathogenesis by regulating pathogenic T cell responses. A better understanding of the functions of autoreactive T cells in type I diabetes will be necessary for choosing desirable targets for immunotherapy.T ype I diabetes mellitus in humans is an autoimmune disease that results from the selective destruction of pancreatic ␤-cells by T cells (1, 2). The nonobese diabetic (NOD) mouse develops spontaneous autoimmune diabetes that shares many characteristics with the human disease (1, 3, 4). The principal islet cell antigens targeted by autoreactive T cells in NOD mice include insulin (5), glutamic acid decarboxylase 65 (GAD65) (6), 65-kDa heat shock protein (7), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (8). Among these, T cell responses to GAD65 and insulin are detected early preceding the onset of clinical disease (3-5 weeks of age in the NOD mouse) (9-11). This result has led to the speculation that GAD65 may be among the first autoantigens targeted by T cells that initiate the diabetes pathogenesis.The hypothesis for a pathogenic role of GAD65 is supported by a GAD65-specific T cell clone that induces insulitis and diabetes upon adoptive transfer (12) and by the finding that prevention of GAD65 expression in the pancreatic islets by GAD antisense cDNA prevented diabetes (13). In contrast, induction of deletional T cell tolerance by widespread expression of a GAD65 transgene did not alter diabetes pathogenesis (14) but exacerbated the disease (15). In addition, several GAD65-specific T cell clones, lines, and T cell antigen receptor (TCR) transgenic mice were not pathogenic and exhibited a diabetesdelaying capacity (16-18). Thus, it appears that GAD65 may not be a required initiating antigen for diabetes pathogenesis but rather induces a protective response.To further examine the functions of GAD65-reactive T cells in the pathogenesis of diabetes, we have ge...

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Section: Antigen-specific Proliferation and Cytokine Production By G2mentioning

confidence: 97%

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Kim

Tarbell

Sanna

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Comparisons on susceptible and non susceptible [47] with susceptibility mice and affected and unaffected twins.…”

Section: Gad65 6 Immunodominant Epitopes Identifiedmentioning

confidence: 99%

Transgenic models of autoimmune disease

Boyton¹,

Altmann

2002

Clinical and Experimental Immunology

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SUMMARY Transgenic and knockout mouse models have been invaluable for the elucidation of basic mechanisms in autoimmunity and have contributed new experimental models of human autoimmune diseases. Transgenic models of self tolerance have helped to change our view of this state from a process mediated purely by thymic deletion to a more complex process encompassing deletion, peripheral anergy, down‐regulation of receptors and modulation by regulatory cells. Experiments in which the genes for the candidate target antigens in autoimmune disease are over‐expressed or under‐expressed have helped to clarify the targets of attack. Several examples of T cell receptor transgenic mice have been described in which T cells carry the receptor derived from a human or mouse autoimmune T cell clone. Such mice allow the characterization of T cell specificities contributing to disease and of the additional factors and checkpoints influencing disease development. In addition, the expression of disease associated HLA alleles in ‘humanised’ transgenic lines allows the mapping of HLA‐restricted T cell epitopes and investigation of the mechanisms underlying these genetic associations. These approaches are leading to the generation of new disease models, offering hope for the design and testing of novel immunotherapeutic strategies.

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“…These mice can generate efficient islet autoantigen-specific immune responses after immunisation with GAD and proinsulin, or peptides derived from these molecules. This has facilitated mapping of the peptide epitopes of GAD65 for HLA DR4 [64,65], HLA DQ8 [62,66,67] and HLA DR3 [68,69]. Although different studies do not necessarily identify the same epitopes, it is important to note that the genetic background (whether NOD or B6, B10) may also play a role in the outcome of immune responses [69,70].…”

Section: Do Hla Class II Transgenic Mice Develop Autoimmune Diabetes?mentioning

confidence: 99%

What can the HLA transgenic mouse tell us about autoimmune diabetes?

Wong

2004

Diabetologia

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Type 1 diabetes mellitus is a polygenic disease strongly associated with the class II molecules DR3, 4 and the linked DQ2, 8 alleles. These molecules play an important role in presentation of peptide antigens after intracellular processing to CD4 T lymphocytes. A number of in vitro approaches have been used to elucidate the molecular basis for the association of particular HLA alleles with susceptibility to or protection from Type 1 diabetes mellitus. These have focused on the structure of the antigen-presenting molecules, together with their peptides. Binding studies, peptide elution, molecular modelling and crystallisation of the peptide MHC complex have between them made it possible to define the peptide-binding regions and to examine the stability of binding of peptides from putative autoantigens. It is difficult to study the role of these molecules in vivo in humans, and HLA transgenic mice have been generated to overcome this problem. Studies of mice expressing the HLA class II alleles associated with diabetes have shown that the presence of HLA molecules alone does not cause disease except in the presence of an islet "insult", even when this "insult" would in itself be insufficient to precipitate disease in the absence of the HLA class II transgene. HLA transgenic mice offer a way to elucidate the in vivo role of these molecules, and could help the development of targeted immunotherapy.

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Glutamic acid decarboxylase T lymphocyte responses associated with susceptibility or resistance to type I diabetes: analysis in disease discordant human twins, non-obese diabetic mice and HLA-DQ transgenic mice.

Cited by 38 publications

References 48 publications

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Transgenic models of autoimmune disease

What can the HLA transgenic mouse tell us about autoimmune diabetes?

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