Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice.

Li, Wen; Wong, F. Susan; Burkly, Linda C.; Altieri, Martha; Mamalaki, Clio; Kioussis, Dimitris; Flavell, R.A.; Sherwin, Robert S.

doi:10.1172/jci2723

Cited by 53 publications

(57 citation statements)

References 61 publications

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“…The DQ8 transgenic line described here was created directly in the NOD background. Descriptions of at least two other DQ8 transgenic, IAb knockout mouse lines (and their derivatives) have been published by David and colleagues (19)(20)(21) and Wen and colleagues (22)(23)(24); those lines have been used to investigate a number of autoimmune models, particularly type 1 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Elliott

Liu

Yuan

et al. 2003

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

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A line of nonobese diabetic (NOD) mice expressing the human diabetes-associated HLA-DQ8 transgene in the absence of mouse IA␤ failed to show spontaneous insulitis or diabetes, but rather developed dilated cardiomyopathy, leading to early death from heart failure. Pathology in these animals results from an organ-and cell-specific autoimmune response against normal cardiomyoctes in the atrial and ventricular walls, as well as against very similar myocytes present in the outermost muscle layer surrounding the pulmonary veins. Progression of the autoimmune process could be followed by serial ECG measurements; irradiation of young animals significantly delayed disease progression, and this effect could be reversed by adoptive transfer of splenocytes taken from older animals with complete heart block. Disease progression could also be blocked by cyclosporin A treatment, but was accelerated by injection of complete Fruend's adjuvant. The constellation of findings of spontaneously arising destructive focal lymphocytic infiltrates within the myocardium, rising titers of circulating anticardiac autoantibodies, dilation of the cardiac chambers, and gradual progression to end-stage heart failure bears a striking resemblance to what is seen in humans with idiopathic dilated cardiomyopathy, a serious and often life-threatening medical condition. This transgenic strain provides a highly relevant animal model for human autoimmune myocarditis and postinflammatory dilated cardiomyopathy.I diopathic dilated cardiomyopathy (IDCM) describes a condition whereby previously healthy individuals develop lifethreatening heart failure associated with enlargement of the heart, but with no apparent underlying cause (1, 2). The cardiac pathology seen in the majority of IDCM patients indicates a recent or more long-standing immune-mediated inflammatory process within the muscle tissue of the heart (i.e., myocarditis) (3,4). IDCM patients often demonstrate circulating anticardiac autoantibodies, and the myocarditis is generally thought to arise from an autoimmune response against cardiac tissues (5). Research on IDCM has been hampered by the lack of an appropriate animal model, that is, a model where animals develop disease spontaneously, show severe life-threatening pathology, and display an immunological and histological picture similar to that seen in humans with IDCM.The human MHC class II molecule DQ8 (i.e., haplotype DQA1*0301, DQB1*0302) is known to be associated with type 1 diabetes (T1D). To map DQ8-restricted T cell epitopes for T1D autoantigens we crossed DQ8 transgenic nonobese diabetic (NOD) mice with a NOD MHC class II ␤-chain knockout line (6). Because the resulting animals express the human MHC class II molecule but not the mouse, any CD4 ϩ T cells arising would be restricted to the human MHC molecule. We chose the NOD strain because it is known to have defects in self-tolerance, which we hypothesized would aid our efforts to induce immune responses against self-antigens such as GAD65. Although replacement of the murine T1D-asso...

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Section: Discussionmentioning

confidence: 99%

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Elliott

Liu

Yuan

et al. 2003

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

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“…Adoptive transfer of disease with GAD Recipients needed pretreatment with [58] 247-266 and 509-528 specific lines streptozotocin to generate islet insult HLA-DQB1*0302…”

Section: Gad65mentioning

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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“…It has, however, been shown that sufficient CD4 T cells can be selected in the thymus without human CD4, although the numbers may be lower than in in conventional mice. These T cells selected on human HLA molecules are functional in the presence of mouse CD4 and in the absence of human CD4 molecules [57,58,59,60]. Altmann and co-workers [61] directly compared immune responses in HLA transgenic mice with or without a human CD4 transgene and found that the immune responses were not significantly different in these mice.…”

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

confidence: 99%

“…It is therefore not surprising that the HLA transgenic animals that have been studied either in the presence or absence of endogenous mouse MHC class II do not spontaneously develop the HLA-associated diseases [58,60]. This is also true when the HLA transgene is expressed on the NOD background [62] in the absence of the predisposing I-A g7 .…”

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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Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice.

Abstract: Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA10301/ DQB10302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8

Cited by 53 publications

References 61 publications

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Transgenic models of autoimmune disease

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

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Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice.

Abstract: Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA1*0301/ DQB1*0302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8

Cited by 53 publications

References 61 publications

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Transgenic models of autoimmune disease

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

Contact Info

Product

Resources

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Abstract: Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA10301/ DQB10302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8