Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease

Geng, Liping; Solimena, Michele; Flavell, Richard A.; Sherwin, Robert S.; Hayday, Adrian

doi:10.1073/pnas.95.17.10055

Cited by 48 publications

(40 citation statements)

References 81 publications

(78 reference statements)

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“…For example, various treatments with GAD protein, peptide or DNA by various routes of administration were shown to inhibit disease, and antisense GAD, expressed only in pancreatic islets, protected mice from diabetes (9, 10, 21, 29 -31, 33). Nonetheless, the incidence of diabetes was unchanged in GAD knockout mice (57), and expressing GAD as a transgene was not protective (in some lines disease was actually accelerated) (58). Recently, von Boehmer and colleagues (59) clearly demonstrated normal diabetes incidence in GAD Tg mice, despite complete tolerance to GAD.…”

Section: Discussionmentioning

confidence: 99%

Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer

Arnold

Burton

Vignali

2004

The Journal of Immunology

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TCR transgenic mice are valuable tools for dissecting the role of autoantigen-specific T cells in the pathogenesis of type 1 diabetes but are time-consuming to generate and backcross onto congenic strains. To circumvent these limitations, we developed a new approach to rapidly generate mice expressing TCR using retroviral-mediated stem cell gene transfer and a novel picornavirus-like 2A peptide to link the TCR α- and β-chains in a single retroviral vector. We refer to these as retrogenic (Rg) mice to avoid confusion with conventional transgenic mice. Our approach was validated by demonstrating that Rg nonobese diabetic (NOD)-scid mice expressing the diabetogenic TCRs, BDC2.5 and 4.1, generate clonotype-positive T cells and develop diabetes. We then expressed three TCR specific for either glutamate decarboxylase (GAD) 206–220 or GAD 524–538 or for hen egg lysozyme 11–25 as a control in NOD, NOD-scid, and B6.H2g7 mice. Although T cells from these TCR Rg mice responded to their respective Ag in vitro, the GAD-specific T cells exhibited a naive, resting phenotype in vivo. However, T cells from Rg mice challenged with Ag in vivo became activated and developed into memory cells. Neither of the GAD-reactive TCR accelerated or protected mice from diabetes, nor did activated T cells transfer or protect against diabetes in NOD-scid recipients, suggesting that GAD may not be a primary target for diabetogenic T cells. Generation of autoantigen-specific TCR Rg mice represents a powerful approach for the analysis of a wide variety of autoantigens.

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Section: Discussionmentioning

confidence: 99%

Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer

Arnold

Burton

Vignali

2004

The Journal of Immunology

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“…Apparently, some of these T cells are driven so early toward the Th1 phenotype that these proinflammatory responses cannot be prevented by neonatal immunotherapy. Indeed, even the widespread expression of a GAD transgene early in the development of NOD mice does not prevent the spontaneous development of GAD autoimmunity (52).…”

Section: Discussionmentioning

confidence: 99%

Antigen-Based Immunotherapy Drives the Precocious Development of Autoimmunity

Tian

Olcott

Kaufman

2002

The Journal of Immunology

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During the development of type I diabetes mellitus in nonobese diabetic (NOD) mice, T cell autoimmunity gradually spreads among β cell Ags. Little is known about how autoantigen-based immunotherapies affect this spreading hierarchy. We treated newborn NOD mice with different autoantigenic β cell peptides (in adjuvant) and characterized their T cell responses at 4 wk of age, when autoimmunity is usually just beginning to arise to a few β cell Ag determinants. Surprisingly, we found that regardless of whether an early, or late target determinant was administered, autoimmunity had already arisen to all tested β cell autoantigen determinants, far in advance of when autoimmunity would have naturally arisen to these determinants. Thus, rather than limiting the loss of self-tolerance, immunotherapy caused the natural spreading hierarchy to be bypassed and autoreactivities to develop precociously. Evidently, young NOD mice have a broad array of β cell-reactive T cells whose activation/expansion can occur rapidly after treatment with a single β cell autoantigen. Notably, the precocious autoreactivities were Th2 type, with the exception that a burst of precocious Th1 responses was also induced to the injected autoantigen and there were always some Th1 responses to glutamic acid decarboxylase. Similarly treated type 1 diabetes mellitus-resistant mouse strains developed Th2 responses only to the injected Ag. Thus, autoantigen administration can induce a cascade of autoimmune responses in healthy (preautoimmune) mice that are merely genetically susceptible to spontaneous autoimmune disease. Such phenomena have not been observed in experimental autoimmune disease models and may have important clinical implications.

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“…Our results are consistent with the observation that robust T cell responses to crude islet preparations are detectable at early time points where only weak responses are found against the known autoantigens (21, 22). Recently, experiments with NOD mice engineered to express GAD65 ubiquitously have shown that such mice are not protected from diabetes, nor do they develop evidence of widespread autoimmunity distinct from that observed in NOD (62). Likewise, GAD65-deficient mice bred onto the NOD background are not protected from autoimmune disease (63).…”

Section: Identity Of Early Autoantigens and Role Of Early Islet-infilmentioning

confidence: 99%

Restricted islet-cell reactive T cell repertoire of early pancreatic islet infiltrates in NOD mice

Baker

Lee

Chien

et al. 2002

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

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The mechanisms responsible for initiating autoimmune diabetes remain obscure. Here, we describe a method for identifying both the ␣-and ␤-chains of the T cell receptor (TCR) from individual pancreatic islet-infiltrating T cells at the earliest stages of disease in nonobese diabetic mice (NOD). Analysis of the TCR repertoire of these early islet infiltrates reveals enrichment for a small subset of TCR sequences. Reconstitution of these TCR in vitro demonstrates that these receptors confer reactivity to islet cells but not to the well characterized autoantigens, glutamic acid decarboxylase (GAD65) and insulin. Thus, autoimmune diabetes in NOD may be initiated by a limited number of antigens distinct from GAD65 and insulin.

show abstract

Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease

Cited by 48 publications

References 81 publications

Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer

Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer

Antigen-Based Immunotherapy Drives the Precocious Development of Autoimmunity

Restricted islet-cell reactive T cell repertoire of early pancreatic islet infiltrates in NOD mice

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