Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes

Abstract

Insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice results from the T-lymphocyte-mediated destruction of the insulin-producing pancreatic beta-cells and serves as a model for human IDDM. Whereas a number of autoantibodies are associated with IDDM, it is unclear when and to what beta-cell antigens pathogenic T cells become activated during the disease process. We report here that a T-helper-1 (Th1) response to glutamate decarboxylase develops in NOD mice at the same time as the onset of insulitis. This response is initially limited to a confined region of glutamate decarboxylase, but later spreads intramolecularly to additional determinants. Subsequently, T-cell reactivity arises to other beta-cell antigens, consistent with intermolecular diversification of the response. Prevention of the spontaneous anti-glutamate decarboxylase response, by tolerization of glutamate decarboxylase-reactive T cells, blocks the development of T-cell autoimmunity to other beta-cell antigens, as well as insulitis and diabetes. Our data suggest that (1) glutamate decarboxylase is a key target antigen in the induction of murine IDDM; (2) autoimmunity to glutamate decarboxylase triggers T-cell responses to other beta-cell antigens, and (3) spontaneous autoimmune disease can be prevented by tolerization to the initiating target antigen.

Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase

“…We found that the production of IL-4 increased, whereas the production of IFN-γ decreased, indicating that the immunisation of NOD mice with rVV-GAD65 induced a Th2 immune response in an antigenspecific manner. Our finding is consistent with the results of previous reports on NOD mice treated with GAD protein systemically, nasally or orally [28,29,33,34,35] or vaccinated with GAD encoding plasmid DNA [41]. Th2 immune responses induced by rVV-GAD immunisation could play an important role in the prevention of autoimmune diabetes in this animal model.…”

“…In Type I diabetes, GAD and insulin have been identified as major autoantigens and tolerisation against these autoantigens has been attempted as a method for the prevention of the disease [14,32]. It has been reported that administration of purified GAD protein or peptide or insulin protein or peptide to NOD mice by a variety of routes can tolerise the T cell-mediated immune response against pancreatic beta cells, resulting in the prevention or delay of the development of insulitis and diabetes [28,29,33,34,35,36,37,38,39]. In many cases, the preventive effect was found to be associated with a Th2 shift [14,32].…”

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes

“…With the onset of periinsulitis, beta-cell-antigenspecific T cells become detectable [25,32,33]. These islet-specific T cells are of TH1 phenotype and show signs of activation [33,34].…”

“…These islet-specific T cells are of TH1 phenotype and show signs of activation [33,34]. Therefore, it seems that these T cells encounter their cognate antigen, get primed, expand clonally and acquire a TH1-phenotype as soon as periinsulitis develops.…”

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

“…Multiple immune-related genes involving different biological functions, from antigen processing and presentation to T cell activation, migration and apoptosis, have been suggested as candidates for these Idd loci [17]. Nevertheless, several studies reported abnormal APC function in NOD mice, which might be related to the known T cell dysfunction in this strain [18][19][20].We previously identified a region within GAD65, p524-543 (p543), to which spontaneous T cell responses arise in young NOD mice as early as 3-4 weeks of life [1]. Interestingly, this 20mer peptide appeared to be comprised of two distinct determinants: an N-terminal moiety (p524-538 (p524)) and a C-terminal moiety (p530-543 (p530)).…”