The NOD mouse is an animal model of insulin-dependent diabetes mellitus with striking similarities to human type I diabetes (42,43). Similarly to the human disease, the induction of diabetes in these mice is under polygenic control and involves at least three autosomal recessive genes located outside of chromosome 17 [location of the major histocompatibility complex (MHC)] and MHC-linked gene(s) responsible for the generation and activation of autoreactive T cells inherited in dominant fashion [44-46]). Although genetic predisposition appears to be an important prerequisite in the development of type I diabetes, it seems that certain environmental factors (viral or bacterial infections, chemicals, diet) are mainly responsible for inducing the initial lesions and/or precipitating the disease.
Of primary significance in the pathogenesis of type I diabetes is the progressive infiltration of islet cells of the pancreas by mononuclear cells (insulitis). The infiltration of islets encompasses several, stages. First (at about 5 weeks of age), the immune cells surround and invade islet vasculature, arteries, and venules (47). At approximately 6-7 weeks of age, lymphocytes begin to accumulate around the islet cells (nondestructive peri-insulitis) and then invade the islets, targeting insulin-secreting p cells (destructive intrainsulitis) at 8-13 week of age. Insulitis is observed in both sexes; however, in NOD mice, the incidence is higher in females (75% in our colony) than in males (25%).
The gradual destruction of insulin-secreting P cells and the consequent insulin deficiency gives rise to overt diabetes (at 20-35 weeks of age).
Several lines of evidence indicate that T cells play a critical role in the development of insulitis and diabetes. Characterization of their autoantigen targets has become essential in understanding specific p-cell destruction. Over the past years, several laboratories have isolated T-cell clones responding to islet cells (48,49). Islet-specific CD4+ T cells isolated from spleen and lymph nodes of diabetic NOD mice have been shown to recognize and destroy islet transplants when incorporated to the graft sites (48). In adoptive transfer studies, CD4+ T-cell clones derived from islet-infiltrating T cells were able to induce insulitis in diabetes-resistant NOD mice (50). However, both CD4+ and CD8+ T cells were required for transfer of the diseases (50). The studies on biopsies from human diabetic pancreas revealed that the specific destruction of p cells is carried out by CD8+ effector cells (51) which recognize islet cell antigens in the context of MHC class I molecules.
Some islet cell antigens, to which the T-cell and antibody immune responses are directed, have been identified recently (52-56). It appears (5-7) that mycobacterial hsp 60 is one of the putative antigens stimulating proliferation of diabetogenic CD4+ CD8+ T cells.
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