DECREASED IL-2 SYNTHESIS IN TYPE I DIABETES

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The immune system is designed to recognize foreign invaders and to eliminate them from the body. Upon occasion, however, this mechanism can turn against itself and initiate and attack against shelf components leading to an autoimmune disease. Insulin dependent diabetes (IDD) is one autoimmune disease directed against the insulin producing beta cells. The working hypothesis of this study is that the abnormality in IL-2 levels may lead to aberrant effector responses mediated by T cells. the long-term goal of this proposal is to increase knowledge of the immunological abnormalities associated with IDD by defining the mechanism(s) underlying one of them, the deficiency in Interleukin-2 (IL-2) synthesis observed in IDDs. This phenomenon was first reported by us and has subsequently been confirmed by other investigators. It is one of few immunological defects affecting T cell function on a non-clonal level. In this resubmission, we will include non-diabetic, HLA-identical sibs of our patients in the research plan, in order to study whether any of the abnormalities associated with this defect may precede the onset of frank disease. The primary aim of the study is to test the hypothesis that IL-2 defect is regulated at the level of the expression of the IL-2 gene. In addition, we will examine whether signalling independent of the T cell receptor results in normal IL-2 synthesis and whether there are inhibitory lymphokines which prevent the IL-2 from stimulating T cell growth. The work described, largely based upon techniques of molecular biology, will build upon our earlier studies which used exclusively cellular techniques. Recent data have shown that Cyclosporin A can induce remission in newly diagnosed IDDs. The demonstration that the autoimmune process can be interrupted makes an understanding of the pathogenesis of IDD all the more important, since it may suggest additional therapeutic modalities. The elucidation of the IL-2 defect may lead to the development of such approaches, by precisely defining the level of control resulting in abnormalities of the cell medited immune system.