This project is based on our discovery that stimulation of the antigen receptor of mature T cells following exposure of the cells to mitogenic lymphokines such as IL-2 leads to the induction of programmed cell death or apoptosis (propriocidal regulation). This process can lead to the deletion of specific antigen-reactive T cells without affecting bystander cells. We are interested in three aspects of this effect: 1) the molecular events that take place, 2) whether this mechanism can explain certain phenomenon of immunological """"""""suppression"""""""" that have been previously studied, and 3) the possibility of using this mechanism to pharmacologically induce the elimination of T cells involved in disease processes. Our results indicate that antigen-induced apoptosis can only occur at specific stages of the cell cycle. Further insights into the molecular mechanism of this effect may elucidate how CD+ T cells die in AIDS, which recent evidence has suggested occurs by programmed death. This may lead to therapeutics that block CD4+ cell loss in AIDS. Several types of diseases arise from the over-stimulation of the immune system including: allergies, autoimmune disorders such as multiple sclerosis, myasthenia gravis, insulin-dependent diabetes, and rheumatoid arthritis, and tissue graft rejection. Activated T cells are the driving force behind the destructive immune responses in these diseases. Current therapies involve drugs such as steroids and cyclosporin A that impair, in a general way, T lymphocyte function and thus increase susceptibility to infections. We have discovered that the cytokine IL-2 causes T cells to die if they are subsequently stimulated through their antigen receptor. This previously unknown property of IL-2 should allow the specific elimination of certain receptor-bearing T cells which could form the basis for new clinical applications of IL-2. Our results thus far indicate that mature T cell deletion by the propriocidal mechanism can be useful for ameliorating disease in mouse models for multiple sclerosis and autoimmune eye disease. Other disease models are currently under investigation. This method for treatment of T cell mediated diseases should avoid the severe immunosuppression which is a side-effect of current therapies.
