INDUCTION OF SPECIFIC IMMUNE TOLERANCE

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DESCRIPTION: (Adapted from the Investigator's abstract): The immune system is the major biological defense system responsible for fighting disease. However, immune responses can also be detrimental. In the case of transplantation, although the immune system reacts appropriately, it nevertheless causes harm by destroying the transplanted organs. In autoimmune diseases, the immune system turns against self and attacks otherwise normal tissue. In both situations, it is important to suspend the destructive function of the immune system while maintaining normal immune responses. Presently, in the clinical situation, a general immune suppression is induced, and the patients' defenses against infectious challenges are impaired. Strategies are now being sought that successfully induce specific non-responsiveness (tolerance) without affecting normal immune functions. Important cells of the immune system are T cells. They control many immune responses and also act as effector cells. Their suppression is crucial for the induction of tolerance. Only cells that react with a given organ, e.g. a transplant or a target of an autoimmune disease, should be removed. As different types of cells express tissue-specific antigens, complete tolerance towards a given tissue is best induced by the tissue itself. This should be true for transplant rejections and also autoimmune diseases. It has long been held that the disease mechanisms underlying autoimmune diseases mimic those seen in transplant rejection. Therefore, it should be possible to adapt strategies that induce specific transplantation tolerance to the treatment of autoimmune diseases. The so-called veto-effect (conventional veto) has been shown to efficiently and specifically tolerize T cells. It functions by expression of the co-receptor CD8 on stimulator cells. Based on this original observation, the approach has been expanded toward the development of hybrid antibodies (hAb) that combine a targeting antibody moiety with the functional region of the CD4 or CD9 accessory molecules. The cells coated with these hAbs inhibited the activation of either CD4+ or CD8+ activation in a highly specific fashion. In the current application, it is proposed to examine the function and activity of the CD8 targeting hAb in animal models of organ transplantation.