The genetic program of the human T cell is a complex one which includes both immunoregulation as well as the capacity to recognize specific antigens and execute unique effector programs. One of the consequences of T cell recognition by allo-MHC is the generation of both specific cytotoxic T lymphocytes and inflammatory responses high can result in graft rejection. T cell activation and proliferation are initiated through interactions of the T cell receptor complex with accessory cells crosslinking the TCR with the natural ligand, for example, allo-MHC or mimicked by antibodies directed at the TCR or its noncovalently associated T3 molecules. Crosslinking of the TCR is markably enhanced by the associative recognition structures, T4 and T8. Under physiologic conditions, a quaternary structure involving T3/TCR, T4, T8 and class I and class II MHC structures is generated which leads to T cell activation and the associated MHC restrictions. T cell help results from the activation of the T4+4B4+ network and suppression by the activation of the T4+2H4+ network. Some antibodies directed at the T4, T8 and T3 structures have been shown to be immunosuppressive. The mechanism by which anti-T cell antibodies result in suppression is of major importance for the treatment of patients undergoing renal graft rejection. Antibodies used therapeutically have been selected for their ability to facilitate target cell depletion rather than their """"""""independent immunosuppressive effects"""""""". The purpose of this proposal to generate antibodies with therapeutic ability whose major virtue is their capacity to either modulate the host immune response or prevent activation of the cellular immune response. We plan to develop antibodies which can block the association of the T3/TCR complex and relevant accessory molecules such as T4, T8, and Tll. Since this association represents a potent branch point for T cell activation, we believe that blocking this interaction should facilitate the abrogation of T cell mediated renal graft rejection. In addition, we will prepare new antibodies capable of directly enhancing the induction of suppression or by the blocking of the induction of help. The helper circuit is necessary for the activation of an antibody production and the generation of cytotoxic T cells. Lastly, we will develop antibodies specific for cytotoxic effector T cells which spare the suppressor pathway.
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