Allograft rejection remains a major problem in clinical transplantation. In the first year post transplantation, nearly 20% of first cadaver renal allografts and 35% of retransplant grafts are rejected irreversibly despite the use of cyclosporine. Moreover, approximately 50% of renal allograft recipients suffer an acute rejection episode in the early post transplantation period which threatens the long term function of the graft and mandates additional immunosuppressive therapy. This proposal will investigate strategies for achieving long term graft acceptance in an established subhuman primate model of renal transplantation. Much of the proposal will examine the utility of highly specific immunosuppressive agents directed against the interleukin 2 receptor. lt has been shown that anti-TAC, a monoclonal antibody with specificity for the human IL-2 receptor, will prolong the survival of renal allografts. Having thus demonstrated the value of the IL-2 receptor as a target for immunosuppressive therapy, additional agents directed against this target, including monoclonal antibodies, antibody-toxin conjugates, and lymphokine- toxin conjugates, will be examined in an effort to improve and extend these results.
The specific aims of this portion of the proposal are: 1) to investigate the efficacy of additional monoclonal antibodies directed against the interleukin-2 receptor in prolonging renal allografts; 2) to develop monoclonal antibodies with specificity for the high affinity IL-2 receptor; 3) to improve the efficacy of monoclonal antibody therapy by the use of antibody- toxin conjugates; 4) to determine the effects of an interleukin-2 diphtheria toxin conjugate on the immune responsiveness of the cynomolgus monkey; and 5) to assess methods for circumventing the host immune response to administered monoclonal antibodies.
Other specific aims will study the effects of Mab's defining subsets of T lymphocytes which induce help or suppression and of antibodies directed to varied epitopes of CD4. The experiments will be conducted in cynomolgus monkey recipients of renal allografts treated with one or a combination of the agents. In addition to graft survival, the impact of these agents on immune function and the host immune response to the therapy will be investigated. It is anticipated that these experiments will lead to the identification of agents which may be of value in clinical transplantation.
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