This program project on immunoregulation in human transplantation, interdisciplinary and interinstitutional, is designed to develop and apply new knowledge of the signals involved in blocking activation of effector T cells and in promotion of an active suppressor cell response. Project 1 will explore the nature of antigens recognized by alloactivated suppressor cells in man, and will utilize novel monoclonal antibodies which subdivide the CD4(T4) and CD8(T8) subsets to isolate the suppressor circuit for more detailed study. Unusual subsets, either doubly positive for CD4+CD8+, or bearing the gamma-delta T cell receptor (T3-Ti), have been identified in blood and kidney graft infiltrates, and they will be studied as potential regulatory cells. Project 2 will expand development of monoclonal antibodies to the T200 family of molecules to use in study of the signals transduced by these molecules to preferentially activate effector or suppressor cells, and will also develop sets of anti-CD4, anti-CD8, and anti-CD3 antibodies which either block, enhance, or have no effect on T cell activation. The molecular basis of these effects will be studied in detail. Project 3 will continue to establish the optimal conditions for in vivo immunosuppression using monoclonal anti-IL- 2 receptor antibodies in a cynomolgus primate model of renal allotransplantation, and will assess other strategies for targeting activated T cells via the de novo synthesized high affinity IL-2 receptor. New antibodies of specific interest from Project 2 will be utilized in the in vitro analysis of suppressor/modulator circuits in Project 1, and some will be selected for testing as immunosuppressive agents in the primate renal transplant model. Renal transplant recipients of the Brigham and Women's and Beth Israel Hospitals will participate in a variety of immuno- therapeutic trials. Selective study of their cellular responses will be performed in Project 1. A Clinical Core consists of the investigative staff caring for the patients and responsible for protocols. A Pathology Core provides immunopathologic study of renal material from patients and monkeys for analysis of cellular subsets and states of activation. The long-term goal is to develop new approaches to regulating the T cell dependent immune response based upon more precise knowledge of regulatory circuits.
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