Despite significant improvement in early post-transplant survival rates, the pressing need for continuing refinement of clinical immunosuppressive protocols is emphasized by the morbidity and annual attrition rate of 3-5% still observed in chronically treated allograft recipients. The objective of this project is to evaluate systematically the mechanisms of immune modulation induced by monoclonal antibodies (mAbs) or cytokine antagonists and to provide a final pre-clinical proving ground for new protocols employing these agents. To date, most Mabs have been added to clinical protocols on an empirical basis. In view of the large numbers of these agents now available, it is essential that a systematic pre-clinical approach to their evaluation be continued. The immediate goal of this project is to refine chronically administered regimens so that effective, yet selective, depression of the immune response is provided. Instrinsic to this goal is a more thorough clarification of the roles that various mononuclear cell populations play in either the rejection or the "down regulation" response to an allograft and the importance of factors, such as cell subset reactivity or cell clearing efficacy, which are most important in determining the immunosuppressive activity of mAbs. With this approach, it should be possible to identify the most appropriate targets for new, highly selective clinical protocols which employ "novel" mAbs such as chimeric mouse-human molecules or bi- specific antibodies chosen for their reactivity only with "activated" or other cell subsets. These studies are planned with the expectation that they will lead to the ultimate goal of providing long-term donor- specific unresponsiveness which can be induced by only a limited course of treatment in the peri-transplant period.