This proposal focuses upon understanding the functions of antigen activated populations of host leukocytes, their products and their interrelationships which are mobilized in response to a vascularized organ allograft; these responses include both the events of acute rejection of cardiac grafts in untreated histoincompatible rat recipients and those responsible for prolonged survival in immunologically modified hosts. The role of activated leukocytes developing receptors for interleukin 2 (IL2R+ cells) in rejection will be emphasized, and their modulation by various IL2R targeted therapies assessed, a novel approach to specific immunosuppression. In particular, these therapies will be used as probes to determine function and kinetics of IL2R+ cells infiltrating the graft and occurring in host peripheral lymphoid tissues, the influence of these cells on other populations and their effect on cytokine production. For comparison, IL2R+ cells will be investigated in other states of host unresponsiveness, including animals treated with cyclosporine (CsA), or in immunological enhancement. The differential functions, interactions and migrational properties of T helper (Th,CD4) and T cytotoxic/suppressor (Tc/s,CD8) phenotypes will be defined serially; specifically, the putative sparing effect of IL2R directed therapies on cells with suppressor activity will be examined. Isolated IL2R+ macrophages, an important component of the IL2R+ infiltrate, will be cultured then stimulated with cytokines or down regulated with CsA. Function of these regulated cells will then be assessed in vivo by transfer studies. Dendritic cells will be studied as inducers of immune responsiveness in the context of transplantation, with emphasis on their role in activating resting T lymphocytes to develop IL2R, as well as their migration patterns. The differential production and function of cytokines will be investigated in anti-IL2R treated recipients, stressing their effects on lymphocyte subpopulations in vivo. Taken together, these studies should delineate the role of antigen activated IL2R+ leukocytes in host responsiveness toward vascularized organ allografts. Their modulation by specific therapies may be critical in clinical transplantation.
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