IMMUNE MECHANISMS IN ORGAN ALLOGRAFT REJECTION

Abstract

Sublethally irradiated (780 rad) rats receiving fully allogeneic heart transplants were reconstituted with sensitized lymphocytes fractionated into helper and cytotoxic/suppressor T cell subsets according to reactivity with monoclonal antibodies W3/25 and OX8, and the phenotype and functional activity of cells causing rejection was examined. Though the adoptive transfer of T cells of either subset in adequate numbers (0.5 .times. 106) was able to cause rejection, helper T cells were significantly (P < 0.02) more potent on a per-cell basis. The reconstituting inocula in this model system acted not simply to amplify a specific immune response by the irradiated host. Cytotoxic T cells appearing in sublethally irradiated heart graft recipients reconstituted with unfractionated T cells were shown to derive from the reconstituting inoculum. Cells with cytotoxic activity for donor-strain thymic blasts were undetectable in spleen or graft of recipients reconstituted with isolated T helper cells (OX8-), but were present in grafts of a high proportion of rats reconstituted with OX8+ cells. T cells within the helper subset (W3/25+ OX8-) were shown to be responsible for adoptive transfer of delayedtype hypersensitivity (DTH) and were phenotypically distinct from cytotoxic cells and their precursors (W3/25- OX8+). Heart graft rejection appears, to be mediated independently by lymphocyte subsets responsible exclusively for DTH or lymphocytotoxicity. Support for this observation was obtained by demonstrating prominent nonspecific recruitment of lymphocytes and monocytes in graft rejection, and frequent direct anatomic contact between infiltrating mononuclear cells and myofibers. Substantial evidence for a primary role for DTH in vascularized organ allograft rejection is provided. At the same time, cytotoxic T cells may play an independent pathogenic role. pathogenic role.