A number of observations have suggested that host lymphocytes, specifically cytotoxic T cells (CTL) play a significant role in mediating allogenic marrow graft rejection. In a murine model system, CTL were cloned from the spleens of sublethally irradiated animals which had rejected MHC disparate marrow grafts. It was found that cloned CTL were in fact sufficient to effect rejection of T cell depleted allogeneic marrow in lethally irradiated animals. The rejection of marrow grafts by CTL was specific for the MHC gene products expressed by the marrow cells & correlated with the cytotoxic specificity of the individual clones. Because host CTL in isolation could reject donor marrow grafts, the ability of cell populations which could suppress host CTL responses to regulate marrow engraftment was studied. Cells with a specific type of suppressor activity, termed veto cells, which might regulate host rejection responses & also mediate self tolerance, have been reported to be present in marrow, and an ability of IL-2 to enhance the activity of veto suppressor cell populations remaining in marrow after T cell depletion had been previously found. Such cells did enhance engraftment of MHC- mismatched, T cell depleted marrow in vivo. It was found that veto cells exerted their effect by clonal deletion of precursor CTL, & that such clonal elimination involved an active participation by precursor CTL. Specifically, triggering of veto cells was found to be mediated by target cell activation with release of perforin which was sufficient to trigger veto cells. These findings indicate a possible role for perforin in the maintenance of self tolerance. In other studies, the in vivo regulatory role of donor Th2 cytokine type cells was evaluated. Such cells were found to modulate transplantation responses in vivo with effects on cytokine profiles and cell populations, &corresponding protection from graft versus host disease. Conditions were defined for the in vitro propagation of antigen, specific, cytokine-defined Th cells which were found to be similarly regulate transplantation responses in vivo.
