Immune responses induced by alloantigenic differences include induction of lymphokine secretion from alloreactive T cells and activation of antigen specific cytotoxic T cells. In both in vitro and in vivo models of alloresponsiveness, it has been demonstrated that CD4/L3T4 (+) T cells produce lymphokines, proliferate and give rise to allospecific cytotoxic T cells (CTL) in response to class II major histocompatibility (MHC) antigens whereas responses to class I MHC differences are similarly mediated by CD8/Lyt2 (+) T cells. Because of the difficulty in separating helper cells from cytotoxic effector cells within these two T cell subsets, it has been difficult to delineate clearly the specific functional activities of T cells which are essential for evolution of various in vivo aspects of alloantigen-induced phenomena. A series of investigations in the applicant's laboratory has described the selective effects of L-leucyl-L-leucine methyl ester (Leu- Leu-OMe) on human and murine cytotoxic cells. Specifically, after brief incubation with this agent, NK cells and both CD4/L3T4 (+) and CD8/Lyt2 (+) CTL or pre-CTL are killed whereas helper T cells, B cells, or murine bone marrow stem cells remain viable and functionally intact. Furthermore, in a murine model of bone marrow transplantation across full MHC barriers, treatment of donor cells with this agent has been shown to prevent development of lethal GVHD. The proposed studies will examine the role of cytotoxic cells in the evolution of graft versus host disease and the mechanism whereby initial elimination of such cells by Leu-Leu-OMe treatment modulates the course of alloantigen-induced immune responses in this syndrome or in models of allograft rejection. The effect of cytotoxic cell delineation on the induction of allospecific immunologic tolerance will be examined. In addition, protocols for in vivo administration of Leu-Leu-OMe will be developed and this approach will be used to examine the ability of this agent to modulate GVHD or allograft rejection at various time points during the evolution of these immune responses. It is anticipated that new insights into the role of cytotoxic cells in the mediation of alloimmune responses will be obtained and information provided regarding new strategies for preventing GVHD or allograft rejection in man.
