FACTORS CONTROLLING GRAFT HOST INTERACTIONS

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It is the long-term objective of this research project to elucidate the immunogenetic, cellular, and ultimately molecular, mechanisms underlying the natural host resistance to the proliferation of foreign, parental, and possibly syngeneic or autologous, grafts of hemopoietic stem and progenitor cells. Among the major rationales for this project are 1) possible existence of a class of immunocompetent non T cells capable of mediating this resistance via immunogenetically specific recognition of cell surface antigens controlled by hemopoietic histocompatibility (Hh) genes, 2) possible relevance of the resistance as a manifestation of cellular interactions regulating or maintaining normal hemopoiesis, and 3) possible role of such resistance in clinical bone marrow transplantation. In the present proposal, a series of in vivo and in vitro studies are planned, mainly taking advantage of a newly developed competitive inhibition analysis of in vivo resistance and a new in vitro model of hemopoietic resistance. The in vitro model, though its properties are stil imcompletely understood, will serve for analysis of contact-dependent and independent, immunogenetically specific and nonspecific, stimulatory and suppressive, cellular interactions between natural killer (NK) cell-like splenic effector cells and primitive hemopoietic progenitor cells of bone marrow origin. Analysis in vivo of the genetics of effector-target cell interactions will be applied to selected Hh-incompatible allogeneic and semisyngeneic (F1 hybrid-parental) host-graft donor combinations. Functional analysis in vitro of effector-target bone marrow cell interactions will focus on specific and nonspecific regulatory influences on erythroid and myeloid progenitors and relevance of such cellular interactions in normal hemopoiesis. Further studies in vitro will characterize the effector cells in relation to NK cells, and will analyze genetic and other mechanisms that modulate effector activities.