FACTORS CONTROLLING GRAFT HOST INTERACTIONS

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The objective of this project is 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. Amomg the major rationales for this project are 1) possible existence of a class of immunocompetent non-T cells capable of mediating this resistance via immunogeneticaly 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. A series of in vivo and in vitro studies are planned mainly taking advantage of an analysis of in vivo resistance and a new in vitro model of hemopoietic resistance. The in vitro model will serve for analysis of contact-dependent and independent, immunogenetically specific and nonspecific,k 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. In vivo studies examining the immunogenetic control of the cellular interactions between the effector cells and hemopoietic target cells are being completed with respect to the natural resistance involving the H-1D/Hh-1 locus. In vitro studies are being actively pursued in two areas; the identification of committed hemopoietic progenitors that are subjected to modulation by NK-like effector cells in vitro and further characterization of the effector cells themselves. We are also introducing two approaches that supplement the in vitro analysis, namely, analysis of the susceptibility in vivo of various types of hemopoietic colony forming cells (as detected in vitro) and the proliferative capacity in vivo of stem/progenitor cells that had been exposed in vitro to defined effector cell populations.