IMMUNOBIOLOGY OF HYBRID RESISTANCE

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Bone marrow cell (BMC) transplantation is a successful treatment modality for leukemia, aplastic anemia, severe combined immunodeficiency (SCID), and even some solid tissue tumors. Transfer of allogeneic BMC presents 3 major complications: failure to engraft or rejection, graft-versus-host disease (GVHD) and recurrence of disease. Depletion of T cells from the marrow prevents serious GVHD often, but increases the likelihood for rejection and recurrence of disease, e.g. leukemia. T cell depleted (TCD) BMC would be the choice if one could prevent rejection and leukemia recurrence, since GVHD would be ameliorated. The purpose of this proposal is to analyze those host effector cells which prevent engraftment, and to develop strategies to allow engraftment of TCD BMC in a murine model. Host NK cells recognize 'recessively inherited' Hemopoietic histocompatibility (Hh-1) antigens on stem cells, the basis of Fl hybrid resistance to BMC grafts. Host CD8+ T cells recognize class I antigens on donor stem cells. Specific Aims: 1. Characterize NK cells which recognize specific Hh-1 antigens specifically. Clone the genes for the NK markers 5E6 and 1OA7 associated with the specific rejection of BMC expressing Hh-1 determinants 2 and 5, respectively. Produce transgenic mice to test the idea that 5E6 and/or 1OA7 are specific NK receptors. 2. Analyze the mechanisms by which TCD BMC are more sensitive to rejection and develop strategies to allow growth without causing GVHD. Test the ideas i) myeloid stem cells are rejected by NK cells or by newly sensitized T cells; ii) donor T cells inhibit host effectors; and iii) host T cells reject those donor T cells. Characterize marrow T cell after separation from stem cells by counter current elutriation, a technique used clinically to prevent GVHD. Determine the nature of the host T cell that rejects donor T cells by cell transfer studies involving T cell-deprived SCID host mice. 3. Develop an in vitro assay for BMC rejection to allow better evaluation of these immune cell interactions. This work may provide data relevant to clinical BMC transplantation.