Hybrid resistance to bone marrow cell (BMC) grafts in mice is mediated by natural killer (NK) cells which recognize Hemopoietic histocompatibility (Hh) antigens (Ag) on stem cells. The major Hh region, Hh-1, maps in the S/D interval centromeric of TNF of H-2. Hh-1 are not class I or II Ag, and NK cells do not rearrange Ig or T cell receptor genes. Thus, this is an opportunity to study a novel Ag-receptor interaction in the immune system. 1) BMC allografts often fail in patients with severe combined immune deficiency (SCID), devoid of T and B but not NK cell functions; 2) Allogeneic BMC depleted of T cells (T-) to prevent graft versus host disease often fail to engraft. 3) An assay for typing donors/hosts for clinical BMC transplants is needed. We have 4 specific aims. 1. Analyze subsets of NK cells which recognize Hh-1 Ag specifically. a) Transfer subpopulations of NK cells separated by flow cytometry, using newly developed anti-NK monoclonal antibodies (mab), to confer specific Hh-1 reactivity to irradiated mice. b) Generate and evaluate mab to receptors for Hh-1 Ag. Receptors will be identified by examining conjugates between NK cells and Hh-1 specific target cells by immunofluorescence. 2. Determine mechanisms by which T-BMC are sensitive to hybrid resistance and devise strategies to prevent rejection. SCID mice will be selectively repopulated with T cell subsets to identify the cell which prevents hybrid resistance to their BMC. 3. Characterize T and NK cells capable of inhibiting BMC graft rejection. T cells of radiation chimeras "tolerant" to Hh-1 Ag will be characterized, and the subsets of NK cells capable of inhibiting BMC graft rejection will be evaluated. 4. Develop an vitro assay for hybrid resistance. A step-wise approach will involve transfer of NK cells propagated in IL-2 into hosts; mixing these NK cells with BMC in vitro before transfer into hosts; finally using an in vitro assay for BMC viability or function.