Resistance to hematopoietic progenitor cell allografts is problematic, even after HLA-matched allogeneic BMT. The use of T cell depleted inoculum and the continuing efforts to diminish chemo / radiation preparative regimens to reduce post-BMT immunosuppression will increase the need to better understand the `barrier response' to engraftment. In the proposed studies, the cellular and effector pathways underlying resistance to engraftment following allogeneic BMT will be investigated using a model of MHC matched, minor H antigen (MiHA) mismatched BMT. To examine the kinetics and strength of the barrier response in differing host compartments immediately post-BMT, progenitor function will be directly assessed by CFU function. Stem cells representative of committed and multi potential populations will be examined by CFU assay to address for selective resistance against differing populations. MiHA recombinant inbred strains will be used as marrow donors /recipients to examine immunodominance in barrier responses. Studies will challenge the notion that cell-mediated cytotoxicity via the major pathways of perforin and FasL are the crucial molecular pathways used during host resistance by transplants into cytotoxic double deficient (cdd) recipients. Progenitor cells from TNF receptor 1 and/or 2 knock out donors transplanted to cdd recipients will create a novel `cytotoxic triple deficient' model to assess the role of these signaling pathways. Direct apoptotic killing of purified Lin-Sca-1+ pluripotential stem cell populations will be examined. If apoptosis is detected, expression of progenitor cell RNA for death receptors will be examined by RT-PCR If stem cell killing is not detected, functional inhibition will be examined by forward transplant to assess if the `resistance' is reversible and may be mediated by cytokines with demonstrable anti-hematopoietic activity. Differences from these studies in the types of progenitor cells affected as a consequence of differing functional deficits in transplant recipients would provide novel insights towards linking distinct effector pathways to the targeting of differing hematopoietic progenitor populations.
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