In vitro studies have shown that normal T lymphocytes and their products can augment growth of hematopoietic colony forming units. Small numbers of HLA-compatible T cells and monocytes contaminating in vitro assays can elaborate growth promoting activities in situ, thereby optimizing growth. Various subpopulations of T cells can augment or limit this activity, whereas allosensitized primed T cells (PTC) can inhibit this activity in a target specific manner. Given that these observations have in vivo correlates, these data would suggest that graft failure or graft rejection may not require reactivity against stem cells, but could be mediated by interference with regulatory cell function. To address this issue, we propose to identify cellular interactions critical for establishing marrow allografts with particular emphasis on the positive and negative roles T cells may play in this process. In vivo antibody facilitate marrow engraftment in SL/SL mutant mice will be used to identify critical regulatory cells required for proper hematopoiesis and determine how defined populations of T cells effect their function. We will try to establish a human correlate by defining the phenotype and function of cells associated with marrow failure in patients receiving T-cell depleted marrow or unmanipulated HLA-nonidentical marrow. Additional studies using lymphocytes stimulated by alloantigens in vitro will focus on the cellular signals that elicit pertinent T cell responses, the phenotype of the effectors, and the mechanism by which they influence hemtopoietic colony growth. We believe these studies will provide a more complete understanding of the cellular interactions critical for sustained engraftment and will contribute directly to improving the efficacy of marrow transplantation.
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