Three major problems associated with bone marrow transplantation are: (1) engraftment; (2) reconstitution of a normal immune system; and (3) graft-versus-host disease (GVHD). Our program attempts to study these problems at a molecular and cellular level. We have brought together investigators with expertise in the areas of hematopoiesis, immunology, molecular biology, and cell biology. Six projects in this proposed program are directed at the above-mentioned issues and rely upon """"""""reagents"""""""" from the transplanted patients or their donors. A core section has been requested to treat appropriate patients with T-cell-depleted bone marrow transplants. The treated patients and their donors will provide reagents required by the researchers in the six proposed projects. These reagents will consist of blood, skin, fibroblast, and other tissues from the transplant patients and their donors. The six projects are: (1) phenotypic characterization of returning cells after bone marrow transplantation. Flow cytometry will be used to study the cells of the immune system that repopulate the transplant patients; (2) hematopoiesis following bone marrow transplantation will be studied in an attempt to delineate the basis for the difficulty found for stem cell engraftment, especially in haploidentical patients; (3) molecular biology applications to the study of bone marrow transplantation. Molecular probes will be used to study B- and T-cell ontogeny, specifically when gene rearrangement occurs in the immature T and B cells that repopulate the transplant patient; (4) T-cell function after bone marrow transplantation. Murine model systems will be utilized to study the problems of engraftment and T-cell functions in the human bone marrow transplant patient will be evaluated; (5) B-cell function after bone marrow transplantation. We will attempt to determine whether the frequent B-cell aberrations observed in these patients are due to dysfunctions in T-B interactions or whether the dysfunction is inherent in the B cell itself; and (6) effector-target cell interactions and GVHD in the skin. Skin histopathology will be studied as a window on the tissue damage that occurs in GVHD. (TT)
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