Bone marrow transplantation (BMT) is currently an established mode of therapy for immune deficiency disorders, aplastic anemia, and hematologic malignancies. Due to the rapid advancements being made in molecular biology and genetics, one can easily envision that in the near future BMT will be employed as a therapeutic modality to treat a number of life- threatening genetic diseases. Sickle cell disease, beta-thalassemia, and a variety of other disorders that are the result of genetic abnormalities of hematopoietic stem cells represent likely candidates for the future of BMT therapy. A major concern facing BMT technology today relates to the significant morbidity and mortality associated with the procedure. The chemoradiotherapy used as a preparative regimen for marrow transplantation creates a state of immunodeficiency during which graft recipients are extremely susceptible to life-threatening infections. While some immune functions recover rather rapidly and completely following marrow grafting, many patients exhibit significant deficits in cellular immune function that persist for years after successful engraftment. Much of the research effort to understand the depression of cell-mediated immune potential in marrow graft recipients has focused primarily on the consequences of graft-versus-host disease. However, this condition alone cannot fully explain the severity of the immunologic deficits observed in BMT recipients. It is well known that the time course of immunologic reconstitution within human twin and autologous BMT recipients is remarkably similar to that observed in allogeneic BMT. It is our hypothesis that the preparative regimens used to condition patients prior to marrow grafting are in part responsible for the long- term immunologic deficits observed in BMT recipients. Our studies which have been designed to compare the recovery of cell-mediated immune function in lethally irradiated and stem-cell reconstituted mice that possess either irradiated or radiation-spared thymic grafts have determined that exposure of the thymus to ionizing radiation (during TBI) has a detrimental impact on the regeneration of T-cell function by the reconstituting host. Within this grant application a detailed series of experiments are planned to establish the mechanisms associated with this phenomenon. Specifically, we plan to determine whether the T cells that develop within a thymic epithelial graft that has been exposed to gamma- irradiation (during TBI) are quantitatively, qualitatively, or functionally distinct from T cells that have differentiated within a radiation-spared thymic epithelial graft. These studies may provide insight into the mechanisms responsible for the long-term deficits in immune function observed following TBI.
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