In animal models, it has been demonstrated that acute GVHD is caused by immunocompetent donor T-lymphocytes which recognize histocompatibility antigens of the recipient. Pilot studies have been carried out to evaluate the effects of in vitro depletion of T-lymphocytes from donor marrow in patients receiving HLA-identical marrow grafts for treatment of hematologic malignancies. Although initial engraftment was not affected, the incidence of subsequent graft failure was strikingly increased. These findings suggested that certain T-cells in the donor marrow serve a beneficial function by eliminating host cells that can cause graft failure. In addition, despite at least 2-3 log depletion of T-cells, half of the patients who received no posttransplant immunosuppression developed grade II acute GVHD. Finally, two patients developed a fatal Epstein-Barr virus (EBV)-related lymphoproliferative syndrome after receiving T- cell-depleted allogeneic marrow. The proposed studies are therefore aimed at the problems of graft failure, GVHD and immune reconstitution in patients receiving T-cell depleted allogeneic marrow transplants. Clinical protocols will explore whether cells that facilitate engraftment can be distinguished from cells that cause GVHD and whether additional pretransplant immunosuppression can facilitate durable engraftment by ablating host cells that can cause graft failure. If GVHD occurs, studies will be carried out to determine whether this reflects inadequate T-cell depletion or immune dysregulation of host cells. Finally, the effects of T-cell depletion on humoral an cellular responses to EBV will be assessed. If durable engraftment and immune reconstitution were assured, depletion of T-cells from donor marrow could become a highly effective and safe method for preventing acute GVHD after allogeneic marrow transplantation. More importantly, it might become possible to decrease the morbidity associated with transplantation of marrow from HLA- non-identical donors.
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