GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS IN ALLOGENIC BONE MARROW TRANSPLANTATION

正在努力预防或控制

Efforts are being directed towards the prevention or control of graft-versus-host disease in human allogeneic bone marrow transplantation. Since such graft-versus-host disease is mediated by alloreactive T cells in the inoculated marrow, reagents and techniques have been developed to remove these T cells from the marrow inoculum and to measure the extent of that depletion. To this end, several murine monoclonal antibodies specific for antigens expressed on human T cells have been developed, three of which are cytotoxic. These antibodies have been untilized, in conjunction with other depletion techniques, for complement-mediated lysis of T cells in marrow. By a clonogenic assay now available, residual T cells in marrow following such a depletion are at a level of less than 0.01% of the total cell population. Therefore a bank of such T cell depleted and characterized marrows has been generated for use in the therapy of human malignancy. With respect to the control of alloreactive T cells mediating graft-versus-host disease, studies on the origin or generation of such alloreactivity have been undertaken in murine radiation bone marrow chimeras. It has been shown that the generation is influence by a unique interaction of T cell genotype and the T cell maturation environment. The fine specificity of human CTL has been demonstrated to be sufficient to distinguish among alpha 1 and alpha 2 domain changes of class I major histocompatibility complex molecules. Such mature alloreactive human cytotoxic T cells have been further studied with respect to cell surface molecules utilized in their interactions with target cells as the basis for therapeutic interventions with the intent of preventing tissue damage mediated by such alloreactive cytotoxic T cells. This in vitro generated information has been applied to bone marrow transplantation models in monkey and swine. Utilizing T cell depleted marrow, extended solid organ allograft survival (without exogoneous immunosuppression), but not long term tolerance induction, can be achieved in rhesus monkeys.