CD40 and its ligand, CD154, have been shown to play an integral role in the regulation of cell- mediated immunity. As a result of interfering with antigen presenting cell function and diminishing inflammatory responses, anti-CD154 can ablate the immune response to transplantation antigens; thus opening the way for the transplantation of allogeneic/xenogeneic tissues and organs. A humanized anti-human CD154 has been produced and the purpose of this proposal is to evaluate the potential value of this antibody as an immunosuppressive agent for allogeneic bone marrow transplantation [ABMT]. There are a number of critical feasibility studies that are needed that will help resolve if this antibody has potential usefulness in blocking graft vs host disease [GVHD] and facilitating the engraftment of human hematopoetic stem cells in humans. To evaluate its potential utility in managing GVHD in humans, the first goal will be to determine if h-anti-hCD154 blocks human T cell responses to xenoantigens in vivo [hu-SCID model]. The second goal is to determine if human anti-hCD154 interferes with the engraftment of human hematopoetic stem cells in vivo. The last goal is to determine if h-anti-hCD154 blocks graft vs leukemia [GVL] responses, a response that significantly contributes to the eradication of residual tumor cells and long lasting remission.
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