Transplantation of hematopoietic stem cells from marrow or blood of an allogeneic donor may be followed by graftversus- host disease (GVHD) despite the best available regimens for immunosuppression that employ methotrexate in combination with cyclosporine or tacrolimus. Experimental animal data and results in human clinical trials have demonstrated that T cells play a central role in GVHD. Recent advances in the understanding of the basic mechanisms for induction of central and peripheral T cell tolerance to specific antigens have made it feasible to test the hypothesis that immunological tolerance can be achieved in man by selective immunosuppression administered for a short period of time. Transplantation tolerance is facilitated by activation-induced apoptosis of peripheral T cells triggered by specific antigens in absence of costimulation. Signals through the T cell receptor (TCR) are indispensable for induction of antigen-specific tolerance. Mycophenolate mofetil (MMF) can promote tolerance by activating apoptosis of T cells that replicate in response to antigens. The advantage of MMF over methotrexate is the relative selectivity for lymphocytes and, therefore, its improved efficacy/safety therapeutic ratio. In mice, TCR triggering with non-Fc receptor (FcR)-binding anti-CD3 antibodies induces apoptosis of donor T cells that selectively recognize recipient alloantigens, thereby preventing GVHD. Preliminary results in humans support the notion that a non-FcR-binding anti-human CD3 achieves profound immunosuppression in patients with severe acute GVHD. Blockade of costimulation through CD28 and CD40-ligand with specific inhibitors, and interleukin-2 (IL2) receptor signaling by rapamycin (sirolimus) promotes transplantation tolerance. We propose here to study immunosuppressive regimens with the potential for preventing GVHD and inducing donor-recipient tolerance after allogeneic transplantation of marrow or blood stem cells in humans. We will pursue the following specific aims: 1: Determine whether MMF is safer and more effective than methotrexate for the prevention of GVHD, when used in combination with cyclosporine, in a controlled, randomized multicenter trial. 2: Determine the safety and efficacy of sirolimus in the prevention of acute GVHD after unrelated donor transplantation, when used in combination with tacrolimus and methotrexate. 3: Determine whether HuM291 can replace glucocorticoids as primary therapy for patients with grades II-IV acute GVHD. 4: Determine whether donor-recipient tolerance can be facilitated by murine monoclonal anti-CD28 antibody 9.3.