) Preliminary studies hae shown that stable allogeneic mixed hematopoietic chimerism can be accomplished in randombred dogs by administering a sublethal dose of 200 cGy total body irradiation (TBI) before and immunosuppressive therapy after dog leukocyte antigen (DLA) - identical marrow transplants. The novel immunosuppression of mycophenolate mofetil (MMF) and cyclosporine (CSP) given for 4-5 weeks has synergistic properties that can control both host- versus-graft (HVG) and graft-versus-host (GVH) reactions,and establish a stable state of graft-host tolerance. With this approach, allogeneic transplants have become safe without severe toxicities and myeloablation characteristic of traditional high- dose conditioning programs. Based on additional preliminary data. We hypothesize that the major role of low-dose TBI before transplant has been to provide host immunosuppression. If this hypothesis proves correct, less toxic immunosuppression could be substituted for TBI. Accordingly, we propose to use this canine model of mixed donor - host hematopoietic chimerism after nonmyeloablative conditioning to achieve three broad specific aims. First, we propose to confirm that TBI works through immunosuppresion and not through """"""""creation of marrow space."""""""" Second, we will determine whether TBI can be reduced or even completely replaced by immunosuppressive agents that are expected to have less toxicity than irradiation. We hypothesize that, as in cancer therapy, combinations of therapeutic agents may be better than single agents. We will study pharmaceutical and biological reagents, such as rapamycin, monoclonal antibodies to T-cell surface antigens, CTLA4Ig (cytotoxic T-cell lymphocyte antigen 4 - immunoglobulin fusion protein). And anti-CD40 ligand, for their immunosuppressive properties in the mixed chimerism model. Promising agent should be combined with currently used ones and evaluated for control of HVG and GVH reactions. Third, we will determine whether, and in what manner, donor lymphocyte infusions can be used to safely convert mixed donor-host to all-donor type hematopoiesis.
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