New approaches for the prevention of rejection and graft-vs.-host disease in clinical bone marrow transplantation.

The two major barriers to successful allogeneic bone marrow transplantation (BMT) in animals and man are graft-vs.-host disease (GVHD) and the risk of graft rejection. GVHD is the result of alloreactivity of mature donor T-lymphocytes present in the graft-vs.-host tissues and can be completely prevented by pregraft depletion of T-lymphocytes. Graft rejection results from residual host immunocompetent lymphocytes that survive heavy chemoradiotherapy prior to allogeneic BMT. Host resistance to allograft cannot be eradicated even by conventional conditioning with high-dose cyclophosphamide (120 mg/kg) and lethal whole body irradiation (1,200 rad). In the present report we have utilized two new techniques to overcome GVHD and graft rejection following allogeneic BMT. GVHD can be prevented by a new monoclonal rat antihuman lymphocyte antibody, CAMPATH-1, which binds human complement, enabling donor serum to serve as the source of complement. Prevention of rejection of T-lymphocyte-depleted marrow allografts can be achieved by the application of total lymphoid irradiation (TLI) in addition to conventional chemoradiotherapy, prior to allogeneic BMT. TLI causes potent immunosuppression with minimal side effects. A combination of TLI for overcoming host resistance to allograft, and CAMPATH-1 for overcoming GVHD, leads to a relatively smooth posttransplant outcome with no evidence of GVHD and with no need for posttransplant immunosuppression.