Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig,and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant

Stable mixed chimerism can be established in dogs given a sublethal dose of 200 cGy total body irradiation (TBI) before and immunosuppression with myc ophenolate mofetil(MMF) and cyclosporine (CSP) for 28 and 35 days, respecti vely, after dog leukocyte antigen-identical marrow transplantation. Most li kely, the role of pretransplant TBI was to provide host immunosuppression, since stable mixed chimerism was also achieved in MMF/CSP-treated dogs when 450 cGy irradiation, targeted to cervical, thoracic, and upper abdominal l ymph nodes, was substituted for TBI. When TBI was reduced from 200 to 100 c Gy, all grafts were rejected within 3 to 12 weeks. Here, we asked whether s table engraftment after 100 cGy TBI could be accomplished by first reducing the intensity of host immune responsiveness with help of the fusion peptid e CTLA4lg, which blocks T-cell costimulation through the B7-CD28 signal pat hway. Accordingly, recipient T cells were activated with intravenous (IV) i njections of 10(6) donor peripheral blood mononuclear cells (PBMC)/kg per d ay on days -7 to -1 before 100 cGy TBI, with concurrent administration of C TLA4lg 4 mg/kg/d IV. All 7 dogs so treated showed initial mixed chimerism. Two rejected their allografts after 8 and 20 weeks, respectively, and survi ved with autologous marrow recovery; 1 mixed chimera was unevaluable becaus e of death at 3 weeks from intussusception; and 4 showed persisting mixed c himerism, including unirradiated marrow and lymph node spaces, for now more than 46 to 70 weeks after transplant. Data support the hypothesis that sta ble marrow allografts can be established by combining nonmyeloablative pret ransplant host immunosuppression with posttransplant host and donor cell im munosuppression using MMF/CSP. (C) 1999 by The American Society of Hematolo gy.