STABLE MIXED HEMATOPOIETIC CHIMERISM IN DLA-IDENTICAL LITTERMATE DOGSGIVEN SUBLETHAL TOTAL-BODY IRRADIATION BEFORE AND PHARMACOLOGICAL IMMUNOSUPPRESSION AFTER MARROW TRANSPLANTATION

Postgrafting cyclosporine (CSP) given for 35 days resulted in establis hment of stable marrow grafts from DLA-identical canine littermates af ter otherwise suboptimal, but nevertheless, lethal conditioning with 4 50 cGy of total body irradiation (TBI). We now asked whether sustained allografts could be achieved after sublethal TBI or without TBI. Five groups of recipients were studied. Dogs in group 1 were given 200 cGy TBI and postgrafting CSP, 15 mg/kg twice daily by mouth on days -1 to 35 posttransplant. Dogs in group 2 were given 200 cGy TBI and methotr exate (MTX), 0.4 mg/ kg intravenously (IV) on days 1, 3, 6, and 11 alo ng with CSP. Dogs in group 3 were given 200 cGy TBI and CSP along with mycophenolate mofetil (MMF), 10mg/kg twice daily subcutaneously (SC) on days 0 to 27 after transplant, a novel immunosuppressive combinatio n. Dogs in group 4 were given 100 cGy TBI and MMF/CSP. Dogs in group 5 were not given TBI and they received MMF/CSP posttransplant. Allograf ts were assessed by (Ca)(n) dinucleotide repeat polymerphism studies i n cells from peripheral blood, lymph nodes, and marrow. Dogs in group 1 had transient mixed donor-host hematopoietic chimerism for no more t han 4 weeks. Three of six dogs in group 2 had transient mixed chimeris m for 3 to 11 weeks, and three have remained stable mixed chimeras for up to 60 weeks now, Four of five dogs in group 3 have remained stable mixed chimeras for 54 to 57 weeks now, while one lost the allograft a fter 12 weeks, All dogs in groups 4 and 5 rejected their allografts af ter 2 to 12 weeks. In summary, the establishment of stable mixed hemat opoietic chimerism following nonmyelosuppressive and nontoxic conditio ning programs has remained a difficult goal. Here we present evidence in a large random-bred animal species that this goal may be achievable with pharmacological immunosuppression postgrafting, capable of inhib iting bath host-versus-graft (HVG) and graft-versus-host (GVH) reactio ns in the setting of DLA-identical grafts. (C) 1997 by The American So ciety of Hematology.