In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice

摘要: We tested whether the in vivo infusion of recombinant, soluble CTLA4 fused with Ig heavy chains, as a surrogate ligand used to block CD28/CTLA4 T-cell costimulation, could prevent efficient activation and thereby reduce graft-versus-host disease (GVHD). Lethally irradiated B10.BR recipients major histocompatibility complex disparate C57BL/6 donor grafts received intraperitoneal injections human CTLA4-Ig (hCTLA4-Ig) or murine (mCTLA4-Ig) various doses schedules beginning on day -1 0 bone marrow transplantation (BMT). In all five experiments, had significantly higher actuarial survival rate compared mice injected an irrelevant antibody control (L6) saline alone. Survival rates hL6 PBS were 0% at 29 45 days post-BMT. CTLA4-Ig, high 63% surviving 3 months However, protection was somewhat variable not GVHD-free by body weight, clinical appearance, histopathologic examination. There no significant differences comparing injection dose, duration, species (hCTLA4-Ig v mCTLA4- Ig). Splenic peripheral blood flow cytometry studies long-term hCTLA4-Ig-injected survivors showed B-cell CD4+ lymphopenia, consistent GVHD. A kinetic study splenic reconstitution performed that hCTLA4-Ig mature localized CD8+ repopulation different hL6, despite increase experiment. These data suggest beneficial effect is mediated interfering donor- derived Neither nor mCTLA4-Ig interfered hematopoietic recovery conclude CTLA4- (most likely combination other agents) may represent important new modality for GVHD prevention.