Use of CTLA-4Ig in combination with conventional immunosuppressive agents to prolong allograft survival

Background. The objective of our study was to determine the effectiveness of CTLA4-Ig, a novel immunosuppressive agent, in augmenting allograft survival when combined with either cyclosporine, sirolimus, donor-specific bone marrow alone (BM), or bone marrow in conjunction with antilymphocyte serum (ALS), Methods. Full-thickness skin allografts were used in C3H to B6AF1 (class I mismatch) and AKR to C57BL/6 (complete mismatch) models, Groups of mice (n=6-14) were treated with various combinations of the following treatment protocols: murine CTLA4-Ig, L-6 control Ig, sirolimus, cyclosporine, ALS, or ALS/BM. Results. In the class I mismatch model, L-6 control Ig had no effect whereas use of CTLA4-Ig alone resulted in a doubling of the median graft survival compared with controls, The addition of either sirolimus or cyclosporine to CTLA4-Ig increased graft survival over that achieved with CTLA4-Ig alone, CTLA4-Ig demonstrated no efficacy when used in combination with BM, ALS, or ALS/BM, CTLA4-Ig was clearly less effective in the complete mismatch model. Conclusion. These data suggest that CTLA4-Ig may be effective clinically in combination with cyclosporine or sirolimus but offers no additional effectiveness in combination with antilymphocyte serum with or without donor-specific bone marrow.