SUPERIORITY OF SIROLIMUS (RAPAMYCIN) OVER CYCLOSPORINE IN AUGMENTING ALLOGRAFT AND XENOGRAFT SURVIVAL IN MICE TREATED WITH ANTILYMPHOCYTE-SERUM AND DONOR-SPECIFIC BONE-MARROW

Background. Sirolimus is a potent immunosuppressive agent with great t herapeutic potential. The objective of our study was to evaluate the e fficacy of sirolimus versus cyclosporine in augmenting the unresponsiv eness induced by an antilymphocyte serum (ALS)/donor-specific bone mar row (BM)-based regimen across three levels of histoincompatibility: cl ass I and II disparate (DBA/2 to B6AF1), complete mismatch (AKR to C57 BL/6), and xenograft (ACI rat to B6AF1). Methods. Full-thickness skin grafts were taken from donors and placed on recipients in standard fas hion, Seven groups of recipient mice (n=10-28) received various combin ations of the following treatment protocols: sirolimus, 1.5 mg/kg (3.0 mg/kg for xenografts) every other day from day 0 to day 12; cyclospor ine, 50 mg/kg every other day from day 10 through 22; ALS, 0.5 mi on d ays -1 and 2 for allografts and days -1, 2, and 4 for xenografts; and BM, 25 million donor-specific cells IV on day 7. Results. The administ ration of ALS or ALS/BM resulted in modest but significant prolongatio n of skin graft survival in all combinations tested, Cyclosporine comb ined with ALS or ALS/BM significantly extended allograft survival comp ared with ALS or ALS/BM alone (P<0.05) but had no effect on xenograft survival, In contrast, the combination of sirolimus with ALS or ALS/BM resulted in a two- to threefold increase in allograft survival and ov er a fourfold increase in xenograft survival when compared with the co mparable cyclosporine-based regimen, Additionally, lymphocytes isolate d from class I and II incompatible mice with skin grafts surviving >10 0 days demonstrated markedly reduced interleukin 2 and interferon-gamm a secretion in response to irradiated donor-specific lymphocytes in cu lture. Conclusions. In the regimens tested, sirolimus was superior to cyclosporine in augmenting donor BM-induced skin graft prolongation in ALS-treated mice across all levels of histoincompatibility.