Background: We have previously reported that a monoclonal antibody to CD45RB is a novel immunosuppressive agent; however, the optimal regimen in cardiac allografts remains unknown. The present study was undertaken to determine the optimal protocol of this therapy and its interaction with cyclosporine.
Methods: A heterotopic heart allograft model was used in C57BL/6 to BALB/c mice. The following studies were conducted: 1) dose response study (low, intermediate, and high doses at 1, 3, and 9 mg/kg/day respectively), 2) short course (2 days) therapy vs. long course (9 days) therapy, 3) pretreatment (starting on day -1) vs no pretreatment, 4) daily therapy vs. alternative day therapy, and 5) monoclonal antibody treatment with and without cyclosporine.
Results: The efficacy of the CD45RB monoclonal antibody was dose and duration dependent (p<0.01). Pretreatment significantly improved the efficacy of this therapy (74.5+/-13.4 days vs. 30.6+/-1.5 days, p<0.01). Daily therapy was superior to alternate day therapy (74.5+/-13.4 days vs. 30.4+/-1.5 days, p<0.03). Interestingly, we found that administration of cyclosporine prior to, at the same time as, or after administration of the CD45RB monoclonal antibody had a detrimental effect on graft survival compared to mAb treated alone (16.6+/-0.4 days, 25+/-2.3 days, and 35.3+/-0.9 days respectively vs. 74.5 days, p<0.01).
Conclusions: Immunosuppression with CD45RB monoclonal antibody is dose and duration dependent. Pretreatment and daily therapy improves results. Addition of cyclosporine inhibits long-term graft survival achieved by the monoclonal antibody alone.