Cyclosporine inhibits long-term survival in cardiac allografts treated with monoclonal antibody against CD45RB

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. J Heart Lung Transplant 1999;18:441-447.