Prolongation of xenograft survival using monoclonal antibody CD45RB and cyclophosphamide in rat-to-mouse kidney and heart transplant models

Background. Intrigued by the finding that a monoclonal antibody (mAb) direc ted against the B exon of restricted CD45 (CD45RB mAb) induced renal allogr aft tolerance in the mouse model, we hypothesized that CD45RB mAb may preve nt xenograft rejection. We explored the role of CD45RB mAb in preventing xe nograft rejection in rat-to-mouse kidney and heart transplant models. Methods. Mice with rat kidney and heart xenografts were treated with a shor t course of mAb, cyclosporine, cyclophosphamide, or mAb + cyclophosphamide combination therapy. Untreated heart and kidney xenografts served as contro ls. Results. Untreated controls developed acute vascular and cellular rejection rapidly with a median survival time of only 6 days. Long-term kidney (medi an survival time = 70 days) and heart xenograft survival (median survival t ime = 65 days) was achieved using the combination therapy of mAb + cyclopho sphamide. One-third of the kidney recipients with combination therapy survi ved 100 days. Immunohistochemistry and xenospecific-antibody analysis demon strated that combination therapy remarkably reduced IgG and IgM deposition and also inhibited CD4(+), CD8(+), and Mac-1(+) cell infiltration at early stages. This therapy, however, did not induce tolerance in this model as ev oked xenoreactive antibodies and cellular responses may be the cause of lat e xenograft failure. Conclusion. A short course of CD45RB mAb combined with cyclophosphamide eff ectively inhibits cellular and humoral immunoresponses and remarkably prolo ngs xenograft survival in rat-to-mouse heart and kidney transplant models.