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

Abstract

Intrigued by the finding that a monoclonal antibody (mAb) directed against the B exon of restricted CD45 (CD45RB mAb) induced renal allograft tolerance in the mouse model, we hypothesized that CD45RB mAb may prevent xenograft rejection. We explored the role of CD45RB mAb in preventing xenograft rejection in rat-to-mouse kidney and heart transplant models. Mice with rat kidney and heart xenografts were treated with a short course of mAb, cyclosporine, cyclophosphamide, or mAb + cyclophosphamide combination therapy. Untreated heart and kidney xenografts served as controls. Untreated controls developed acute vascular and cellular rejection rapidly with a median survival time of only 6 days. Long-term kidney (median survival time = 70 days) and heart xenograft survival (median survival time = 65 days) was achieved using the combination therapy of mAb + cyclophosphamide. One-third of the kidney recipients with combination therapy survived 100 days. Immunohistochemistry and xenospecific-antibody analysis demonstrated 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 evoked xenoreactive antibodies and cellular responses may be the cause of late xenograft failure. A short course of CD45RB mAb combined with cyclophosphamide effectively inhibits cellular and humoral immunoresponses and remarkably prolongs xenograft survival in rat-to-mouse heart and kidney transplant models.