Inhibition of rejection of hamster-to-rat heart xenografts.

Abstract

Prolonged survival of concordant organ xenografts as typified by hamster-to-rat heart transplants is difficult to produce. Studies have revealed that T cells are not primarily involved in rejecting such xenografts and that the rat recipients produce high titres of lytic anti-hamster antibodies. In this study, 200 hamster-to-rat cardiac xenografts performed in 30 different experiments revealed that cyclophosphamide (CyP) and cyclosporin A (CyA) could inhibit this antibody production. CyP alone was relatively ineffective in prolonging graft survival (the median survival time was 14 days versus 3 days in untreated controls). Combining CyP and CyA virtually abolished rejection in this model. Four critically timed doses of CyP combined with continuous CyA resulted in recipients not producing anti-hamster antibodies, despite cessation of CyP therapy, and prolonged graft survival time (median survival time was more than 100 days). Cessation of CyA at 60 and 100 days resulted in the rejection of the xenografts and the appearance of the rat anti-hamster antibodies. Xenografts in recipients given only one or two doses of CyP (and continuous CyA) had a median survival time of 7 and 12 days respectively. However xenograft rejection in rats given only 1 or 2 doses of CyP could be averted by complement depletion using a 3-week course of cobra venom factor (CoF) starting on day 4 or day 7 post-transplantation respectively. Discontinuation of CoF after 3 weeks did not result in graft rejection. These results showed that immunosuppressive therapies directed at inhibiting antibody production may be of value in preventing rejection of concordant xenografts. Short-term complement depletion could rescue xenografts from rejection such that rescued grafts appear to be accommodated.