EFFICACY OF RS-61443 IN REVERSING ACUTE REJECTION IN A RAT MODEL OF HINDLIMB ALLOTRANSPLANTATION

The requirement for effective, minimally toxic immunosuppression remai ns a major obstacle to performing human composite tissue allotransplan tation. The skin component of composite tissue (e.g., limb) allografts is especially antigenic, necessitating toxic immunosuppressant doses to prevent or reverse acute rejection. In previous experiments, RS-614 43, an experimental mycophenolic acid ester that inhibits lymphocyte p roliferation with minimal toxicity, prevented acute limb allograft rej ection in rats for more than 8 months when started on the day of trans plantation, In this study, the ability of RS-61443 to reverse establis hed acute rejection was tested in a rat model of hindlimb allotranspla ntation. Brown-Norway donors and Fischer 344 recipients provided a MHC mismatch for orthotopic midfemur limb transplants that were performed with microsurgical repair of femoral vessels and sciatic nerve. Three groups were studied: untreated allografts (n=6); allografts receiving RS-61443 at 30 mg/kg/day, started on postoperative day 7 (n=11); and allografts receiving RS-61443 at 30 mg/kg/day, started on postoperativ e day 9 (n=9). Skin and soft tissues were biopsied periodically to ass ess rejection. Untreated allografts had complete acute rejection withi n 12-13 days.:Animals in both the 7- and 9-day groups developed modera te to severe rejection clinically and histologically before initiation of immunosuppressive therapy. In both groups, RS-61443 was able to re verse rejection completely in all animals from which biopsies were obt ained at the time of death at 9-16 weeks after transplantation (P<0.00 7). RS-61443 was highly effective as a primary immunosuppressant for r eversing established acute rejection in rat hindlimb allografts.