Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine

Background Although transplantation of musculoskeletal allografts in humans is technically feasible, the adverse effects of long-term immunosuppressio n subject the patient to high risks for correcting a non-life-threatening c ondition. Achieving immunologic tolerance to musculoskeletal allografts, wi thout the need for chronic immunosuppression, could expand the clinical app lication of limb tissue allografting, Tolerance to musculoskeletal allograf ts has been accomplished previously in miniature swine in our laboratory. A lthough stable, mixed chimerism has been suggested as the mechanism underly ing long-term tolerance in a rat limb model, the mechanism of this toleranc e induction has not been established. This report explores the possible rel ationship between hematopoietic chimerism and tolerance to musculoskeletal allografts in swine. Methods. Twelve miniature swine underwent vascularized musculoskeletal allo graft transplantation from histocompatibility complex (MHC) matched, minor antigen-mismatched donors. Eight animals received a 12-day course of cyclos porine, one of which was excluded due to subtherapeutic levels, Four recipi ents were not immunosuppressed, Serial biopsies to assess graft viability a nd flow cytometry to assess chimerism were performed. Donor and third-party skin grafts were placed on recipients with surviving allografts greater th an 100 days to validate tolerance. Results, Both groups developed early peripheral chimerism, but this chimeri sm became undetectable by postoperative day 19 in the cyclosporine group an d by day 13 in the control group, Animals receiving cyclosporine developed permanent tolerance to their allografts, whereas those not receiving cyclos porine rejected their allografts in 6-9 weeks. Animals demonstrating tolera nce to their bone allografts also demonstrated prolonged donor skin graft s urvival, Conclusions. Induction of tolerance to musculoskeletal allografts can be ac hieved in the MHC matched swine. Although hematopoietic chimerism is presen t in the immediate postoperative period, persistent, long-term chimerism do es not seem to be necessary for maintenance of such tolerance.