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 immunosuppression subject the patient to high risks for correcting a non-life-threatening condition. Achieving immunologic tolerance to musculoskeletal allografts, without the need for chronic immunosuppression, could expand the clinical application of limb tissue allografting. Tolerance to musculoskeletal allografts has been accomplished previously in miniature swine in our laboratory. Although stable, mixed chimerism has been suggested as the mechanism underlying long-term tolerance in a rat limb model, the mechanism of this tolerance induction has not been established. This report explores the possible relationship between hematopoietic chimerism and tolerance to musculoskeletal allografts in swine. METHODS: Twelve miniature swine underwent vascularized musculoskeletal allograft transplantation from histocompatibility complex (MHC) matched, minor antigen-mismatched donors. Eight animals received a 12-day coprse of cyclosporine, one of which was excluded due to subtherapeutic levels. Four recipients were not immunosuppressed. Serial biopsies to assess graft viability and flow cytometry to assess chimerism were performed. Donor and third-party skin grafts were placed on recipients with surviving allografts greater than 100 days to validate tolerance. RESULTS: Both groups developed early peripheral chimerism, but this chimerism became undetectable by postoperative day 19 in the cyclosporine group and by day 13 in the control group. Animals receiving cyclosporine developed permanent tolerance to their allografts, whereas those not receiving cyclosporine rejected their allografts in 6-9 weeks. Animals demonstrating tolerance to their bone allografts also demonstrated prolonged donor skin graft survival. CONCLUSIONS: Induction of tolerance to musculoskeletal allografts can be achieved in the MHC matched swine. Although hematopoietic chimerism is present in the immediate postoperative period, persistent, long-term chimerism does not seem to be necessary for maintenance of such tolerance.

Successful in situ treatment of an infected ascending aortic graft.

Infection of an ascending aortic prosthesis is a grave complication associated with a high mortality. In most cases, extraanatomic bypass and removal of the infected vascular graft are not possible. Furthermore, the standard approach to this problem, which includes excision and replacement or debridement and repair of infected thoracic aortic grafts, carries a high early mortality. We report the successful treatment of this life-threatening complication using a conservative strategy in which the aortic prosthesis was salvaged by in situ disinfection followed by coverage with tissue flaps.

Strategies for tolerance induction to composite tissue allografts.

The emerging field of composite tissue transplantation offers the potential to replace lost tissues from cadaveric sources. Two major obstacles currently limit the future of composite tissue allotransplantation. The first is chronic rejection, attributed to both antibody deposition and cell-mediated destruction of transplanted tissue. The second obstacle is complications associated with the chronic use of immunosuppressive agents. Our laboratory has been investigating several strategies to induce tolerance to limb tissue allografts to provide solutions to many of the current limitations in allotransplantation. Three strategies show promise in the ability to induce tolerance to organ allografts. The first involves genetic matching at the HLA loci followed by a short course of immunosuppression. The second is the application of a "mixed chimerism" regimen followed by transplantation. The third is costimulatory blockade using a short course of monoclonal antibodies, such as anti-CD40 ligand and CTLA4-Ig after transplantation. Inducing a state of tolerance to limb allografts would eliminate the need for chronic immunosuppression and may also prevent the onset of chronic rejection. The ability to induce allograft tolerance would greatly expand the indications for composite tissue transplantation.

Hand transplantation: pertinent data and future outlook.

Transplantation of composite tissue allografts, such as a hand, offers immense potential in reconstructive surgery. Review of current replantation literature suggests the prospect for significant functional return following hand transplant, provided appropriate patient is selected and allograft rejection is prevented. Experimental studies of limb transplantation in rodents have demonstrated the efficacy of combination therapy using multiple immunosuppressants. However, long-term survival of limb allografts could not be achieved in large animal models without significant drug toxicity. Given the potential for organ failure, opportunistic infection, and malignancy resulting from long-term immunosuppression, the risk-benefit ratio for hand transplant must be carefully weighed. Our laboratory has been able to achieve allograft survival with minimum immunosuppression by MHC matching or donor antigen exposure prior to immune maturity in the swine. Future transplantation of composite tissue allografts, therefore, may depend upon such modalities to induce host tolerance without long-term immunosuppression.