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.