異種移植はここまできている 世界・ハーバード大学・鹿児島大学

臨床応用を視野に入れた臓器置換最先端戦略

抄録

The shortage of donors for organ transplantation continues to be a health care crisis. Recently the techniques for reprogramming of adult cells by gene transduction to produce pluriopotent stem cells (iPS) have increased interest in the possibility of tissue regeneration with minimal ethical issues.However, there is no report demonstrating normal functional capacity of solid organs utilizing either reprogramming or regenerative technology. Thus, these technologies will need much further development to reach a preclinical stage for solid organ replacement. Therefore, I believe that donor organs from other species,?xenotransplantation?remains at the forefront of the search for a solution to the organ shortage.Overcoming both antibody-mediated and cellular-mediated immunity are of particular importance to the success of xenotransplantation. The pig is generally considered the most suitable donor species for xenotransplantation. The major obstacle preventing the successful transplantation of porcine organs into primates was the existence of natural antibodies against a terminal saccharide epitope, galactose-a1,3-galactose(Gal), produced by a1,3-galactosyltransferase(GalT). Recently, we have eliminated this barrier through our new breed of a-1,3-galactosyltransferase knockoutWhile GalT-KOgrafts did not undergo hyperacute rejection, additional strategies are required to overcome xenogeneic cellular rejection. Although titration of immunosuppressive drugs is generally manageable for allotransplantation, the amount of suppression required to avoid rejection of xenografts may lead to unacceptable level of susceptibility to infection. Thus, we have studied strategies to induce tolerance to xenogeneic organs. I have developed the innovative strategy to induce transplant tolerance by transplanting?vascularized donor thymus?. We have reported that cotransplantation of porcine thymus tissue as a vascularized graft can induce tolerance across full allogeneic barriers to kidneys and hearts in a miniature swine model. Using GalT-KOdonors, which eliminate humoral rejection by anti-Gal antibodies, a survival advantage was conferred by the vascularized porcine thymus graft, resulting in life-supporting renal xenograft survivals greater than80 days with normal creatinine levels in baboons which is the world longest-survival record of lifesupporting organs in pig-to-baboon models.More recently, I have started xenotransplantation projects, GalT-KOkidney, lung, and islets in Japan. I have developed a new strategy with hepatocyte growth factor(HGF), aimed at prolonging xenogeneic islet survival. Preliminary data in this pig to non-human primate model demonstrate euglycemia up to 2 months following porcine islet transplantation in an IDDM monkey.