Induction of Xenograft Tolerance and Chimerism as an Alternative Prevention of Xenograft Rejection

As an alternative prevention of xenograft rejection, induction of immunological tolerance status is another strategy in which the host immune system of human recipients is specifically not responsive to the xenografted organs of pigs [1–3], but the human immune system is normally with the responding ability to infectious pathogens. There are huge progresses in strategies to induce tolerance across xenoantigenic hurdles and rejection barriers. Also, immune tolerance induction is potentially beneficial in xenotransplantation. By advanced progress in recent technologies of gene editing, survival time of xenotransplanted grafts of multiple-transgenic α1,3Gal-T KO pigs has greatly been prolonged, which is ranged from several days to months for transplanted organ grafts, allowing life-supporting healthy. For example, 2 years more survivals have been observed in non-life-supporting heterotopic model of xenotransplantation of cardiac xenografts. To achieve such success, continuous treatment with immunosuppressive drugs is prerequisite. In fact, to obtain much improved outcome, immunosuppression is required in host recipients and hence, anti-CD40 or anti-CD154 monoclonal Abs as immunosuppression agents are continuously administered. The status eventually causes death of recipient host from infectious diseases involved in chronically administered immunosuppression or from immune rejection of xenografts [4, 5], because immunosuppression is unsuccessful [6]. Human T-cell responses against xenoantigenic barriers of pigs are much strong rather than those of allogeneic antigens [7]. This invites a new strategic option for the tolerance induction in human host. Because two different immune responses including low T-cell-dependent Abs levels and innate immune response activation are directly associated with responsible damages of xenografts, immune tolerance against xenografts has been achieved using by approaches of mixed chimerism and thymus transplantation in pig-to-mouse xenotransplantation model. Such successful application has also been applied to pig-to-baboon xenotransplantation model as an experimental extension. To achieve such immune tolerance, alternative studies are cooperatively required for macro-chimerism persistence, prolonged survival of pig xenografts, and donor unresponsiveness [8]. Successful tolerance induction reflects success in xenotransplantation.