Xenoreactions and their modulation with bone marrow transplantation to induce tolerance

Abstract

There is a severe shortage of organs for transplantation that many conclude will never be solved by increasing organ donation. Xenotransplantation may offer a permanent solution to the donor organ shortage. The vigorous nature of immune responses to xenografts and our inability to control these responses using conventional immunosuppressive regimens limit the application of xenotransplantation to the clinic. Natural antibody-mediated hyperacute and cell-mediated delayed rejection constitute two forms of xenograft rejection reactions that have been the subject of intensive studies. Although these studies resulted in the design of molecular approaches, including phenotypic manipulation of the host and genetic modification of the donor, that have been effective in preventing hyperacute rejection in the preclinical pig-to-primate model, graft rejection remains a major limitation. The induction of donor-specific tolerance to xenografts remains a far-reaching goal of clinical transplantation and will probably be one key component in enabling xenotransplantation to become a clinical reality. The use of bone marrow transplantation to induce durable hematopoietic stem cell xenogeneic chimerism, however, holds great promise for achieving such a goal.