The Induction Of Transplantation Tolerance And Prevention Of Autoimmune Disease By Grafting With Mixed Fetal Thymus In Nude Mice

Background: As a result of the recent success of organ transplantation, the number of potential recipients for allogeneic organs has outgrown the number of available donors by more than twofold, and continues to increase. Alternatives to allogeneic organ transplantation, such as the use of xenogeneic donors, have therefore engendered considerable interest. Although current immunosuppressive protocols provide satisfactory short- and medium-term results after allotransplantation, these regimens are unlikely to be sufficient to prevent rejection of xenografts, which involves several additional immunological mechanisms that are not relevant to allograft rejection. In view of the frequently greater difficulty encountered attenuating xenoresponses than alloresponses, and the severity of side-effects of chronic immunosuppressive treatment, such as infections, malignances and organ toxicities, a simple increase in the amount of non-specific immunosuppression is not a feasible option for successful xenografting. Therefore, induction of tolerance prior to organ xenotransplantation might be essential for the successful application of xenotransplantation.There are two major approaches for the induction of xenotransplantation tolerance, one of which involves creation of a state of mixed hematopoietic chimerism by bone marrow transplantation; the other involves xenogeneic thymic transplantation. In various models the induction of xenogeneic bone marrow chimerism over either a concordant or discordant barrier has been successfully achieved. However, clinical application of xenogeneic chimerism may still be associated with serious complications. Indeed, various species incompatibilities, such as between host-derived growth factors or bone marrow stroma and donor-derived hemopoietic stem cells, may prevent the establishment of long term and stable chimerism. Next, the risk for GVHD after bone marrow transplantation remains a concern for clinician. The thymus is well known to play critical roles not only in establishing and shaping a functional T cell repertoire, but also in inducing and maintaining self-tolerance as well as deletional transplantation tolerance. In xenogeneic combinations, restoration of T cell functions and induction of donor tissue xenograft tolerance has been documented incongenitally nude or neonatally thymectomized mice implanted with thymus xenografts, such as from concordant rat or from discordant swine donors. These experiments indicate that xenogeneic thymus transplantation is a useful and reliable approach to support a functional T cell repertoire and to induce T cell-specific xenotolerance, at least for nonprimarily vascularized Xenografts, the rejection of which depends predominantly on T cells.The major concern of xenothymus transplantation is whether host T cells develop enough self tolerance for host Ags after maturation within a xenothymus. The recently studies showed that multiple organ-localized inflammatory diseases occurred in BALB/c nude mice receiving all xenogeneic embryonic thymus grafts under their renal capsules, but not with syngeneic or allogeneic thymi. The organs affected were the thyroid, the lacrimal, submandibular and sublingual glands, the stomach and ovaries. An explanation for this autoimmune syndrome could be that xenothymus leads to an imbalance between autoimmune effector and regulatory T cells. Ectopic or promiscuous expression of mRNA for numerous self- Ags such as insulin, thyroglobulin, and myelin proteolipid proteins has been demonstrated in the thymus. Thus, thymus epithelium is now generally believed to be very important for the induction of tissue-specific tolerance.In the present study, we transplanted mixed F344 rat and BALB/c mouse thymic grafts into the renal subcapsule of athymic BALB/c nude mice, to see whether this method could induce donor-specific transplantation tolerance, and moreover might also prevent the autoimmune disease.Methods: 1.Fetal thymic tissue implantation. One lobe of fetal (15d gestation) F344 rat thymus tissue was impla...