title: Induction of human T-cell tolerance to pig xenoantigens via thymus transplantation in mice with an established human immune system.
abstract: Thymus xenotransplantation has been shown to induce tolerance to porcine xenografts in mice and to permit survival of alpha1,3Gal-transferase knockout porcine kidney xenografts for months in nonhuman primates. We evaluated the ability of porcine thymus xenotransplantation to induce human T-cell tolerance using a humanized mouse (hu-mouse) model, where a human immune system is preestablished by implantation of fetal human thymus tissue under the kidney capsule and intravenous injection of CD34(+) hematopoietic stem/progenitor cells. Human T-cell depletion with an anti-CD2 mAb following surgical removal of human thymic grafts prevented the initial rejection of porcine thymic xenografts in hu-mice. In these hu-mice, porcine thymic grafts were capable of supporting human thymopoiesis and T-cell development, and inducing human T-cell tolerance to porcine xenoantigens. Human T cells from these mice responded strongly to third-party pig, but not to the thymic donor swine leukocyte antigen (SLA)-matched pig stimulators in a mixed lymphocyte reaction (MLR) assay. Anti-pig xenoreactive antibodies declined in these hu-mice, whereas antibody levels increased in nontolerant animals that rejected porcine thymus grafts. These data show that porcine thymic xenotransplantation can induce donor-specific tolerance in immunocompetent hu-mice, supporting this approach for tolerance induction in clinical xenotransplantation.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Habiro
authors.forename: M
authors.initials: M
authors.lastname: Sykes
authors.forename: Y-G
authors.initials: YG
authors.lastname: Yang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D018801:CD2 Antigens / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D013552:Swine; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D013950:Thymus Gland / Q000637:transplantation*; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018801:CD2 Antigens