title: Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity.
abstract: Bone marrow transplantation from diabetes-resistant strains with complete replacement of the recipient immune system by the allogeneic donor has led to tolerance to donor islets and cure of diabetes in a mouse model of type 1 diabetes. However, the ability to tolerize host T-cells of diabetic NOD mice is unknown. We demonstrate that nonmyeloablative conditioning achieves mixed hematopoietic chimerism across major histocompatibility complex (MHC) barriers in spontaneously diabetic NOD mice. This conditioning preserves alloreactive and autoreactive diabetogenic host NOD T-cells, but when mixed chimerism was established, diabetic NOD mice accepted donor-type allogeneic islet grafts and were cured of diabetes, despite a significant recipient T-cell contribution. Furthermore, induction of mixed chimerism permitted acceptance of NOD islet grafts, demonstrating reversal of autoimmunity. Allogeneic bone marrow transplantation was critical for tolerization of diabetogenic and alloreactive host T-cells. Thus, mixed hematopoietic chimerism induces tolerance to donor islets and reverses established autoimmunity in diabetic NOD mice.
authors.affiliation: Renal Unit, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Nikolic
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Igor
authors.initials: I
authors.lastname: Leykin
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fudaba
authors.forename: R Neal
authors.initials: RN
authors.lastname: Smith
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous / Q000502:physiology*