title: Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice.
abstract: Embryonic stem cell (ESC)-derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC-derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant complication, graft-versus-host disease (GVHD). Herein, we demonstrate that ESC-derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c-kit expression, and injected either i.v. or intra-bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end-stage diabetes. All mice with >5% donor chimerism remained free of diabetes and insulitis, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic-specific autoantigen, but responded normally to third-party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC-derived HSC cells treating disease in an animal model.
authors.affiliation: Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Larissa
authors.initials: L
authors.lastname: Verda
authors.forename: Duck An
authors.initials: DA
authors.lastname: Kim
authors.forename: Susumu
authors.initials: S
authors.lastname: Ikehara
authors.forename: Laisvyde
authors.initials: L
authors.lastname: Statkute
authors.forename: Delphine
authors.initials: D
authors.lastname: Bronesky
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Petrenko
authors.forename: Yu
authors.initials: Y
authors.lastname: Oyama
authors.forename: Xiang
authors.initials: X
authors.lastname: He
authors.forename: Charles
authors.initials: C
authors.lastname: Link
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Vahanian
authors.forename: Richard K
authors.initials: RK
authors.lastname: Burt
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D053595:Embryonic Stem Cells / Q000276:immunology / Q000637:transplantation*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D011828:Radiation Chimera / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous