title: Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice.
abstract: Myeloablative transplantation of bone marrow (BM) engineered to express myelin oligodendrocyte glycoprotein (MOG) establishes central intrathymic tolerance and completely prevents MOG-induced experimental autoimmune encephalomyelitis (EAE) in mice. Here we asked whether non-myeloablative transplantation of MOG expressing BM (pMOG-bone marrow transplantation (BMT)) can also provide the same protection. Using stepwise reduction of irradiation doses, 275 cGy irradiation with pMOG-BMT protected 100% of mice from EAE development even with two subsequent re-challenge with MOG. Irradiation doses <275 cGy produced dose-dependent partial protection with significant disease protection still evident at 50 cGy. Splenocytes from 275 cGy recipients proliferated to MOG stimulation in vitro, indicating that MOG-reactive cells are present in the periphery but failed to induce disease. MOG-stimulated splenocytes produced little or no interleukin-17, interferon-γ, granulocyte-monocyte colony stimulating factor and tumor necrosis factor-α compared with EAE control. Adoptive transfer of CD4 T cells from EAE-resistant mice into Rag2(-/-) mice devoid of MOG expression resulted in MOG-induced EAE in ~74% of mice. Treatment of EAE-resistant mice with anti-programmed death 1 (PD-1) monoclonal antibody-induced EAE in 67% of mice. We conclude that non-myeloablative transplantation of self-antigen expressing BM induces robust peripheral tolerance that completely prevented EAE development. Our findings implicate clonal anergy and the PD-1 pathway in the maintenance of peripheral tolerance.
authors.affiliation: Autoimmunity Laboratory, Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, Victoria, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Hosseini
authors.forename: D Y
authors.initials: DY
authors.lastname: Oh
authors.forename: S T
authors.initials: ST
authors.lastname: Chan
authors.forename: X T
authors.initials: XT
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Nasa
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: F
authors.initials: F
authors.lastname: Alderuccio
authors.forename: B-H
authors.initials: BH
authors.lastname: Toh
authors.forename: J
authors.initials: J
authors.lastname: Chan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004307:Dose-Response Relationship, Radiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D018836:Inflammation Mediators / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000276:immunology; D061166:Peripheral Tolerance / Q000235:genetics*; D061026:Programmed Cell Death 1 Receptor; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
chemical_list: D000906:Antibodies; D000943:Antigens, Differentiation; D001324:Autoantigens; D016207:Cytokines; D018836:Inflammation Mediators; D063308:Myelin-Oligodendrocyte Glycoprotein; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor