title: Perinatal tolerance to proinsulin is sufficient to prevent autoimmune diabetes.
abstract: High-affinity self-reactive thymocytes are purged in the thymus, and residual self-reactive T cells, which are detectable in healthy subjects, are controlled by peripheral tolerance mechanisms. Breakdown in these mechanisms results in autoimmune disease, but antigen-specific therapy to augment natural mechanisms can prevent this. We aimed to determine when antigen-specific therapy is most effective. Islet autoantigens, proinsulin (PI), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) were expressed in the antigen-presenting cells (APCs) of autoimmune diabetes-prone nonobese diabetic (NOD) mice in a temporally controlled manner. PI expression from gestation until weaning was sufficient to completely protect NOD mice from diabetes, insulitis, and development of insulin autoantibodies. Insulin-specific T cells were significantly diminished, were naive, and did not express IFN-γ when challenged. This long-lasting effect from a brief period of treatment suggests that autoreactive T cells are not produced subsequently. We tracked IGRP206-214-specific CD8+T cells in NOD mice expressing IGRP in APCs. When IGRP was expressed only until weaning, IGRP206-214-specific CD8+T cells were not detected later in life. Thus, anti-islet autoimmunity is determined during early life, and autoreactive T cells are not generated in later life. Bolstering tolerance to islet antigens in the perinatal period is sufficient to impart lasting protection from diabetes.
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Gaurang
authors.initials: G
authors.lastname: Jhala
authors.affiliation: The Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chee
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Prerak M
authors.initials: PM
authors.lastname: Trivedi
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Selck
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Graham
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Thomas Wh
authors.initials: TW
authors.lastname: Kay
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Krishnamurthy
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology; D001324:Autoantigens; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000517:prevention & control*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011384:Proinsulin / Q000627:therapeutic use*
chemical_list: D001324:Autoantigens; D011384:Proinsulin; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse