title: Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice.
abstract: In nonobese diabetic (NOD) mice, beta-cell reactive T-helper type 1 (Th1) responses develop spontaneously and gradually spread, creating a cascade of responses that ultimately destroys the beta-cells. The diversity of the autoreactive T-cell repertoire creates a major obstacle to the development of therapeutics. We show that even in the presence of established Th1 responses, it is possible to induce autoantigen-specific anti-inflammatory Th2 responses. Immune deviation of T-cell responses to the beta-cell autoantigen glutamate decarboxylase (GAD65), induced an active form of self-tolerance that was associated with an inhibition of disease progression in prediabetic mice and prolonged survival of syngeneic islet grafts in diabetic NOD mice. Thus, modulation of autoantigen-specific Th1/Th2 balances may provide a minimally invasive means of downregulating established pathogenic autoimmune responses.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California-Los Angeles 90095, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tian
authors.forename: M
authors.initials: M
authors.lastname: Clare-Salzler
authors.forename: A
authors.initials: A
authors.lastname: Herschenfeld
authors.forename: B
authors.initials: B
authors.lastname: Middleton
authors.forename: D
authors.initials: D
authors.lastname: Newman
authors.forename: R
authors.initials: R
authors.lastname: Mueller
authors.forename: S
authors.initials: S
authors.lastname: Arita
authors.forename: C
authors.initials: C
authors.lastname: Evans
authors.forename: M A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: Y
authors.initials: Y
authors.lastname: Mullen
authors.forename: N
authors.initials: N
authors.lastname: Sarvetnick
authors.forename: A J
authors.initials: AJ
authors.lastname: Tobin
authors.forename: P V
authors.initials: PV
authors.lastname: Lehmann
authors.forename: D L
authors.initials: DL
authors.lastname: Kaufman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control* / Q000601:surgery; D018450:Disease Progression; D005260:Female; D005968:Glutamate Decarboxylase / Q000627:therapeutic use*; D006085:Graft Survival / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D010194:Pancreatin / Q000276:immunology; D017634:Self Tolerance; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015848:Interleukin-5; D015847:Interleukin-4; D010194:Pancreatin; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase