title: The clinical and immunological significance of GAD-specific autoantibody and T-cell responses in type 1 diabetes.
abstract: Antigen-specific interventions are desirable approaches in Type 1 Diabetes (T1D) as they can alter islet-specific autoimmunity without systemic side effects. Glutamic acid decarboxylase of 65 kDa (GAD65) is a major autoantigen in type 1 diabetes (T1D) and GAD-specific autoimmunity is a common feature of T1D in humans but also in mouse models of the disease. In humans, administration of the GAD65 protein in an alum formulation has been shown to reduce C-peptide decline in recently diagnosed patients, however, these observations were not confirmed in subsequent phase II/III clinical trials. As GAD-based immune interventions in different formulations have successfully been employed to prevent the establishment of T1D in mouse models of T1D, we sought to analyze the efficacy of GAD-alum treatment and the effects on the GAD-specific immune response in two different mouse models of T1D. Consistent with the latest clinical trials, mice treated with GAD-alum were not protected from diabetes, although GAD-alum induced a GAD-specific Th2-deviated immune response in transgenic rat insulin promoter-glycoprotein (RIP-GP) mice. These observations underline the importance of a thorough, preclinical evaluation of potential drugs before the initiation of clinical trials.
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Boettler
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Pagni
authors.forename: Rachel
authors.initials: R
authors.lastname: Jaffe
authors.forename: Yang
authors.initials: Y
authors.lastname: Cheng
authors.forename: Peter
authors.initials: P
authors.lastname: Zerhouni
authors.forename: Matthias
authors.initials: M
authors.lastname: von Herrath
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000276:immunology* / Q000378:metabolism; D007328:Insulin / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D011401:Promoter Regions, Genetic; D051381:Rats; D055647:Rats, Transgenic / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase
keywords: GABA; GAD-alum; GAD65; Glutamic acid decarboxylase of 65 kDa; IFN-γ; IL; Immunotherapy; LCMV; NOD; PBMC; PFU; RIP-GP; RIP-LCMV; T-helper; T1D; TNF; Th; Type 1 diabetes; interferon-γ; interleukin; lymphocytic choriomeningitis virus; non-obese diabetic; peripheral blood mononuclear cells; plaque-forming units; rat insulin promoter-glycoprotein; tumor necrosis factor; type 1 diabetes; γ-aminobutyric acid