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.
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.
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