Immune response differs between intralymphatic or subcutaneous administration of GAD-alum in individuals with recent onset type 1 diabetes.

Abstract

Immunomodulation with autoantigens potentially constitutes a specific and safe treatment for type 1 diabetes (T1D). Studies with GAD-alum administrated subcutaneously have shown to be safe, but its efficacy has been inconclusive. Administration of GAD-alum into the lymph nodes, aimed to optimise antigen presentation, has shown promising results in an open-label clinical trial. Herein, we compared the immune response of the individuals included in the trial with a group who received GAD-alum subcutaneously in a previous study. Samples from T1D individuals collected 15months after administration of either three doses 1month apart of 4μg GAD-alum into lymph nodes (LN, n=12) or two doses 1month apart of 20μg subcutaneously (SC, n=12) were studied. GADA, GADA subclasses, GAD65 -induced cytokines, peripheral blood mononuclear cell proliferation, and T cells markers were analysed. Low doses of GAD-alum into the lymph nodes induced higher GADA levels than higher doses administrated subcutaneously. Immune response in the LN group was characterised by changes in GADA subclasses, with a relative reduction of IgG1 and enhanced IgG2, IgG3, and IgG4 proportion, higher GAD65 -induced secretion of IL-5, IL-10, and TNF-α, and reduction of cell proliferation and CD8+ T cells. These changes were not observed after subcutaneous (SC) injections of GAD-alum. GAD-specific immune responses 15months after lymph node injections of GAD-alum differed from the ones induced by SC administration of the same autoantigen.