Immunological effect of GAD-alum injections into lymph node in recent onset Type 1 diabetes.

Background: Type 1 diabetes (T1D) is the result of the progressive attack against insulin-producing β-cells by the immune system. Despite many attempts, effective interventions to preserve residual β-cells functions are lacking. Immunomodulation with autoantigens could potentially constitute the most specific and safe treatment for T1D. DIAGNODE-1, an open-label pilot trial in which GAD-alum is given directly into lymph nodes to T1D patients, resulted in preservation of C-peptide that was similar to promising results from other trials. In this study, the immunomodulatory effect of giving low doses of GAD-alum into lymph nodes (LN) versus that induced by subcutaneous (SC) administration of larger doses was evaluated.

Methods: Samples from T1D patients (n=12) who received 4 μg GAD-alum into LN followed by two booster injections one month apart, and from patients (n=12) who received two SC injections (20 μg) given one month apart were compared. GADA, IA-2A, GADA subclasses, IgE, GAD₆₅-induced cytokines, PBMC proliferation and T cells markers were analyzed.

Results: Lower doses of GAD-alum into LN induced GADA levels much higher than SC injections, and reduced proliferation and IgG1 GADA subclass, while enhanced IgG2, IgG3 and IgG4. The cytokine profile was dominated by the Th2-associated cytokine IL-13, and GAD₆₅-stimulation induced activated CD4 T cells. Patients responding clinically best account for most of the immunological changes. In contrast, SC treatment resulted in predominant IgG1, predominant IFN-γ, higher proliferation and activated CD4 and CD8 cells. These results show that LN GAD-treatment induce a strong immune response with Th2-deviation with common immune correlates for the patients with best metabolic outcome.