1488-P: A Novel Combination Therapy to Treat Autoimmune Type 1 Diabetes

Introduction & Objective: Type 1 diabetes (T1D) is a complex disease characterized by loss of immune tolerance to self-autoantigens and destruction of insulin-producing beta-cells. No single therapy confronts the several contributors to the disease. We developed an oral Salmonella-based vaccine that provides autoantigen in combination with TGFβ, IL10, and anti-CD3. The vaccine partially prevented and reversed autoimmune diabetes in mice. We also found that the hormone gastrin was beneficial to human islets in vitro and prevented, to a degree, autoimmune diabetes in mice. We hypothesized that the vaccine in combination with a gastrin analogue (GAST-17) would be more salutary in rodents with T1D than either agent alone.

Methods: The vaccine and GAST-17 combination were administered to autoimmune diabetic mice and outcomes compared with animals that received the vaccine or gastrin alone. Effects on glucose metabolism, islet cellular infiltration, and specific immune cells were characterized. The tolerogenic mechanisms of the combination therapy were examined.

Results: Administration of the vaccine with GAST-17 in combination reversed disease in 80% of diabetic mice compared to 63% of vaccine alone and 5% of GAST-17 alone treated animals. This was associated with increased antigen-specific regulatory T-cells, decreased islet-infiltrating lymphocytes, and increased beta-cell mass. As well, combination treated mice showed increased serum levels of the tolerogenic cytokine IL10 and decreased inflammatory cytokines (IFNγ, GM-CSF, IL1-alpha, IL12).

Conclusion: A novel combination treatment of an oral diabetes vaccine and GAST-17 was superior in the reversal of established T1D in mice. This combination strategy could be worthwhile examining in individuals with autoimmune diabetes.