Salmonella-Based Combination Immunotherapy for Type 1 Diabetes

Program: Late-Breaking Abstracts
Session: LBSun-42 - LBSun-51-LB Diabetes & Glucose Metabolism (Posters) - Sunday

Sunday, April 3, 2016: 1:15 PM-3:15 PM
Exhibit/Poster Hall (BCEC)

Poster Board LBSun-46
Mohamed I. Husseiny Elsayed, Weiting Du, Ding Wang, Jeffrey Rawson, Daniel Mendez, Alexander Kaye, Fouad R Kandeel and Kevin George Ferreri
Diabetes & Metabolic Research Institute, Beckman Research Institute of City of Hope, Duarte, CA
Type 1 diabetes (T1D) is a metabolic disease that is initiated by the autoimmune destruction of pancreatic insulin-producing beta-cells due to loss of tolerance to specific self-antigens (autoantigens). One of the most promising approaches to restore the balance within the immune system is the oral administration of diabetic autoantigens, which diminishes the islet-specific destructive responses and induces regulatory responses. Evidence from other studies suggested that presentation of antigen by the gut associated lymphoid tissue (GALT) would improve tolerance induction, and this would be augmented in the presence of specific tolerogenic cytokines such as TGFβ and IL10. We recently reported the development of an oral vaccine for T1D based on live attenuated Salmonella using the mouse preproinsulin (mPPI) gene as the autoantigen fused to SseF effector protein of type-III secretion system (T3SS) encoded by Salmonella Pathogenicity Island-2 (SPI2) under the control of the intracellular regulated promoter. The SPI2-T3SS of Salmonella is only expressed inside of antigen-presenting cells (APCs) allowing preferential delivery of fused protein into the APC cytosol for optimal immunogenicity. The Salmonella-based delivery of autoantigen was co-administered with Salmonella-based delivery of DNA for mammalian expression of TGFβ or IL10 by the host APCs. We showed that oral vaccination with the combined mPPI+TGFβ or mPPI+TGFβ+IL10 prevented diabetes in non-obese diabetic (NOD) mice and restored normal glucose tolerance, and we have observed similar efficacy using another diabetic autoantigen, glutamic acid decarboxylase (GAD)-65, with TGFβ. In this study our results showed that combination therapy of oral vaccination with (mPPI and TGFβ+IL10) combined with sub-therapeutic dose of anti-CD3 prevented diabetes in the NOD mice and restored normal glucose tolerance. Initially we have shown that combined vaccine therapy increases the Tregs in splenocytes, and local Tregs in PLN and pancreas of vaccinated NOD mice. Additionally, the combination therapy significantly increased regulatory cytokines (IL10 and IL2) and inhibited the inflammatory IFNγ. Together these results indicated that the vaccine suppressed the autoimmunity and increased regulatory mechanisms leading to a conclusion that a Salmonella-based oral vaccine expressing autoantigens in combination with tolerogenic cytokines and sub-therapeutic dose of Anti-CD3 is a promising therapy for the prevention of T1D.

Nothing to Disclose: MIHE, WD, DW, JR, DM, AK, FRK, KGF

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Sources of Research Support: DMRI-Diabetes Pilot Program Award of the City of Hope and John C. Hench Foundation