AUTHOR=Mbongue Jacques C. , Alhoshani Ali , Rawson Jeffrey , Garcia Pablo A. , Gonzalez Nelson , Ferreri Kevin , Kandeel Fouad , Husseiny Mohamed I. 

TITLE=Tracking of an Oral Salmonella-Based Vaccine for Type 1 Diabetes in Non-obese Diabetic Mice

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00712

DOI=10.3389/fimmu.2020.00712

ISSN=1664-3224

ABSTRACT=<p>Type 1 diabetes (T1D) arises secondary to immune-driven destruction of pancreatic β-cells and manifests as insulin-deficient hyperglycemia. We showed that oral vaccination with live attenuated <italic>Salmonella</italic>, which simultaneously delivers autoantigens and a TGFβ expression vector to immune cells in the gut mucosa, provides protection against the progression of T1D in non-obese diabetic (NOD) mice. In this study we employed the Sleeping Beauty (SB) transposon system that is composed of a transposase and transposon encoding the td-Tomato to express red fluorescent protein (RFP) to permanently mark the cells that take up the <italic>Salmonella</italic> vaccine. After animal vaccination, the transposon labeled-dendritic cells (DCs) with red fluorescence appeared throughout the secondary lymphoid tissues. Furthermore, Sleeping Beauty containing <italic>tgf</italic>β<italic>1</italic> gene (SB-tgfβ1) co-expressed TGFβ and RFP. The labeled DCs were detected predominantly in Peyer’s patches (PP) and mesenteric lymph nodes (MLN) and expressed CD103 surface marker. CD103<sup>+</sup> DCs induced tolerogenic effects and gut homing. TGFβ significantly increased programmed death-ligand-1 (PDL-1 or CD274) expression in the DCs in the MLN and PP of treated mice. Also, TGFβ increased cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) levels in CD4<sup>+</sup> cells in MLN and PP. Interestingly, DCs increased in all lymphatic organs of mice vaccinated with oral live <italic>Salmonella</italic>-based vaccine expressing preproinsulin (PPI), in combination with TGFβ, IL10, and subtherapeutic-doses of anti-CD3 mAb compared with vehicle-treated mice. These DCs are mostly tolerogenic in MLN and PP. Furthermore the DCs obtained from vaccine-treated but not vehicle-treated mice suppressed <italic>in vitro</italic> T cell proliferation. These data suggest that the MLN and the PP are a central hub for the beneficial anti-diabetic effects of an oral <italic>Salmonella</italic>-based vaccine prevention of diabetes in rodents.</p>