Abstract
A therapy that includes an oral vaccine for type 1 diabetes (T1D) using live attenuated Salmonella MvP728 (ΔhtrA/ΔpurD), cytokines (IL10 and TGFβ) and preproinsulin (PPI) antigen in combination with a sub-therapeutic dose of anti-CD3 mAb was developed by our team. The vaccine combination therapy reduced insulitis and prevented and reversed diabetes in non-obese diabetic (NOD) mice. Here, we show the effectiveness of an alternative Salmonella mutant (ΔmsbB) as a carrier strain, which is anticipated to have lower risks of an inflammatory response and septicemia as a result of modification in the lipopolysaccharide (LPS) via detoxification of lipid A. This mutant strain proved to have highly reduced pathogenic side effects. Salmonella strain ΔmsbB expressed autoantigens and in combination with cytokines and anti-CD3 mAb, successfully prevented and reversed T1D to levels comparable to the previously used carrier strain ΔhtrA/ΔpurD. Additionally, the Salmonella msbB mutant resulted in higher rates of host cell infection. These results further demonstrate the potential of an oral Salmonella-based combined therapy in the treatment of early T1D.
Highlights
Oral delivery of antigens directly to the gut-associated lymphoid tissue (GALT) is an effective means of inducing tolerance [1,2,3]
We have developed an oral Salmonella-based delivery system using the Salmonella Pathogenicity Island 2-encoded type III secretion system (SPI2-T3SS) effective in delivering an autoantigen, in combination with plasmids encoding cytokines that are known to support the immune suppression (TGFb and IL-10), to prevent and reverse type 1 diabetes (T1D) in non-obese diabetic (NOD) mice [4,5,6]
To evaluate the expression and translocation of the foreign protein into the host cell cytosol via the SPI2-T3SS of Salmonella, murine macrophages were infected with different Salmonella mutants carrying the mouse preproinsulin (mPPI) construct, namely a fusion protein of SPI2-T3SS effector SPI2-T3SS as fusion to effector protein (SseF) and mPPI
Summary
Oral delivery of antigens directly to the gut-associated lymphoid tissue (GALT) is an effective means of inducing tolerance [1,2,3]. The Salmonella-containing vacuoles (SCV) within antigenpresenting cells (APCs) allow for self-propagation of the bacteria From this location, the bacteria safely deliver a recombinant antigen into the host cell cytosol or deliver vectors that are expressed by the host cell directly, while bypassing the intestinal degradation [7, 9,10,11]. The flexibility of the system allows rapid development of new immunotherapies which provides a robust delivery of multiple antigens in a safe and inexpensive manner Such vaccines were very effective in eliciting CD8 and CD4 T cell-mediated immune responses in animal models of infection and cancer [7, 11, 15, 16]
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