Abstract
Antigen (Ag)-specific tolerization prevents type 1 diabetes (T1D) in non-obese diabetic (NOD) mice but proved less effective in humans. Several auto-Ags are fundamental to disease development, suggesting T1D etiology is heterogeneous and may limit the effectiveness of Ag-specific therapies to distinct disease endotypes. Colonization factor antigen I (CFA/I) fimbriae from Escherichia coli can inhibit autoimmune diseases in murine models by inducing bystander tolerance. To test if Ag-independent stimulation of regulatory T cells (Tregs) can prevent T1D onset, groups of NOD mice were orally treated with Lactococcus lactis (LL) expressing CFA/I. LL-CFA/I treatment beginning at 6 weeks of age reduced disease incidence by 50% (p < 0.05) and increased splenic Tregs producing both IL-10 and IFN-γ 8-fold (p < 0.005) compared to LL-vehicle treated controls. To further describe the role of these Tregs in preventing T1D, protective phenotypes were examined at different time-points. LL-CFA/I treatment suppressed splenic TNF-α+CD8+ T cells 6-fold at 11 weeks (p < 0.005) and promoted a distinct microbiome. At 17 weeks, IFN-γ+CD4+ T cells were suppressed 10-fold (p < 0.005), and at 30 weeks, pancreatic Tbet+CD4+ T cells were suppressed (p < 0.05). These results show oral delivery of modified commensal organisms, such as LL-CFA/I, may be harnessed to restrict Th1 cell-mediated immunity and protect against T1D.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by host-mediated destruction or loss of functional pancreas β-cells with consequential deficiency in the ability to produce insulin and control blood glucose levels[1]
These findings suggest that the non-colonizing Lactococcus lactis (LL) vector[32], which is generally recognized as safe (GRAS) by the United States Food and Drug Administration (FDA)[33], expressing Colonization factor antigen I (CFA/I) is an excellent therapeutic candidate for treating type 1 diabetes (T1D)
Oral Treatment with LL-CFA/I Ameliorates T1D in non-obese diabetic (NOD) Mice
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by host-mediated destruction or loss of functional pancreas β-cells with consequential deficiency in the ability to produce insulin and control blood glucose levels[1]. CFA/I fimbriae are an important virulence factor of enterotoxigenic Escherichia coli, though it has been shown to induce anti-inflammatory cytokine responses when expressed by a Salmonella vaccine vector (Salmonella-CFA/I)[23] or when the recombinant protein is administered orally[24] This anti-inflammatory potential has been further studied in the context of experimental models of multiple sclerosis and rheumatoid arthritis. Expansion of Tregs, independent of Ag, to effectively prevent and reverse T1D in the NOD mouse, and IL-10 and TGF-β are critical for protection in Treg-mediated therapies[30,31] These findings suggest that the non-colonizing LL vector[32], which is generally recognized as safe (GRAS) by the United States Food and Drug Administration (FDA)[33], expressing CFA/I is an excellent therapeutic candidate for treating T1D. We evaluate the ability of LL-CFA/I to induce Tregs and thereby, protect NOD mice against T1D
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