| Various defects in antigen-presenting cells (APCs) and T-cells, including regulatory cells, have been associated with type-1 diabetes and lupus development in NOD and BWF1 mice, respectively. CD4+CD25+ regulatory cells play a crucial role in controlling various autoimmune diseases by keeping at bay pathogenic cells, and a deficiency in their number or function could tilt the regulatory cell-pathogenic cell balance and lead to type-1 diabetes and lupus development. Various infectious agents have been shown to prevent autoimmune diseases including type-1 diabetes and lupus in mice, and can evade the immune response by inducing tolerogenic APCs and regulatory T-cells. Furthermore, Lactobacilli have been shown to prevent colitis and allergic diseases in humans. However, the mechanism underlying the protective effect afforded by infections against autoimmune diseases is poorly understood.; In the current study, we hypothesized that microorganisms may prevent autoimmune diseases by inducing regulatory cells and/or tolerogenic APCs, thereby reestablishing the balance between regulatory cells and pathogenic cells. To test this hypothesis, we first characterized the immunoregulatory defects observed in NOD and BWF1 mice. Next, we characterized the mechanisms underlying the protective effect of complete Freund's adjuvant (CFA) against diabetes development in NOD mice. Finally, we characterized the mechanisms underlying the protective effect of Lactobacilli against diabetes and lupus development in NOD and BWF1 mice, respectively.; We have found that NOD and BWF1 mice do not exhibit an inherent defect in CD4+CD25+ regulatory cells, but possess a deficient APC compartment that does not allow for efficient activation of these regulatory cells especially as the mice age and become sick. Regulatory cells from both mice exhibit some phenotypic abnormalities, including lower percentages of CD4+CD25+ regulatory cells expressing CD62L, CD103, and GITR. In addition, CD4+CD25+ regulatory cells expressing lower levels of Foxp3 and lower percentages of CD4+CD25+ regulatory cells expressing membrane-bound TGF-beta(m-TGF-beta) were found in NOD mice. However, we found that APCs from NOD mice were not able to activate properly CD4+CD25 + regulatory cells as reflected by a lower ability of these cells to induce down-regulation of responder cell proliferation, sustain Foxp3 expression in CD4+CD25+ regulatory cells, and induce granzyme B expression in CD4+CD25+ regulatory cells. Moreover, APCs from NOD and BWF1 mice exhibit defects in costimulatory molecules.; We next examined the protective effect of injecting CFA, which contains heat killed Mycobacterium tuberculosis, into NOD mice. We have found that CFA injection delayed the onset of diabetes and prevented diabetes development in 55% of the mice and induced potent regulatory cells that accumulated to the site of inflammation i.e. the pancreas. Moreover, CFA injection restored the ability of NOD APCs to activate CD4+CD25 + regulatory cells as reflected by the activation of regulatory cell function both in vivo and in vitro, the restored percentages of CD4+CD25+ regulatory cells expressing CD103, m-TGF-beta, and Foxp3, the maintenance of Foxp3 expression in vitro, and the induction of granzyme B expression in vitro in CD4+CD25+ regulatory cells.; We finally examined the effect of Lactobacilli on disease development in NOD and BWF1 mice. We have found that feeding Lactobacilli delayed diabetes and lupus development and restored normal levels of B7-1 and B7-2 expression on the surface of both NOD BM-DCs and BWF1 BM-DCs. Moreover, Lactobacillus casei induced more IL-10 than IL-12 production by both NOD BM-DCs and BWF1 BM-DCs suggesting that Lactobacilli can polarize DCs towards a tolerogenic phenotype. Furthermore, feeding Lactobacilli induced high levels of CD4+Foxp3 + regulatory cells and IL-10 production by T-cells in BWF1 mice. More importantly, a single injection of Lactobacilli-treated NOD BM-DCS... |
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