Abstract
Oral tolerance is the physiological process that enables the immune system to differentiate between harmless dietary and microbiota antigens from pathogen derived antigens. It develops at the mucosal surfaces and can result in local and systemic regulatory and anti-inflammatory effects. Translation of these benefits to the clinical practice faces limitations involving specificity and doses of antigen as well as regimens of feeding. To circumvent these problems, we developed a recombinant Hsp65 delivered by the acid lactic bacteria Lactococcus lactis NCDO 2118 directy in the intestinal mucosa. Hsp65 is a ubiquitous protein overexpressed in inflamed tissues and capable of inducing immunoregulatory mechanisms. L. lactis has probiotic properties and is commonly and safely used in dairy products. In this study, we showed that continuous delivery of HSP65 in the gut mucosa by L. lactis is a potent tolerogenic stimulus inducing regulatory CD4+LAP+ T cells that prevented collagen-induced and methylated bovine serum albumin-induced arthritis in mice. Clinical and histological signs of arthritis were inhibited as well as levels of inflammatory cytokines such as IL-17 and IFN-γ, serum titers of anti-collagen antibodies and rheumatoid factor. Oral administration of L. lactis induced alterations in microbiota composition toward an increased abundance of anaerobic bacteria such as Bifidobacterium and Lactobacillus. Tolerance to HSP65 and arthritis prevention induced by the recombinant L. lactis was associated with increase in IL-10 production by B cells and it was dependent on LAP+ T cells, IL-10 and TLR2 signaling. Therefore, HSP65-producing treatment induced effective tolerance and prevented arthritis development suggesting it can be used as a therapeutic tool for autoimmune diseases.
Highlights
The gastrointestinal mucosa harbors the largest lymphoid tissue in the human body, with the number of lymphoid cells exceeding the cells in other lymphoid organs by orders of magnitude
Synovial wash from untreated mice had a high number of leukocytes, while L. lactis-empty plasmid (EP) treated animals scored less and most animals from group heat shock protein (HSP) did not show any infiltrating cell in the synovial fluid (Figure 1D)
Inflammatory infiltrate, pannus formation and bone degeneration were observed in Hematoxylin & Eosin (HE) stained sections of control mice and there were absent from Hsp65-lac-treated mice (Figures 1E,F)
Summary
The gastrointestinal mucosa harbors the largest lymphoid tissue in the human body, with the number of lymphoid cells exceeding the cells in other lymphoid organs by orders of magnitude. Antigenic stimulation in the gut is intense, with daily absorption of 130–190 g of dietary protein and hundred trillion of commensal bacteria from the microbiota [1, 2]. Oral tolerance is the physiological process by which the immune system suppresses specific inflammatory immune responses toward innocuous antigens such as microbiota and food proteins, while maintaining protective responses to pathogenic agents. Mechanisms involved in oral tolerance includes regulatory cytokines and regulatory lymphocytes. Mucosal surfaces are populated by a large number and diversity of these regulatory lymphocytes that are able to control local and systemic immune responses [3, 4]. Therapeutic applications of oral tolerance for chronic inflammatory diseases have been experimentally demonstrated for decades, but translation to the clinic practice faces limitations, mainly related to identification of the target antigen, feeding protocols and doses of antigen required [5]
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