Hsp65-Producinglactococcocus Lactisprevents Antigen-Induced Arthritis In Mice

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 bacteriaLactococcus lactisNCDO 2118 directy in the intestinal mucosa. Hsp65 is a ubiquitous protein overexpressed in inflamed tissues and capable of inducing immunoregulatory mechanisms.L. lactishas 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 byL. lactisis 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-gamma, serum titers of anti-collagen antibodies and rheumatoid factor. Oral administration ofL. lactisinduced alterations in microbiota composition toward an increased abundance of anaerobic bacteria such asBifidobacteriumandLactobacillus. Tolerance to HSP65 and arthritis prevention induced by the recombinantL. lactiswas 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.