HSP65 e imunorregulação na mucosa intestinal em modelo experimental de diabetes tipo 1

Abstract

In previous studies by our group, we have shown that oral administration of Hsp65-producing Lactococcus lactis is a successful strategy to prevent the development of chronic inflammatory disease models such as ulcerative colitis and experimental autoimmune encephalomyelitis (EAE). This treatment was able to induce oral tolerance to Hsp65, a protein usually expressed in inflamed tissues, generating regulatory T cells that interfere in the pathogenesis of these diseases. Herein, we show that oral treatment with Hsp65- producing Lactococcus lactis triggers an expansion of CD4+Foxp3+ and CD4+LAP+ regulatory T cells in a toll-like-receptor-2(TLR2)-dependent fashion, without disturbing the immunity to pathogens in C57BL/6 mice. Mice treated with L. Lactis-Hsp65 were able to maintain the protective immune response during Salmonella thyphimurium infection. Moreover, there was a reduction in the intestinal inflammatory reaction suggesting that the treatment boosted the Immunoregulatory axis of gut mucosa. We also observed that gd T cells in Peyer's patches express membrane TGF-b (associated with the peptide LAP), which may represent another important mechanism for gut immune regulation. Although treatment with L.lactis-Hsp65 has been very successful in experimental models of colitis and EAE, it showed no beneficial effect in the spontaneous diabetes in NOD mice even when associated with the administration of IL-10 producing L.lactis. Our hypothesis to explain these results was that NOD mice present defects on Immunoregulatory elements at the gut mucosa. Indeed, oral tolerance to ovalbumin could not be induced in this strain of mice even when a continuous regimen of feeding was used. In addition, we also found a link between diabetes development and a reduction in several gut regulatory elements. NOD mice showed imbalance between effector and regulatory T cells in the intestine, with increased Th17 response as well as a predominance of inflammatory antigen-presenting cells. It is widely recognized that systemic tolerance can be achieved by antigenic stimulus in the gut meaning that the immune activity in the intestine can affect the overall activity of the immune system, even in unrelated organs. If there is an immunological link between the pancreas and the intestine through the pancreatic lymph nodes, it is not surprising that the loss or reduction of regulatory components in the gut mucosa may contribute to the pathogenic events in autoimmune diabetes. Given the relevance of mucosal immune activity to the organism, it is important to understand the factors and mechanisms that contribute to its balanced function as well as the disturbances that may alter this balance in order to develop safe and successful mucosal strategies for immunomodulatory therapies.