Mucosal Immune Regulation in Intestinal Disease. The role of bacterial products, food components and drugs

Abstract

The challenge of the mucosal gut associated immune system is to remain unresponsive to food products and commensal microbiota, while mounting an appropriate immune response towards pathogens. This implicates the necessity of tight immune regulation within the gut associated lymphoid tissue (GALT). Imbalance between tolerance and immunity (e.g. intestinal homeostasis) contributes to the pathogenesis of intestinal diseases like inflammatory bowel disease (IBD) and food allergies. The first part of this thesis examined strategies to enhance the GALT function and find possible therapies for intestinal inflammation. Prevention of entrance of bacterial products like lipopolysaccharide (LPS) into intestinal tissue will diminish immune activation in the gut. Alkaline phosphatase, expressed by intestinal epithelial cells, is able to detoxify LPS. Administration of alkaline phosphatase in a mouse model for intestinal inflammation indeed reduced disease, but only when severe epithelial damage had occurred. An approach including AP treatment holds a therapeutic promise in case of severe IBD. Other studies on intestinal inflammation aimed to increase regulatory cells in the inflamed tissue via administration of heat shock proteins (HSP). It has been shown that administration of mycobacterial HSP results in the induction regulatory T cells in animal models for rheumatoid arthritis, and that these regulatory T cells ameliorate disease onset. However, administration of HSP did not reduce intestinal inflammation in mouse models, probably due to the acute character of those models. The second part of this thesis investigated the changes in the GALT, immediately after induction of peanut allergy in a mouse model. Furthermore, the effects of food components and drugs on allergic responses were evaluated. Normally, feeding a protein induces immunologic non-responsiveness called oral tolerance. Administration of the mucosal adjuvant cholera toxin induces allergic sensitization to co-administered proteins in mice. We found that induction of allergy resulted in a profound decrease in the percentage of gammadelta T cells in intestinal tissues. Blockade of the gammadelta TCR in vivo (using a specific antibody) resulted in elevated food allergic responses upon sensitization with peanut. This demonstrates a regulatory role for gammadelta T cells, suggesting that targeting gammadelta T cells in the intestine may contribute to strategies to prevent and possibly treat food allergy. Food industry claims a beneficial effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on allergic responses. However, feeding mice n-3 PUFA-rich diets resulted in increased mast cell responses after induction of peanut allergy compared to mice fed with normal diets. Whether this effect is the result of modulation of fatty acid-derived prostaglandin contents or of a direct effect on mast cells is subject to further research. The pain-killer diclofenac also enhanced peanut allergic responses in mice but only when other circumstances are also in favor of allergic sensitization. This finding signifies a relevant risk for the human situation and needs further investigation. Together these studies demonstrate both beneficial and detrimental effects of environmental factors (bacterial products, food components and drugs) on mucosal immune responses in the gut. More research is needed to evaluate the risks and the therapeutic possibilities of present findings.