Background & Aims CCL20 is a chemokine that regulates the homeostatic and inflammatory trafficking of leukocytes to the small intestine and regulates the development of Rabbit Polyclonal to CATL1 (H chain, Cleaved-Thr288). the gastrointestinal lymphoid architecture. and ?/? mice. Results CCR6?/? mice were safeguarded from OVA-induced diarrhea but remarkably were not impaired in mastocytosis or allergen-specific IgE. CCR6?/? mice were also safeguarded from T cell-mediated diarrhea induced by anti-CD3 antibody. Allergic diarrhea was associated with an increased manifestation of Th2 cytokines within the intestinal mucosa that was significantly reduced in MK-2894 CCR6 ?/? mice. Inhibition of lymphocyte homing by treatment with FTY720 did not impair sensitive diarrhea indicating that reactivation of T cells could happen locally within the small intestine. Finally T cell transfer studies shown that CCR6 was required both on the transferred T cells and in the recipient mouse in order to manifest sensitive disease in the gastrointestinal tract. Conclusions These studies spotlight a mast cell- and IgE-independent part for CCR6-bearing T cells in the pathogenesis of gastrointestinal sensitive disease. INTRODUCTION Food allergic reactions are initiated by allergen cross-linking of IgE bound to intestinal mast cells mast cell degranulation and launch of mast cell products that act directly on the intestinal epithelium or indirectly through enteric nerves to induce changes in intestinal ion secretion and barrier function 1 2 Mice systemically sensitized to ovalbumin (OVA) and repeatedly orally challenged with OVA develop a mast cell and IgE-dependent acute diarrhea associated with a Th2 swelling in the small intestine 3. We have previously demonstrated that mesenteric lymph node (MLN) CD4+ T cells from mice with sensitive diarrhea can transfer sensitive disease to na?ve mice 4 highlighting the part of T lymphocytes in an IgE- and mast cell-driven model system. Forbes et al recently showed that transgenic manifestation of the one T cell cytokine IL-9 inside the intestine may lead to an area mastocytosis and diarrhea replicating experimental types of allergen-driven experimental MK-2894 meals allergy 5. Inhibition of IL-4 and IL-13 provided early during repeated dental allergen challenge may also inhibit allergic symptoms 6. Allergen-specific T cells making Th2 cytokines have already been been shown to be within the intestinal mucosa MK-2894 of individual subjects with meals allergic illnesses 7 8 including non-IgE-mediated meals allergic disease. The elements in charge of recruitment of pathogenic T cells towards the intestine in meals hypersensitive disorders aren’t known and we hypothesized that mucosally-expressed chemokines will be crucial for the homing of T cells towards the gut in experimental meals allergy. CCL20 (MIP-3α) is really a chemokine that’s portrayed by gastrointestinal epithelium 9 is normally controlled by NF-κB 10 and it is overexpressed in inflammatory colon disease 10 11 We’ve recently proven that ligation of the reduced affinity IgE receptor on intestinal epithelial cells results in release of useful CCL20 12. Appearance of CCL20 is normally highest within the follicle-associated epithelium from the Peyer’s patch 13 14 nonetheless it is also portrayed by mouse and individual enterocytes 9. The cognate receptor for CCL20 is normally CCR6 and is indicated on memory space T cells B lymphocytes and dendritic cells MK-2894 (DCs). CCR6?/? mice have impaired mucosal but not systemic humoral reactions to immunization and rotavirus illness 15. In addition CCR6?/? mice have alterations in the architecture of structured lymphoid tissue in the gastrointestinal tract MK-2894 including Peyer’s patches isolated lymphoid follicles and cryptopatches 16-18. We hypothesized that this ubiquitous mucosal chemokine would play a role in the homing of T lymphocytes to the gastrointestinal tract in experimental food allergy and tested this using CCR6+/+ and ?/? mice. METHODS Allergic Diarrhea CCR6?/? mice were generated previously by S. Lira 15 back-crossed for 10 decades to the Balb/c background and managed in SPF conditions. Balb/c mice were purchased from NCI (Frederick MD). All experiments were performed with the authorization of the Institutional Animal Care and Use Committee. Woman age-matched CCR6+/+ and CCR6?/? mice (5-8 weeks of age) were sensitized to ovalbumin (OVA) as previously explained4. Symptoms were monitored for 30 minutes after feeding and diarrhea was designated as present or absent. Cholera Toxin and CD3-Induced Diarrhea Cholera toxin-induced diarrhea was.