Inflammatory bowel disease (IBD) is prevalent in industrialized countries, but rare in less‐developed countries. Helminths, common in less‐developed countries, may induce immunoregulatory circuits protective against IBD. IL‐10–/– mice given piroxicam develop severe and persistent colitis. Lamina propria mononuclear cells from colitic IL‐10–/– mice released IFN‐γ and IL‐12. The ongoing piroxicam‐induced colitis could be partially blocked with anti‐IL‐12 monoclonal antibody suggesting that the inflammation was at least partly IL‐12 dependent. Colonization of piroxicam‐treated colitic IL‐10–/– mice with Heligmosomoides polygyrus (an intestinal helminth) suppressed established inflammation and inhibited mucosal IL‐12 and IFN‐γ production. H. polygyrus augmented mucosal IL‐13, but not IL‐4 or IL‐5 production. Transfer of mesenteric lymph node (MLN) T cells from IL‐10–/– animals harboring H. polygyrus into colitic IL‐10–/– recipients inhibited colitis. MLN T cells from worm‐free mice did not. Foxp3 (scurfin) drives regulatory T cell function. H. polygyrus enhanced Foxp3 mRNA expression in MLN T cells that had regulatory activity. This suggests that H. polygyrus inhibits ongoing IL‐10–/– colitis in part through blocking mucosal Th1 cytokine production. Resolution of inflammation is associated with increased IL‐13 production and can be adoptively transferred by MLN T cells.

Crohn's disease results from dysregulated T helper (Th)1-type mucosal inflammation. Crohn's disease is rare in tropical countries but prevalent in developed countries with temperate climates, in which its incidence rose after 1940. In contrast, exposure to helminthic parasites is common in tropical countries but is rare in developed countries. Helminthic parasites induce immunomodulatory T cell responses in the host. We hypothesize that immunomodulatory responses due to helminths may attenuate excessive Th1-type inflammation. To test that hypothesis, mice were exposed to eggs of the helminth Schistosoma mansoni and then challenged rectally with trinitrobenzesulfonic acid (TNBS) to induce colitis. Schistosome egg exposure attenuated TNBS colitis and protected mice from lethal inflammation. Schistosome egg exposure diminished IFN-gamma and enhanced IL-4 production from alphaCD3-stimulated spleen and mesenteric lymph node cells of TNBS-treated mice. Schistosome egg exposure decreased colonic IFN-gamma but increased IL-10 mRNA expression in TNBS-treated mice. Intact signal transducer and activator of transcription 6 was required for attenuation of colitis. Exposure to helminths can decrease murine colonic inflammation.

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Helminth exposure appears to protect hosts from inappropriate inflammatory responses such as those causing inflammatory bowel disease. A recently identified, strongly pro-inflammatory limb of the immune response is characterized by T cell IL17 production. Many autoimmune type inflammatory diseases are associated with IL17 release. Because helminths protect from these diseases, we examined IL17 production in helminth-colonized mice. We colonized mice with Heligmosomoides polygyrus, an intestinal helminth, and analyzed IL17 production by lamina propria mononuclear (LPMC) and mesenteric lymph node (MLN) cells. Colonization with H. polygyrus reduces IL17A mRNA by MLN cells and inhibits IL17 production by cultured LPMC and MLN cells. Helminth exposure augments IL4 and IL10 production. Blocking both IL4 and IL10, but not IL10 alone restores IL17 production in vitro. Colonization of colitic IL10-deficient mice with H. polygyrus suppresses LPMC IL17 production and improves colitis. Antibody-mediated blockade of IL17 improves colitis in IL10-deficient mice. Thus, helminth-associated inhibition of IL17 production is likely an important mechanism mediating protection from inappropriate intestinal inflammation.

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-b, that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell (LPMC) Th1 cytokine generation in an IL-10-dependent manner in WT mice. Helminths also stimulate mucosal TGF-b release. As TGF-b exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-b signaling in helminthic modulation of intestinal immunity. T cell TGF-b signaling is interrupted in TGF-b receptor II dominant negative (TGF-bRII DN) mice by T-cellspecific over-expression of a TGF-bRII DN. We studied LPMC responses in WT and TGF-bRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-b signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-b-signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-bRII DN mice. Thus, T cell TGF-b signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal IFN-c generation and H. polygyrus-mediated suppression of chronic colitis. IntroductionHelminth exposure is associated with immune modulation in the human or murine host and decreased immune reactivity to antigens unrelated to the parasite [1]. This response may be useful in the treatment of autoimmune and immunological diseases, like inflammatory bowel disease [2,3]. Helminths stimulate the host to produce Th2 (IL-4, IL-5, IL-9, IL-13) or regulatory (IL-10, TGF-b) cytokines, while blocking Th1 cytokine responses [4,5].Helminthic parasites limit disease activity in various animal models of inflammatory bowel disease. For example, rectal trinitrobenzene sulfonic acid administration causes a T cell cytokinedriven colitis that is prevented by systemic administration of 1870Schistosoma mansoni eggs or duodenal colonization with Heligmosomoides polygyrus larvae [6,7]. H. polygyrus-mediated regulation of IFN-g, IL-12/23 (p40) production and protection from colitis is in part blocked by inhibiting IL-10 signaling in this trinitrobenzene sulfonic acid model. IL-10 is a major immune regulatory cytokine [8] that helps prevent intestinal inflammation. Accelerated, severe colitis is triggered in IL-10 deficient and not WT mice by Helicobacter hepaticus infection or treatment of the animals with non-steroidal antinflammatory drugs [9][10][11]. Although different cells can produce IL-10 and regulate immune responses, animal studies implicate CD4 T lymphocyte derived IL-10 as a non-redundant regulator of intestinal immune balance [12]. IL-10 is involved in helminthic regulation of mucosal Th1 cytokine responses where T cells constitute the major source of intestinal 14]. The mechanism of how helminths induce IL-10-producing T cells is unknown. ...

This study determined whether Heligmosomoides polygyrus induces intestinal regulatory T cells. Splenic T cells proliferate strongly when cultured with anti-CD3 and antigen-presenting cells (APC). Lamina propria T cells from mice with H. polygyrus mixed with normal splenic T cells from uninfected mice inhibited proliferation over 90%. Lamina propria T cells from mice without H. polygyrus only modestly affected T cell proliferation. The worm-induced regulatory T cell was CD8+ and required splenic T cell contact to inhibit proliferation. The regulation also was IL-10 independent, but TAP-dependent, suggesting that it requires major histocompatibility complex (MHC) class I interaction. Additional studies employed mice with transgenic T cells that did not express functional TGF-beta receptors. The lamina propria T regulator inhibited proliferation of these transgenic T cells nearly 100%, suggesting that TGF-beta signaling via the T cell was not required. CD8+ T cells were needed for worms to reverse piroxicam-induced colitis in Rag mice (T and B cell deficient) reconstituted with IL-10-/- T cells. Thus H. polygyrus induces a regulatory CD8+ lamina propria T cell that inhibits T cell proliferation and that appears to have a role in control of colitis.

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Macrophages secrete the immunoregulatory peptide somatostatin (SOM) that inhibits IFN‐γ release by splenocytes and granuloma cells of schistosome‐infected mice. In this report we demonstrate that granuloma cells express mRNA for the SOM receptor SSTR2 but not the other four SSTR subtypes. Blocking SSTR2 activity with anti‐SSTR2 antiserum prevents SOM inhibition of T cell IFN‐γ production. This demonstrates that SOM regulates T cell function via SSTR2. Two isoforms of SSTR2 exist due to alternative RNA splicing. We developed sensitive and specific competitive PCR assays to quantify total SSTR2, SSTR2A and SSTR2B mRNA levels. The SSTR2A isoform accounts for 99 % of inflammatory cell SSTR2 mRNA and does not appear to be regulated at the transcripitonal level. B cells and macrophage cell lines also express SSTR2 mRNA which raises the possibility that SOM influences T cell IFN‐γ release by regulating accessory cell function. We show that SOM acts directly on T cells to inhibit TCR‐stimulated IFN‐γ release. Thus, SOM may directly regulate T cell IFN‐γ release at inflammatory sites.