Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease.

OBJECTIVES: Inflammatory bowel disease (IBD), especially Crohn's disease (CD), probably results from failure to downregulate a chronic Th1 intestinal inflammatory process. Induction of a Th2 immune response by intestinal helminths diminishes Th1 responsiveness. This study evaluates the safety and effectiveness of helminthic ova in the treatment of active IBD. METHODS: We studied four patients with active CD and three with ulcerative colitis (UC). In an initial treatment and observation period, a single dose of 2500 live Trichuris suis eggs was given orally, and patients were followed every 2 wk for 12 wk. Baseline medications were continued at the same dose throughout the study. Safety was monitored by following the patients' clinical status and laboratory studies at regular intervals. Patients also were monitored regularly using the Crohn's Disease Activity Index, Simple Clinical Colitis Activity Index (SCCAI), and the Inflammatory Bowel Disease Quality of Life Index (IBDQ). To assess safety and efficacy with repetitive doses, two patients with CD and two with UC were given 2500 ova at 3-wk intervals as maintenance treatment using the same evaluation parameters. RESULTS: During the treatment and observation period, all patients improved clinically without any adverse clinical events or laboratory abnormalities. Three of the four patients with CD entered remission according to the Crohn's Disease Activity Index; the fourth patient experienced a clinical response (reduction of 151) but did not achieve remission. Patients with UC experienced a reduction of the Clinical Colitis Activity Index to 57% of baseline. According to the IBD Quality of Life Index, six of seven patients (86%) achieved remission. The benefit derived from the initial dose was temporary. In the maintenance period, multiple doses again caused no adverse effects and sustained clinical improvement in all patients treated every 3 wk for >28 wk. CONCLUSIONS: This open trial demonstrates that it is safe to administer eggs from the porcine whipworm, Trichuris suis, to patients with CD and UC. It also demonstrates improvement in the common clinical indices used to describe disease activity. The benefit was temporary in some patients with a single dose, but it could be prolonged with maintenance therapy every 3 wk. The study suggests that it is possible to downregulate aberrant intestinal inflammation in humans with helminths.

Exposure to schistosome eggs protects mice from TNBS-induced colitis.

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.

Th2-type granuloma development in acute murine schistosomiasis is only partly dependent on CD4+ T cells as the source of IL-4.

Schistosome granulomas produce IL-4, important for Th2 granuloma expression. We defined the origins of IL-4 within these granulomas and the role of IL-4-producing CD4(+) T cells in Th2 granuloma development. Dispersed granuloma cells spontaneously produced IL-4 independently of T cells, whereas IL-5 production was T cell dependent. Granuloma IL-4 mRNA localized to the non-T cells and IL-5 to T cells. Granuloma CD4(+) T and NK cells, but not B cells produced IL-4 and IL-5 in vitro. B cell-/- mice generated Th2 granulomas that produced IL-4 and IL-5 normally. Granuloma eosinophils expressed no IL-4 or IL-5 mRNA. Granulomas in WWv mast cell-deficient mice lacked mast cells. The dispersed granuloma cells from WWv mice released IL-4 only after T cell stimulation, suggesting that mast cells influenced the constitutive component of IL-4 production. Rag-1 animals (T/B/NK T cell deficient) given schistosomiasis after reconstitution with splenocytes from naive mice produced Th2 granulomas. Mice reconstituted to create selective CD4(+) T cell IL-4 knockout animals developed eosinophilic granulomas that made IL-4. Thus, granulomas contain several cell types that produce IL-4. Mast cells are not needed to form Th2 granulomas, but influence IL-4 release. Th2 granuloma development in schistosomiasis is only partly dependent on IL-4-producing CD4(+) T cells.