Proposal No. IBD-0331
Principal Investigator: P'ng Loke, Ph.D.
Applicant Organization: New York University (U.S.A.)
Project Title: Mucosal immunity of ulcerative colitis patients undergoing therapy with Trichuris suis ova (TSO)
Period of Award: February 1, 2012 - December 31, 2014
The concept of helminthic therapy (using worms to treat diseases) is supported by experiments in mouse models as well as several clinical studies. Currently, Trichuris suis ova (TSO) is the only agent that is being produced under Good Manufacturing Practice (GMP) conditions for clinical studies. TSO is being investigated in clinical trials as a therapeutic agent for the treatment of active Crohn’s Disease (CD), relapsing multiple sclerosis, peanut and tree nut allergy and adults with autistic disorders.
The goal of this study is to understand the immune mechanisms activated in the human gut by treatment with Trichuris suis Ova (TSO), which may lead to improvements in the symptoms of ulcerative colitis (UC). UC, a type of inflammatory bowel disease (IBD), involves a complex interplay between genetic and environmental factors. Trichuris suis Ova (TSO), purified eggs from the porcine whipworm Trichuris suis, have been shown to have a clinical benefit on a subset of patients with UC in a previous randomized placebo controlled trial. However, the mechanism of action of TSO on the intestinal mucosa remains unclear.
Our preliminary results from studying the intestinal mucosa of an individual who infected himself with Trichuris trichiura to treat his symptoms of severe ulcerative colitis identified IL-22 and T helper type 2 (TH2) cytokines as candidates for promoting mucosal healing in the colon during periods of helminth colonization. Based on these results, we hypothesize that treatment with TSO will reduce bacterial attachment to the intestinal epithelium of a subset of ulcerative colitis patients with active disease by increasing mucus production from goblet cells through the activity of TH2 cells and IL-22 secretion.
To test this hypothesis, we have designed a small (N = 18) exploratory mechanistic double-blind placebo-controlled randomized crossover study of TSO in patients with established and active UC. This study is designed primarily to characterize the mucosal response of individuals treated with TSO. Subjects will undergo colonoscopies, and pinch biopsies will be assessed using immunohistochemistry, flow cytometry, microarray and real time PCR analysis. Peripheral blood and stool samples will also be collected to characterize changes in the immune response and in the gut microbial flora.
The Specific Aims of this study are to: 1.) Correlate treatment efficacy with mucosal responses and changes to the microbiota and bacterial invasiveness analyzed from pinch biopsies obtained during colonoscopies before and after exposure to TSO; and 2.) Distinguish between the mucosal responses of responders and non-responders to TSO treatment.
A better understanding of the mechanism of action for TSO may lead to the development of alternative therapeutic strategies that can activate the same mucosal mechanisms as TSO. This study may also lead to the identification of candidate parameters that could be developed further as biomarkers to distinguish between individuals who respond or fail to respond to TSO treatment.