BASIC SCIENCE REVIEW ARTICLE Helminth Regulation of Immunity: A Three-pronged Approach to Treat Colitis Fernando Lopes, PhD,* Chelsea Matisz, MSc,* José L. Reyes, PhD,* ,† Humberto Jijon, MD, PhD,* ,‡ Ahmed Al-Darmaki, MD, ‡ Gilaad G. Kaplan, MD, PhD,* ,‡ and Derek M. McKay, PhD* Abstract: By reputation, the parasite is a pariah, an unwelcome guest. Infection with helminth parasites evokes stereotypic immune responses in humans and mice that are dominated by T helper (Th)-2 responses; thus, a hypothesis arises that infection with helminths would limit immunopathology in concomitant inflammatory disease. Although infection with some species of helminths can cause devastating disease and affect the course of microbial infections, analyses of rodent models of inflammatory disease reveal that infection with helminth parasites, or treatment with helminth extracts, can limit the severity of autoinflammatory disease, including colitis. Intriguing, but fewer, studies show that adoptive transfer of myeloid immune cells treated with helminth products/ extracts in vitro can suppress inflammation. Herein, 3 facets of helminth therapy are reviewed and critiqued: treatment with viable ova or larvae, treatment with crude extracts of the worm or purified molecules, and cellular immunotherapy. The beneficial effect of helminth therapy often converges on the mobilization of IL-10 and regulatory/alternatively activated macrophages, while there are reports on transforming growth factor (TGF)-b, regulatory T cells and dendritic cells, and recent data suggest that helminth-evoked changes in the microbiota should be considered when defining anticolitic mechanisms. We speculate that if the data from animal models translate to humans, noting the heterogeneity therein, then the choice between use of viable helminth ova, helminth extracts/molecules or antigen-pulsed immune cells could be matched to disease management in defined cohorts of patients with inflammatory bowel disease. (Inflamm Bowel Dis 2016;22:2499–2512) Key Words: IBD, helminth extract, cellular immunotherapy T here has been a striking increase in the incidence of autoinflam- matory diseases such as arthritis, diabetes and inflammatory bowel disease (IBD) since the early 1960’s. 1 Although the cause of this can be debated and is likely multifactorial, the realization is that IBD is on the rise and alarmingly so in children. 2 In the last 20 years, enhanced understanding of the mechanism(s) of inflammation and the resolution of inflammation has led to new therapeutic ap- proaches to IBD, 3,4 with others in the pipeline. 5 However, both causes and cures for Crohn’s disease and ulcerative colitis remain elusive. Within the concept of the hygiene hypothesis, the postulate has been advanced that infection with parasitic helminths can be used to treat and limit the severity of arthritis, diabetes, multiple sclerosis, airways inflammation, atopic conditions, and IBD. 6–8 IBD has been in the vanguard for “helminth therapy”, with models of colitis 9 and small clinical trials 10 providing intriguing proof-of-concept data for this hypothesis. In the authors’ opinion, helminth therapy can be approached from 3 broad perspectives: (1) use of viable ova/larvae, (2) administration of helminth-derived extracts or purified molecules, and (3) cellular immunotherapy with helminth extract/antigen-pulsed immune cells. Herein, we review each of these approaches in turn, weighing the pro et contra to evaluate if and how helminth therapy may be applied to IBD. IMMUNOPATHOLOGY IN IBD Ulcerative colitis and Crohn’s disease are chronic inflam- matory conditions that affect mostly the intestine and are distin- guished based on histological and endoscopic appearance, distribution, and clinical complications. The pathogenesis of these conditions is the focus of intense study; consensus is that these diseases result from the complex interplay between genetic and environmental factors leading to disruption of the immune bal- ance required to maintain gut homeostasis and tolerance toward the intestinal microbiota 11,12 (see recent reviews on immune activ- ity in IBD 13–15 ). The goal in briefly outlining the immunopathol- ogy of IBD in broad strokes is as a reference against which the anti-inflammatory effect of helminth therapy may be considered. Recently, significant progress has been made in under- standing many of the contributors to IBD. For example, over 200 single-nucleotide polymorphisms have been associated with IBD diseases, and other genes are implicated in very early onset IBD. 16 A remarkable proportion of the proteins encoded by these genes, such as human leukocyte antigen molecules, interleukin (IL)-23, Received for publication May 22, 2016; Accepted June 6, 2016. From the *Gastrointestinal Research Group (GIRG), Department of Physiology and Pharmacology, The Calvin, Phoebe and Joan Snyder Institute for Chronic Dis- eases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Can- ada; † Laboratorio de Immunología Experimental y Regulación de la Inflamación Hepato-Intestine, UBiMED, FES Iztacala, UNAM, Mexico; and ‡ Department of Medicine, University of Calgary, Calgary, Alberta, Canada. The authors have no conflict of interest to disclose. Address correspondence to Derek M. McKay, PhD, Department Physiology and Pharmacology, 1877 HSC University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada (e-mail: dmckay@ucalgary.ca). Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000889 Published online 26 August 2016. Inflamm Bowel Dis  Volume 22, Number 10, October 2016 www.ibdjournal.org | 2499 Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited. Downloaded from https://academic.oup.com/ibdjournal/article/22/10/2499/4561831 by guest on 26 July 2021