Human IBD probably results from a dysregulated mucosal immune response to normal intestinal bacteria. The frequency of Crohn's disease (CD) has increased substantially over the last 50 years in industrialized, temperate regions. CD and ulcerative colitis (UC) are rare in less developed countries. Environmental factors influence the worldwide distribution of IBD. Helminths regulate their host's immune system and prevent excessive immune responses. Until the present era, nearly all children and adults harbored intestinal helminths. Our major hypothesis is that the modern day absence of exposure to intestinal helminths is an important environmental factor contributing to the growth of lBD. There now are substantial human epidemiologic data, and human and animal studies supporting this hypothesis. Others and we showed that helminths prevent TNBS-induced colitis and the colitis of IL 10 deficient animals. We have exciting data suggesting that helminths strongly induce regulatory T cells. Using two IBD models (TNBS and IL 10 KO colitis) and normal WT mice, we will study the immunologic mechanisms used by helminths to prevent and reverse IBD as outlined in the 3 specific aims of this proposal. Experiments will use the murine intestinal helminth Heligrnosomoides polygyrus, which only inhabits the duodenum of the host. Also employed will be transgenic mice, in vitro cell culture methods, adoptive cell transfer, cytokine inhibitors and various other molecular and immunologic techniques.
Aim I derives from studies showing that H. polygyrus prevents TNBS-induced colitis.
Aim I will explore the hypothesis that helminths avert mucosal inflammation by enhancing IL10, TGFbeta, IL4, IL 13 and/or PgE2 regulatory circuits locally in the intestinal mucosa.
Aim II will pursue the hypothesis, supported by preliminary data, that intestinal helminths induce regulatory T cells in the MLN, which migrate to the gut to limit immune responses.
This aim will characterize these regulatory cells and study mechanisms leading to their development.
Aim III will determine how intestinal helminths reverse ongoing colitis in IL 10-/- mice. Helminths use many regulatory circuits to modulate immune responses. This study could lead to new therapies for human IBD and provide insight into disease pathogenesis. Double blind clinical studies have proven the utility of helminths for the treatment of IBD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GMPB (01))
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
United States
Zip Code
Elliott, D E; Weinstock, J V (2017) Nematodes and human therapeutic trials for inflammatory disease. Parasite Immunol 39:
Hang, Long; Blum, Arthur M; Kumar, Sangeeta et al. (2016) Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis. J Immunol 197:2948-57
Weinstock, J V (2015) Substance P and the regulation of inflammation in infections and inflammatory bowel disease. Acta Physiol (Oxf) 213:453-61
Weinstock, Joel V; Elliott, David E (2014) Helminth infections decrease host susceptibility to immune-mediated diseases. J Immunol 193:3239-47
Elliott, David E; Siddique, Sana S; Weinstock, Joel V (2014) Innate immunity in disease. Clin Gastroenterol Hepatol 12:749-55
Weinstock, Joel V; Elliott, David E (2013) Translatability of helminth therapy in inflammatory bowel diseases. Int J Parasitol 43:245-51
Hang, Long; Blum, Arthur M; Setiawan, Tommy et al. (2013) Heligmosomoides polygyrus bakeri infection activates colonic Foxp3+ T cells enhancing their capacity to prevent colitis. J Immunol 191:1927-34
Weinstock, Joel V (2013) Have worms lost their luster? Inflamm Bowel Dis 19:672-3
Blum, Arthur M; Hang, Long; Setiawan, Tommy et al. (2012) Heligmosomoides polygyrus bakeri induces tolerogenic dendritic cells that block colitis and prevent antigen-specific gut T cell responses. J Immunol 189:2512-20
Elliott, David E; Weinstock, Joel V (2012) Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Ann N Y Acad Sci 1247:83-96

Showing the most recent 10 out of 35 publications