The prevalence of IBD increased substantially over the last 50 years. We originally proposed the IBD hygiene hypothesis, which states that living in an exceedingly clean environment affects immune development by altering intestinal flora and fauna, which predisposes to IBD. We also proposed that absence of exposure to intestinal helminths resulting from this hygiene is an important factor contributing to the rise of IBD. Substantial clinical and experimental data suggest that helminths prevent IBD. Helminths regulate host's immunity preventing excessive immune responses. Our central hypothesis is that helminths induce expansion of several distinct regulatory T cell subsets in the gut, with separate regulatory functions that work in concert to limit antigen-specific mucosal effector T cell responses and IBD. This proposal will focus on helminthic control of regulatory-type T cells (e.g. Foxp3+) in the gut because this topic is incompletely addressed, and control of these Tregs appear to be a major mechanism through which helminths protect/treat IBD. There is a critical unmet need to understand the functions of these cells in the gut, independent of parasite mediation. This project has three aims.
Aim I. Characterize the regulatory T cell phenotypes induced in the normal gut, following helminth infection, and ascertain if they have distinct functions and can prevent colitis.
Aim II. In the state of colitis, study the capacity of distinct helminth-induced, regulatory T cell subsets to reverse ongoing colitis and restrict antigen-driven effector T cell function at the site of colitis.
Aim III. Study how regulatory T cells control antigen-specific effector T cell responses in our IBD model Approach: We will use the murine intestinal helminths H. polygyrus (Hp) and T. muris, which are effective at preventing and treating murine IBD. The project employees innovative technology that includes Foxp3+/IL10+ reporter mice and a newly developed Rag/OT2/CD25- transfer model of IBD that permits the study of antigen- specific responses in the gut. We are exploring the novel hypothesis that Hp-induces gut regulatory T cell subtypes which control gut antigen-specific T cell responses and IBD. Our long-term objective is to develop new drugs to treat IBD that can act independent of helminths to trigger these regulatory pathways.

Public Health Relevance

Both the U.S. FDA and European regulatory bodies approved the testing of helminthic agents for therapeutic efficacy in various clinical studies now underway. Our proposed research will provide important new insights into how these organisms work to limit/treat IBD. Filling this gap in knowledge will speed their clinical application and further drug development through targeting immune regulatory pathways known to help control disease, which is our ultimate goal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091987-03
Application #
8517112
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Hamilton, Frank A
Project Start
2011-09-26
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$333,722
Indirect Cost
$123,834
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
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