Epithelial cells lining mucosal surfaces represent the first barrier of the host against exogenous products and pathogens. Intestinal epithelial cells (IEC) have been extensively studied for their role in the digestion and selective absorption of ingested food molecules. IEC produce cytokines that influence the differentiation of classical antigen presenting and other innate cells and subsequently, shape adaptive immune responses. These cells also express the receptor for polymeric immunoglobulins, which allows the transport of polymeric IgA across the epithelium and their secretion as secretory IgA antibodies in the lumen. However, the role of IEC in allergic responses remains poorly understood and it remains unclear how specific signaling pathways in IEC affect allergic sensitization in the GI tract and impact allergic responses at distant mucosal sites such as the airways. We will address the overall hypothesis that selected innate signaling pathway in intestinal epithelial cells shape allergen-specific antibody isotype responses and promote IgA antibodies, which can prevent the development, or reduce the magnitude of allergic inflammation at distant sites. Using genetically modified mice and pharmaceutical inhibitors of the selected innate signaling pathway we propose to 1) address how activation of the non-canonical NF?B signaling in intestinal epithelial cells regulate adaptive immune response during allergic sensitization; 2) Establish mechanisms of protection against allergic inflammation by IgA and IgA+ B cells.

Public Health Relevance

Allergic diseases represent a major public health issue in Western countries affecting more than 50 million persons in the U.S. alone with an annual cost of nearly $14.5 billion. Current strategies for treating allergic diseases include anti-histaminic drugs or anti-IgE antibodies, food avoidance, and desensitization by injection of low doses of allergen. This grant will address our main hypothesis that strategies capable of promoting both monomeric and polymeric IgA responses against ingested allergens can prevent/limit allergic inflammation in distant mucosal sites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK101323-02
Application #
9095324
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Hamilton, Frank A
Project Start
2015-07-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Kim, Eunsoo; Lembert, Melanie; Fallata, Ghaith M et al. (2018) Intestinal Epithelial Cells Regulate Gut Eotaxin Responses and Severity of Allergy. Front Immunol 9:1692
Boyaka, Prosper N (2017) Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems. J Immunol 199:9-16
Martin, Tara L; Jee, Junbae; Kim, Eunsoo et al. (2017) Sublingual targeting of STING with 3'3'-cGAMP promotes systemic and mucosal immunity against anthrax toxins. Vaccine 35:2511-2519
Terrazas, Cesar; Varikuti, Sanjay; Kimble, Jennifer et al. (2016) IL-17A promotes susceptibility during experimental visceral leishmaniasis caused by Leishmania donovani. FASEB J 30:1135-43