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.
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.
| 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 |
