Crohn?s disease (CD), a form of idiopathic inflammatory bowel diseases (IBD), results from uncontrolled T-helper (Th) cell responses to intestinal commensal bacteria in genetically susceptible hosts. While the pathogenic role of Th17 cells in CD patients is controversial, many studies have shown an increase in Th17 cells in intestinal mucosa of CD. Blocking IL-17A, a signature cytokine of Th17 cells, was not effective in clinical studies. This may be due to functional heterogeneity and dynamic plasticity of Th17 cells, especially as it is now understood that some Th17 cells are required for homeostatic maintenance at mucosal surfaces, while others are extremely proinflammatory and pathogenic. However, the mechanism regulating the complexity of Th17 cells in intestinal mucosa is unknown. Our objective in this application is to determine the mechanisms regulating the inflammatory capacity of intestinal Th17 cells in patients with CD. In a recent study we found that receptor-interacting protein 2 (Rip2) deficient T cells preferentially differentiated towards Th17 when exposed to pathogenic conditions (IL- 1?, IL-23, IL-6). Additionally, in a preliminary study using the TNBS model of colitis, Rip2-/- mice developed a severe ileitis with an increased accumulation of Th17 T-cells in the ileum. Many of these Th17 cells were also expressing IFN-?. These IL-17A+ IFN-?+ (Th17/Th1) cells express CCR9, a chemokine receptor that allows them to migrate to the ileal mucosa. In in vitro studies we observed that RIP2 deficient T-cells preferentially develop into these highly pathogenic Th17/Th1. These findings are clinically relevant as mutations of Rip2 have been associated with CD. We have also found that the Rip2 CARD domain can inhibit pathogenic Th17 differentiation and in preliminary studies, induce conventional Th17 development, thus potentially offering the possibility as a therapeutic intervention. Therefore, we wish to address the hypothesize that impaired Rip2 signaling in T cells causes ileal inflammation by promoting the formation and infiltration of Th17/Th1 double positive inflammatory T-cells. Our innovative approaches using robust animal models and in vitro generation of Th cells that are responsive to intestinal commensal bacteria will allow us to fill the current knowledge gap between Th17 cell biology and the pathogenesis of CD in the context of host response to intestinal commensal bacteria. We have also found in preliminary studies that the Rip2 CARD domain can inhibit pathogenic Th17 differentiation and may offer the possibility as therapeutic intervention. Our hypothesis will be addressed via the following Specific Aims: 1) Determine the function of T cell intrinsic Rip2 in the generation and infiltration of pathogenic Th17/Th1 cells that cause ileal inflammation. 2) Determine the therapeutic potential of the Rip2 CARD Domain in ileal inflammation. Understanding the mechanisms regulating intestinal Th17 inflammation may lead to novel pharmacological interventions and innovative approaches in the management of CD patients with ileal involvement.

Public Health Relevance

Crohn's disease (CD) and ulcerative colitis (UC) affects more than 3,000,000 individuals in the US and better understanding of the precise mechanisms and innate immune pathways that cause the disease will allow us to develop novel therapies for this devastating disease. We have found a unique molecular pathway, which may affect the function of a potent inflammatory T cell subset in the intestine in IBD. The accomplishment of this project will provide novel insight into the essential regulatory mechanism of highly aggressive T cell populations, which is expected to have a major impact in our understanding of mucosal immunology as well as in the future therapeutics of many chronic inflammatory diseases including IBD.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Rothermel, Annette L
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Cedars-Sinai Medical Center
Los Angeles
United States
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