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Role of Rip2 in the Generation of Pathogenic Th17/Th1 T-cells and Ileitis

Award Number: R21AI156311
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/07/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Role of Rip2 in the Generation of Pathogenic Th17/Th1 T-cells and Ileitis - 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- 1β, 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-γ. These IL-17A+ IFN-γ+ (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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	7/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $250,500 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	11/23/2021	NON-COMPETING CONTINUATION	$250,500
														Subtotal = $250,500

Issue Date FY: 2021 ( Subtotal = $208,750 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	12/7/2020	NEW	$208,750
														Subtotal = $208,750

Grand Total All Awards = $459,250

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Role of Rip2 in the Generation of Pathogenic Th17/Th1 T-cells and Ileitis

Award Number: R21AI156311

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/07/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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