Monday, June 30, 2025 6/30/2025

Role of IL-7R in CNS autoimmunity

Award Number: R01AI156384
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: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Role of IL-7R in CNS autoimmunity - Summary: Role of IL-7R in CNS Autoimmunity IL-7 is an essential cytokine for the development of T and B cells and plays an important role in inflammation by stimulating Th1, Th17 cells and GM-CSF production. The IL-7 receptor (IL-7R) complex consists of IL-7R alpha-chain (IL-7Rα) and common γ-chain (γc) and polymorphisms in the IL-7Rα gene are associated with an increased risk for the development of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Although these observations suggest that signaling through IL-7R has a pathogenic role in CNS autoimmunity, its underlying mechanisms are unclear. In this regard, we have made the following preliminary observations: 1) Dendritic cells (DCs) express IL-7Rα in homeostatic conditions and during experimental autoimmune encephalomyelitis (EAE), an animal model of MS; 2) conditional knockout (cKO) mice lacking the IL-7Rα gene in DCs are protected from EAE; 3) IL-7Rα cKO EAE mice have a significant increase in IL-9+Foxp3+ regulatory T (Treg) cells; 4) IL-7Rα cKO DCs produce the vasoactive polypeptide Endothelin-1 (Edn-1); 5) DC-derived Edn-1 induces IL-9 production by T cells; and 6) Ab-mediated depletion of Treg cells or IL-9 restores EAE susceptibility in IL-7Rα cKO mice. Together, these and other observations form the bases of our hypothesis that IL-7Rα in DCs enhances EAE severity by suppressing the development of Edn-1- induced IL-9+ Treg cells. We will test this hypothesis in three Specific aims: 1) To dissect the mechanisms by which IL-7Rα downregulates Edn-1 production by DCs and promotes EAE. We will study the mechanisms by which IL-7Rα suppresses Edn-1 in mouse and human DCs, and the role of DC- derived Edn-1 on neuroinflammation by genetic ablation and inducible expression. 2) To investigate the signaling pathways by which Edn-1 induces IL-9+Foxp3+ Treg cells. We will investigate the mechanisms of IL-9 induction in Foxp3+ Treg cells by ETBR signaling by genetic approaches in vivo and in vitro, and study the effect of dimethyl fumarate, a common therapy for MS, on the expression profile of IL-7Rα+DCs, IL-9+Foxp3+ Treg cells and Edn-1 and its receptors in MS patients. 3) To test the therapeutic effect of Edn-1 and its analogues in EAE. This will be tested in myelin-reactive T cells, and multiple EAE models, including relapsing-remitting and chronic progressive EAE. Overall impact: Experiments in this study focusing on IL-7Rα, a genetic risk factor for MS, will enhance our understanding of the pathways and cellular interactions that promote CNS autoimmunity as well as investigate novel approaches to treat MS.


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: 2025 ( Subtotal = $378,300 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	11/26/2024	NON-COMPETING CONTINUATION	$378,300
														Subtotal = $378,300

Issue Date FY: 2024 ( Subtotal = $390,000 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	3	5/15/2024	NON-COMPETING CONTINUATION	$39,000
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	11/13/2023	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $390,000

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	11/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $390,000 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	11/22/2021	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2021 ( Subtotal = $390,000 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	11/25/2020	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $1,548,300

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Role of IL-7R in CNS autoimmunity

Award Number: R01AI156384

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: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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