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Defining the cellular and molecular mechanism of IDO2 function driving autoimmune vs.protective immune responses

Award Number: R01AR083882
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/08/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Defining the cellular and molecular mechanism of IDO2 function driving autoimmune vs.protective immune responses - Project Summary Autoimmune diseases are chronic inflammatory diseases that affect more than 50 million Americans, leading to pain, disability, and increased mortality. While drugs to treat autoimmune diseases exist, alleviation of inflammatory symptoms is often associated with severe side-effects, including increased susceptibility to infections and cancer. Our proposal addresses the urgent need to identify new therapeutic targets to address the underlying causes and associated symptoms of these debilitating diseases. In this proposal, we will investigate indoleamine-2,3-dioxygenase (IDO2) as a novel immunomodulatory target for autoimmune diseases. IDO2 is one of two closely related tryptophan catabolizing enzymes expressed primarily in immune cells. Using a combination of genetic and pharmacological studies in the KRN model of inflammatory arthritis, we identified IDO2 as an essential mediator of autoantibody-mediated inflammatory responses and discovered a novel non-enzymatic function of IDO2 that drives autoimmune responses leading to disease. Mechanistic studies implicate the transcription factor Runx1 as a potential component of this previously unknown IDO2 signaling pathway. IDO2 appears to be essential for only some B cell functions, as IDO2 deficient mice develop normal immune cell compartments and mount productive immune responses to challenge with some, but not all, model antigens in vitro and in vivo. A better understanding of IDO2 biology, in particular the roles that enzymatic and non-enzymatic activity have in regulating immune function is necessary to develop IDO2 as a potential therapeutic target for autoimmune disease. Our working hypothesis is that IDO2 modulation of immune responses involves both enzymatic and non-enzymatic pathways with autoreactive B cell activation/autoantibody production dependent on IDO2’s non-enzymatic function. We propose that this differential use of non- enzymatic vs. enzymatic IDO2 pathways can be specifically targeted as a therapeutic strategy to inhibit IDO2 function in autoimmune responses without affecting its role in protective immunity. In this proposal, we will use preclinical models of autoimmune arthritis, IDO2 and Runx1 conditional knockout mice and overexpressing cell lines, and whole transcriptome RNA-seq analysis to define the cellular and molecular mechanism mediating IDO2 non-enzymatic function (Aim 1). We will then use catalytically inactive IDO2 knock- in mice and a novel IDO2-targeting antibody, together with IDO2-dependent models of autoimmunity and protective immunity, to determine if differential use of non-enzymatic vs. enzymatic pathways distinguishes IDO2 function in autoimmune and protective immune responses (Aim 2). The potential long-term impact of this project would move targeting non-enzymatic IDO2 function into development as a novel strategy to treat autoantibody-mediated autoimmune diseases.


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: 2026 ( Subtotal = $467,203 )
2026	2026	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/14/2026	NON-COMPETING CONTINUATION	$467,203
														Subtotal = $467,203

Issue Date FY: 2025 ( Subtotal = $529,682 )
2025	2025	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/8/2025	NEW	$529,682
														Subtotal = $529,682

Grand Total All Awards = $996,885

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Defining the cellular and molecular mechanism of IDO2 function driving autoimmune vs.protective immune responses

Award Number: R01AR083882

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/08/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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