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Pathogenic role of IL-39/IL-39R signaling in graft-versus-host disease

Award Number: R01HL173777
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Pathogenic role of IL-39/IL-39R signaling in graft-versus-host disease - Abstract Graft-versus-host disease (GVHD) remains a significant source of transplant-related mortality and morbidity after allogeneic hematopoietic cell transplantation (allo-HCT). Inflammatory cytokines play an essential role in T-cell activation and differentiation to pathogenic cells, and thus promote development and progress of GVHD. Among cytokines, IL-12 family especially IL-12 and IL-23 has been shown to substantially contribute to the pathogenesis of GVHD, at least partially through promoting Th1 differentiation and Th17 maintenance, respectively. Recently, IL-39 has been proposed as a new addition to IL-12 cytokine family that consists of p19 and EBV-induced gene 3 (Ebi3). While several groups provided compelling evidence to support the presence and activity of IL-39 in preclinical murine models as well as in clinic, others failed to validate this newly proposed cytokine especially in human cells. Our preliminary study provides evidence that IL-39 exists and correlates with GVHD development not only in preclinical murine models but also in patients after allogeneic HCT. However, the functional relevance of IL-39 has not been established. The goal of this proposal is to evaluate the pathophysiologic relevance of IL-39 in GVHD development in mice and humans. Our central hypothesis is that IL-39/IL-39R signaling promotes T-cell activation and effector function, and thus promotes GVHD pathogenesis. This hypothesis will be tested by pursuing two Specific Aims: 1) To validate the role of IL-39/IL-39R signaling in GVHD and GVL activity in preclinical models; 2) To determine the functional relevance of IL-39 in humans. The research proposed in this application is considered highly innovative, because, as a newly proposed cytokine, validation of IL-39 existence and activity is urgently needed in general, and the current study is expected to be the first investigation of IL-39 in GVHD pathogenesis. The proposed research is significant biologically and clinically, because it is expected to verify the existence and biological function of IL-39 in mouse and man, and to validate IL-39 or its receptor as a potential biomarker for diagnosis or prognosis of GVHD as well as a therapeutic target in GVHD and beyond.


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 = $574,479 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Blood Diseases and Resources Research	000	2	4/29/2026	NON-COMPETING CONTINUATION	$574,479
														Subtotal = $574,479

Issue Date FY: 2025 ( Subtotal = $586,203 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Blood Diseases and Resources Research	000	1	6/4/2025	NEW	$586,203
														Subtotal = $586,203

Grand Total All Awards = $1,160,682

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Pathogenic role of IL-39/IL-39R signaling in graft-versus-host disease

Award Number: R01HL173777

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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