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Pathogenesis, prevention and treatment of corticosteroid-resistant gut GVHD

Award Number: R01HL162847
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Pathogenesis, prevention and treatment of corticosteroid-resistant gut GVHD - Project Summary: Allogeneic hematopoietic cell transplantation (Allo-HCT) can cure hematological malignancies, but this treatment causes graft-versus-host disease (GVHD), an immune response of donor cells against the recipient. Anti-inflammatory corticosteroid medications can often control GVHD, but in some cases, GVHD is resistant to this treatment, especially when it affects the intestinal tract. The goal of this project is to understand the mechanisms that cause steroid-resistant (SR) gut GVHD and to develop effective approaches to prevent or treat SR-Gut-GVHD. Results with a newly established murine model have demonstrated that SR-Gut- GVHD is induced by prolonged administration of corticosteroids. Corticosteroid treatment induces expansion of IL-22-producing Th/Tc22-like cells, IL-22-dependent abnormalities in gut microorganisms, and reduced numbers of anti-inflammatory CX3CR1hi mononuclear phagocytes (MNP) that regulate T cell expansion and control bacterial translocation. Information from our preliminary studies and other investigators suggests that corticosteroid treatment inhibits the polyamine-hypusine pathway in T and MNP cells and regulates the fidelity of T cell lineage differentiation and the expansion of pro- and anti-inflammatory MNP cells. Our studies also suggest that steroid treatment increases Ceacam-1 expression by intestinal epithelial cells, thereby increasing bacterial transcytosis and unfavorably altering the balance between proinflammatory CX3CR1lo MNP and anti- inflammatory CX3CR1hi MNP cells. These changes trigger a feedforward pathogenic loop consisting of expanding IL-22-producing Th/Tc22-like cells, IL-22-dependent dysbiosis, and increased numbers of proinflammatory CX3CR1lo MNP with decreased numbers of regulatory CX3CR1hi MNP, leading to full-blown SR-Gut-GVHD. To test this hypothesis, this application proposes 3 aims. Aim 1 will determine whether corticosteroid inhibition of the polyamine-hypusine pathway in T cells leads to expansion of Th/Tc22-like cells with lineage infidelity. Aim 2 will determine whether corticosteroid inhibition of polyamine-hypusine pathway in CX3CR1+ MNP cells augment expansion of proinflammatory CX3CR1lo MNP with reduced numbers of anti- inflammatory CX3CR1hi MNP in response to challenge by dysbiosis. Aim 3 will determine whether observations in murine models reflect the pathogenesis of SR-Gut-GVHD in humans and whether reversal of abnormalities in the polyamine-hypusine pathway and whether blocking bacterial interaction with Ceacam-1 on intestinal epithelial cells by anti-Ceacam-1 mAb prevents and reverses SR-Gut-GVHD. Relevance: By elucidating in-depth mechanistic understanding of the pathogenesis leading to SR-Gut-GVHD in a well characterized murine model and by assessing the relevance of the experimental results in colon tissue from patients with SR-Gut-GVHD, results of this project could identify potentially effective approaches for translational testing in humans.


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 = $856,728 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Blood Diseases and Resources Research	000	3	12/20/2024	NON-COMPETING CONTINUATION	$771,055
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Blood Diseases and Resources Research	001	3	8/15/2025	NON-COMPETING CONTINUATION	$85,673
														Subtotal = $856,728

Issue Date FY: 2024 ( Subtotal = $839,592 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Blood Diseases and Resources Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$771,055
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Blood Diseases and Resources Research	001	2	6/21/2024	NON-COMPETING CONTINUATION	$68,537
														Subtotal = $839,592

Issue Date FY: 2023 ( Subtotal = $856,728 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Blood Diseases and Resources Research	000	1	2/10/2023	NEW	$856,728
														Subtotal = $856,728

Grand Total All Awards = $2,553,048

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Pathogenesis, prevention and treatment of corticosteroid-resistant gut GVHD

Award Number: R01HL162847

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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