Monday, June 30, 2025 6/30/2025

Notch Signaling in Alloimmunity

Award Number: R01AI091627
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: 04/22/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Notch Signaling in Alloimmunity - ABSTRACT Allogeneic T cell responses against foreign host antigens mediate graft-versus-host disease, the most serious complication of allogeneic hematopoietic cell transplantation (allo-HCT). During the course of this proposal we defined a critical role for Notch signaling in the regulation of pathogenic alloreactive T cells that mediate graft-versus-host disease (GVHD) in multiple mouse models of allo-HCT. Notch inhibition in donor T cells led to long-term protection from GVHD morbidity and mortality. Using monoclonal antibodies, we identified a critical role for Notch1/2 receptors in T cells and Delta-like1/4 (Dll1/4) Notch ligands in the host, with dominant effects of Notch1 and Dll4. Dll1/4 blockade with a short course of antibodies emerged as the most promising strategy to target Notch signaling while avoiding systemic side effects of pan-Notch inhibition. We recently uncovered several remarkable features of Notch regulation in T cell alloimmunity that warrant further investigation. First, we identified specialized radioresistant stromal cells lineage-traced with a Ccl19-Cre transgene as the critical source of Notch ligands in secondary lymphoid organs at the onset of GVHD. These findings uncover a central role for fibroblastic stromal cell subsets in GVHD. Second, short-term inhibition of Delta-like Notch ligands within days after allo-HCT was essential to confer long- term protection from GVHD in multiple mouse models. Within this early time window, Notch induced unique transcriptional effects during the activation of alloantigen-specific T cells that impacted selected aspects of their differentiation. Third, we studied Notch ligand inhibition in a non-human primate allo-HCT model that mimics human transplantation. A single dose of anti-DLL4 antibodies had marked single agent activity to prevent GVHD, showing highly conserved effects of Notch signaling from mice to non-human primates. In both models, we observed an increased ratio of regulatory to conventional T cells in the gut and striking protection from intestinal GVHD, the most dangerous component of acute GVHD. We hypothesize that alloantigen-specific T cells engage in early interactions with specialized subsets of fibroblastic stromal cells expressing Delta-like Notch ligands, inducing a Notch-driven pathogenic and gut-homing program in T cells that promotes GVHD. To explore this hypothesis, we will identify individual subsets of fibroblastic stromal cells that present Dll1 and/or Dll4 Notch ligands to donor-derived T cells early after allo-HCT, map the anatomical sites that support Notch activation in alloreactive T cells, and define the impact of immune- mediate injury on the subsequent integrity of stromal networks in secondary lymphoid organs. In addition, we will identify mechanisms that blunt the accumulation of Notch-deficient T cells in the gut, thus preventing intestinal GVHD, and investigate the early transcriptional effects of Notch signaling in alloreactive T cells. These studies will bring novel insights into the regulation of alloimmunity and might lead to the development of new approaches to limit damaging consequences of T cell reactivity after allogeneic transplantation.


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 = $0 )
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	15	12/31/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $406,250 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	15	5/27/2024	NON-COMPETING CONTINUATION	$406,250
														Subtotal = $406,250

Issue Date FY: 2023 ( Subtotal = $406,250 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	14	5/18/2023	NON-COMPETING CONTINUATION	$406,250
														Subtotal = $406,250

Issue Date FY: 2022 ( Subtotal = $406,250 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	13	5/19/2022	NON-COMPETING CONTINUATION	$406,250
														Subtotal = $406,250

Issue Date FY: 2021 ( Subtotal = $406,145 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	008	12	9/24/2021	COMPETING CONTINUATION	$2,589
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	12	2/22/2021	COMPETING CONTINUATION	$406,145
2021	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	007	11	9/24/2021	NON-COMPETING CONTINUATION	-$2,589
2021	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	006	8	9/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$37,119
2021	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	8	6/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$34,530
2021	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	003	9	9/21/2021	NON-COMPETING CONTINUATION	$37,119
2021	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	005	9	9/21/2021	NON-COMPETING CONTINUATION	-$37,119
2021	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	001	7	6/23/2021	SUPPLEMENT FOR EXPANSION	$34,530
2021	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	004	7	9/21/2021	SUPPLEMENT FOR EXPANSION	-$37,119
														Subtotal = $406,145

Issue Date FY: 2020 ( Subtotal = $388,900 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	11	5/13/2020	NON-COMPETING CONTINUATION	$388,900
														Subtotal = $388,900

Issue Date FY: 2019 ( Subtotal = $401,903 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	10	5/9/2019	NON-COMPETING CONTINUATION	$401,903
														Subtotal = $401,903

Issue Date FY: 2018 ( Subtotal = $474,007 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	004	8	5/21/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$34,530
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	9	5/18/2018	NON-COMPETING CONTINUATION	$474,007
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	8	2/27/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$128,790
2018	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	7	2/27/2018	NON-COMPETING CONTINUATION	-$128,790
2018	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	003	7	5/21/2018	SUPPLEMENT FOR EXPANSION	-$34,530
														Subtotal = $474,007

Issue Date FY: 2017 ( Subtotal = $455,806 )
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	7	5/1/2017	NON-COMPETING CONTINUATION	$388,900
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	001	7	8/1/2017	SUPPLEMENT FOR EXPANSION	$66,906
														Subtotal = $455,806

Issue Date FY: 2016 ( Subtotal = $402,650 )
2016	2016	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	6	6/14/2016	COMPETING CONTINUATION	$402,650
														Subtotal = $402,650

Issue Date FY: 2015 ( Subtotal = $382,503 )
2015	2015	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	5	3/5/2015	NON-COMPETING CONTINUATION	$382,503
														Subtotal = $382,503

Issue Date FY: 2014 ( Subtotal = $382,686 )
2014	2014	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	4	3/3/2014	NON-COMPETING CONTINUATION	$382,686
														Subtotal = $382,686

Issue Date FY: 2013 ( Subtotal = $359,891 )
2013	2013	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	001	3	5/31/2013	NON-COMPETING CONTINUATION	$15,315
2013	2013	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	3	3/15/2013	NON-COMPETING CONTINUATION	$344,576
														Subtotal = $359,891

Issue Date FY: 2012 ( Subtotal = $383,034 )
2012	2012	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	2	3/15/2012	NON-COMPETING CONTINUATION	$383,034
														Subtotal = $383,034

Issue Date FY: 2011 ( Subtotal = $382,600 )
2011	2011	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	1	4/22/2011	NEW	$382,600
														Subtotal = $382,600

Grand Total All Awards = $5,638,875

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Notch Signaling in Alloimmunity

Award Number: R01AI091627

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: 04/22/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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