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Pathogenesis of Restrictive Allograft Syndrome Post-Lung Transplantation

Award Number: R01HL162171
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/08/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Pathogenesis of Restrictive Allograft Syndrome Post-Lung Transplantation - PROJECT SUMMARY/ABSTRACT Restrictive allograft syndrome (RAS) is a particularly aggressive form of chronic rejection post-lung transplantation, marked by an extremely poor prognosis (median survival of < 1 year) and little therapeutic options. Pathogenesis of RAS remains elusive although association with donor specific antibodies and antibody mediated rejection have been found in human studies. We have recently characterized a murine lung transplant model which recapitulates the histologic changes of RAS and establishes the requisite role of humoral immune response in its development. A unique feature noted in the murine RAS lung allograft was the presence of activated B cells, plasmablasts, and fully differentiated plasma cell (PCs). PCs were also identified in human RAS lungs suggesting that a rejecting lung serves as an inflammatory local niche for humoral immune responses. These antibody secreting cells (ASCs) localized along the bronchovascular bundles (BVBs) and sub-pleural space, lying in close association with expanding mesenchymal cells (MCs). The key role of specialized stromal cells, via paracrine factors of C-X-C Motif Chemokine Ligand 12 (CXCL12) and interleukin (IL)-6, in establishment of a stable survival niche for ASCs is well recognized across a variety of lymphoid and hematopoietic tissues. We have recently characterized the in situ niche of a subpopulation of lung-resident mesenchymal cells which expand and contribute to fibroproliferation in a RAS allograft. This Foxf1+/Gli1+/Scal1+/Col1+ mesenchymal stromal cell (MSC) population forms a three dimensional network along the bronchovascular bundle (BVB-MSCs). Our new preliminary data demonstrates that these cells are the high CXCL12/IL-6 expressing population, and lie in close apposition to ASCs in the rejecting lung allograft. A novel mechanism of upregulation of CXCL12 expression in BVB-MSCs by IL-6 transsignaling and downstream JAK/Stat activation, with recruited monocytes contributing to the soluble IL-6R, was identified. In this proposal we will investigate an innovative and novel hypothesis of paracrine signaling between this graft-resident mesenchymal stromal cell population and immune cells and the role of IL-6 transsignaling/CXCL12 axis in regulating the humoral inflammatory niche in a rejecting lung. The proposed experiments will utilize our ability to identify and conditionally target the specific BVB-MSC subpopulation, and the novel orthotropic whole lung transplant model of RAS to elucidate the spatial in vivo niche of APCs, its temporal regulation by CXCl12 expressing BVB-MSCs, and its functional significance in the pathogenesis of RAS (Aim 1). The role of IL-6 and IL-6 trans-signaling in cellular communication between resident MCs and infiltrating immune cells within this niche and the pathogenesis of RAS will be determined (Aim 2). The effect of specific drugs targeting humoral cell responses and IL-6 signaling pathway will be tested in the murine lung allograft model of RAS (Aim 3). Together these studies will offer novel mechanistic insight into lung allograft failure and provide pre-clinical information regarding role of therapeutic modalities targeting humoral immune responses in RAS.


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 = $0 )
2026	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	4	10/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $661,951 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	4	11/19/2024	NON-COMPETING CONTINUATION	$595,755
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	001	4	8/15/2025	NON-COMPETING CONTINUATION	$66,196
														Subtotal = $661,951

Issue Date FY: 2024 ( Subtotal = $629,587 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	001	3	12/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$595,172
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	005	3	7/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$34,415
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	004	3	5/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$835,605
2024	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	003	2	5/15/2024	NON-COMPETING CONTINUATION	-$671,112
2024	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	000	2	12/7/2023	NON-COMPETING CONTINUATION	$0
2024	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	002	1	5/15/2024	NEW	-$164,493
														Subtotal = $629,587

Issue Date FY: 2023 ( Subtotal = $671,112 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	000	2	12/6/2022	NON-COMPETING CONTINUATION	$604,001
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	001	2	2/17/2023	NON-COMPETING CONTINUATION	$67,111
														Subtotal = $671,112

Issue Date FY: 2022 ( Subtotal = $701,112 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	000	1	11/26/2021	NEW	$701,112
														Subtotal = $701,112

Grand Total All Awards = $2,663,762

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Pathogenesis of Restrictive Allograft Syndrome Post-Lung Transplantation

Award Number: R01HL162171

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/08/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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