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T cell Contributions to Neointima Formation in Pulmonary Hypertension

Award Number: K08HL183852
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/15/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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T cell Contributions to Neointima Formation in Pulmonary Hypertension - Pulmonary Hypertension (PH) is a fatal disease where abnormal cells termed “neointima” progressively occlude the pulmonary arteries leading to debilitating right heart failure. PH pathology is characterized by perivascular inflammation, including T cell rich Tertiary Lymphoid Follicles (TLFs). Although perivascular inflammation associates with worse outcomes, preclinical studies implicate T cells as having both pathogenic and protective roles in PH. A repertoire of helper (Th) and regulatory (TReg) T cells shape the immune response by sensing antigen via their T cell Receptors (TCRs) and clonally expanding in response. Current PH therapies do not target neointima or inflammation. Lung transplant remains the only curative therapy. There is a critical unmet need to understand how proliferating T cell lineages and their expressed ligands contribute to neointima development in PH. Here, a mouse model of PH has been developed where human-like perivascular inflammation, including TLFs form alongside occlusive neointimal lesions following chronic intranasal antigen administration. Preliminary data finds that neointima and TLF formation is both T cell and antigen dependent. Ablation of Tregs accelerates neointima formation and implicates a Th17 response. A single cell RNA sequencing “Interactome Map” between T and vascular cells identifies Lymphotoxin (Ltb) as a major T cell- vascular signal. Ltb expression is validated in human PH and Ltb blockade halts neointima and TLF formation in mice. Using bulk and single cell TCR sequencing, the development of neointima formation associates with the growth and suppression of T cell clones responding to antigens. The proposals central hypothesis is neointima development in PH is dependent on a repertoire of pathogenic Cd4+ Th cell clones and the pathogenicity of these clones is mediated by T cell expressed ligands, including Ltb. To test this, three Aims are proposed: (1) Determine the Th cell sub-lineages responsible for pulmonary vascular neointima formation, (2) Functionally test how the T cell specific ligand Ltb mediates neointima development, and (3) Define the neointima-associated T cell repertoire in mouse and human. The proposed training plan augments PI Dr. Adam Andruska’s experience in vascular biology with training in advanced spatial transcriptomic technologies, immunologic mouse models, T cell biology, immune reconstitution, mouse genetics, and single cell paired RNA and TCR sequencing. These studies and training will be guided by co-mentors Maya Kumar, PhD (Aims 1-3) and Mark Nicolls, MD (Aim 1, 2). Consulting will be Dr. Mark Krasnow (Aim 1, spatial transcriptomics), Dr. Ansuman Satpathy (Aim 3, TCR repertoire analysis), and Dr. Rubin Tuder (Aim 1, 3, pathology adjudication). These activities will leverage Stanford University’s research infrastructure and obtain de-identified explanted lung tissue through the Laboratory for Organ Recovery and Bioengineering led by. Dr. Brandon Guenthart. The proposed activities lay a framework for future high impact studies (1) preclinically validating precision immunotherapy in PH and (2) improving the basic understanding of lung vascular inflammation.


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 = $165,888 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	1	4/10/2026	NEW	$165,888
														Subtotal = $165,888

Grand Total All Awards = $165,888

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T cell Contributions to Neointima Formation in Pulmonary Hypertension

Award Number: K08HL183852

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/15/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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