# Activation, Phenotype and Function of CD4 T Cells in Schistosoma-Pulmonary Hypertension

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $557,806

## Abstract

Summary/Abstract
Inflammation has important roles in the pathogenesis of pulmonary arterial hypertension (PAH), but whether
inflammation is causal, an amplifier of alternative triggering mechanisms, or an epiphenomenon remains unclear.
Prior studies in this area have largely focused on innate immunity, sterile models, and single cytokines or cells
in the absence of a well-defined pathobiological context—approaches that cannot address aspects of adaptive
immunity or innate-adaptive immunity crosstalk which contribute to vascular disease. To address these
limitations, our group studies the parasite Schistosoma, the cause of schistosomiasis which may be the most
prevalent form of PAH worldwide. Using a Schistosoma-pulmonary hypertension (PH) murine model, studies in
the prior period identified a series of mechanistic events which are critical for PH development: Th2-activation of
CD4 T cells in the lungs; which recruit of CCR2+ Ly6c+ monocytes to the adventitial space that express
thrombospondin-1 (TSP-1); and the TSP-1 functionally activates latent TGF-β, causing vascular remodeling.
This proposal builds on this foundation by now interrogating adaptive and innate immune interfaces that we
believe to be necessary to Schistosoma-PH pathogenesis. We extend our studies to translational analysis of
human biospecimens, seeking proteins that correlate with PAH presence in an at-risk group with severe
schistosomiasis. This proposal will test the hypothesis that intrapulmonary dendritic cells (DCs) present
Schistosoma antigen to CD4 T cells which support Th2 polarization, causing activation of interstitial
macrophages (IMs), who release the CCR2 ligands CCLs 2, 7 and 12, driving TSP-1+ monocyte recruitment,
TGF-β activation, and PH. We also hypothesize that key proteins that increase risk of PAH—including CCL2,
CCL7, CCL12, and TSP-1—can be detected in human plasma. We propose 4 Aims. Aim 1 will determine that
antigen presentation by a specific DC subset, cDC2s, is required for T cell activation in Schistosoma-PH. Aim 2
will determine if the balance of Th1 to Th2 inflammation drives monocyte/macrophage and PH phenotypes in
Schistosoma-PH. Aim 3 will determine that CCL2/7/12 release by IMs is required for TSP1+ monocyte
recruitment in Schistosoma-PH. Aim 4 will identify plasma proteins associated with PAH development in subjects
with schistosomiasis. This translational Aim will be achieved by developing and characterizing two cohorts of
subjects recruited from 4 clinical centers in Brazil: subjects with the precursor condition schistosomiasis
hepatosplenic disease (SchHSD) who are unlikely to have PAH on the basis of echocardiography screening,
and subjects with SchHSD who have right heart catheterization-confirmed PAH. Completion of these studies will
lead to understanding the role of innate and adaptive immunity in the development of Schistosoma-PAH, and
create opportunities for entirely novel approaches to diagnosing and potentially treating this disease....

## Key facts

- **NIH application ID:** 10914845
- **Project number:** 5R01HL135872-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Brian Barkley Graham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $557,806
- **Award type:** 5
- **Project period:** 2016-12-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914845

## Citation

> US National Institutes of Health, RePORTER application 10914845, Activation, Phenotype and Function of CD4 T Cells in Schistosoma-Pulmonary Hypertension (5R01HL135872-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10914845. Licensed CC0.

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