# Investigation of sex variation in PD-1/pSTAT3/IL-17A signaling in sarcoidosis pathogenesis

> **NIH NIH R56** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $857,679

## Abstract

Project Summary
 Sarcoidosis is a granulomatous disease of unknown etiology with striking disparities in
clinical outcome. Approximately 60% of sarcoidosis patients will spontaneously resolve their
disease, while the remaining subjects experience a gradual loss of lung function, from with ~15-
20% ultimately die.
 We previously reported that the strength of the adaptive immune response is an important
factor in sarcoidosis clinical outcome. Prior investigations demonstrate increased Programmed
Death-1 (PD-1) expression on CD4+ T cells in sarcoidosis patients experiencing disease
progression. Our recent publication in Science Translational Medicine demonstrates that
PD-1+CD4+ T cells have augmented IL-6 expression that induces pSTAT3 transcription,
leading to increased expression of the pathogenic cytokines, IL-17A and TGF-β1. These cells
upon co-culture with human lung fibroblasts induce collagen-1 production. The percentage of
PD-1+CD4+ T cells is significantly higher in female sarcoidosis subjects, compared to males.
 These observations support the hypothesis that estrogen-mediated alteration in
PD-1 pathway/IL-6/pSTAT3 signaling drive the female predominance in sarcoidosis loss
of lung function. This proposal will delineate if the effects of estrogen on Th17 cell
development are directly or indirectly mediated through PD-1 pathway signaling. We will also
conduct in vivo investigations of the efficacy of currently FDA-approved therapeutics against
PD-L1, PD-1, IL-6, pSTAT3 and IL-17A on reduction of collagen production. These analyses
will serve as proof-of-concept investigations, thus laying the foundation for design of innovative
clinical trials of effective therapeutics against pulmonary sarcoidosis progression according to
sex.

## Key facts

- **NIH application ID:** 10266230
- **Project number:** 1R56HL149129-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Wonder P. Drake
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $857,679
- **Award type:** 1
- **Project period:** 2020-09-23 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266230

## Citation

> US National Institutes of Health, RePORTER application 10266230, Investigation of sex variation in PD-1/pSTAT3/IL-17A signaling in sarcoidosis pathogenesis (1R56HL149129-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10266230. Licensed CC0.

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