# Immune Checkpoints in Acute Respiratory Distress Syndrome (IC-ARDS)

> **NIH NIH R01** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2020 · $769,298

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute respiratory distress syndrome (ARDS) is an important cause of morbidity and mortality resulting in over
74,000 intensive care unit deaths per year in the United States. Patients often present with rapidly progressive
respiratory failure requiring prolonged mechanical ventilation which is costly and associated with long term
disability. A more refined understanding of the pathophysiologic mechanisms of ARDS may guide more
personalized approaches for prognostication and therapy. The immune “checkpoint” pathway includes the
receptor Programmed cell death protein 1 (PD-1) and its ligand Programmed death-ligand 1 (PD-L1). The
binding of PD-L1 to PD-1 leads to negative regulation of T cell receptor signaling. PD-1 and PD-L1 have been
associated with defects in immune function in patients with sepsis which is a major risk factor for ARDS. For
example, high PD-1 expression on circulating T cells in patients with sepsis is associated with decreased T cell
interferon-gamma production. However, other studies suggest a role for this pathway in limiting tissue
inflammation. Preliminary data in this proposal shows that patients with ARDS who have prolonged mechanical
ventilation have lower expression of PD-L1 on alveolar macrophages. Further, a serious side effect of
pharmaceutical inhibitors of this pathway termed “checkpoint inhibitors” is immune mediated tissue injury such
as an ARDS-like pneumonitis. Thus the role of this pathway in modulating immune responses may be critical to
our understanding of ARDS. The hypothesis of this study is that immune checkpoint proteins are protective
against poor outcomes in ARDS by limiting tissue injury. This study will also investigate potential mechanisms
of this association through promotion of regulatory T cell responses or limiting inflammatory T cell responses.
Study subjects will be enrolled into a discovery cohort where measurements will be performed using novel high
dimensional mass cytometry to identify expression of these proteins on a single cell basis. A validation cohort
will be recruited externally to confirm these findings. Aim 1 will identify whether cell surface immune checkpoint
protein expression is associated with severity of ARDS, Aim 2 will focus on mechanisms behind the
association in modulating T cell responses, and Aim 3 will identify potential soluble measures of this pathway.
This study aims to identify a biologically relevant immune signature of patients at risk for prolonged mechanical
ventilation and death from ARDS.

## Key facts

- **NIH application ID:** 9857933
- **Project number:** 1R01HL149676-01
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Carmen R Mikacenic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $769,298
- **Award type:** 1
- **Project period:** 2020-09-05 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857933

## Citation

> US National Institutes of Health, RePORTER application 9857933, Immune Checkpoints in Acute Respiratory Distress Syndrome (IC-ARDS) (1R01HL149676-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857933. Licensed CC0.

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