# Immune Airway-Epithelial Interactions in Steroid-Refractory Severe Asthma

> **NIH NIH P01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $1,878,574

## Abstract

Severe asthma (SA) is complex, multifactorial and refractory to treatment by corticosteroids (CS). In recent
years, some progress has been made in its treatment with the advent of biologics. However, despite these
advancements, there still remain challenges in the treatment of these patients because of an incomplete
understanding of the dysfunction of immune and epithelial cells, which underlies this disease. This is further
complicated by the poor biomarkers available to differentiate disease for targeted therapy, and amplified by
their enormous costs, particularly when prescribed imprecisely. Progress made in Project 1 in the current
cycle using mass cytometry/CyTOF, show clustering of SA patients into 2 groups displaying distinct immune
profiles divided along the lines of innate and adaptive immunity. Progress made in Project 2 in studies of
bronchial epithelial cells (BECs) in SA suggest the presence of two fundamentally different molecular
phenotypes. The BECs in one group primarily respond to inhaled environmental stimuli to drive an innate
intrinsic phenotype. In the second group, BEC cell death pathways intersect with CD8 T-cell immune
processes to drive an immune interactive phenotype. Taken together, these findings prompted us to
hypothesize that two distinct immune mechanisms, one regulated by innate immune cells, and the second by T
cells, are critical determinants of SA. Interactions between airway epithelial cells in the context of
genetic/epigenetic risks and immune cells together with induction of cellular death contribute to two SA
phenotypes. This hypothesis will be addressed in the following two highly interactive projects: Project 1 will
use human samples and mouse models of disease to: a) characterize the CITE-seq and TCR-seq airway
immune cells collected by BAL and investigate the impact of dupilumab on immune phenotype, b) study the
importance of FceRI-expressing innate immune cells and IL-7Ra signaling in FceRI+ cells in promoting a SA
phenotype using a novel protease-based mouse model, and c) study mechanisms underlying regulation of
TRM cell phenotype and impact on disease using a T cell-driven mouse model of SA. Project 2 will use fresh
and cultured healthy and asthmatic BECs to: a) determine the mechanisms for and functional implications of
an innate intrinsic epithelial phenotype, b) evaluate the role of GSDMB in the development of a CD8 T-cell
immune interactive phenotype and its functional implications, and c) Integrate immune-inflammatory
phenotypes with epithelial molecular phenotypes ex vivo and in vitro. Synergistic interactions among projects
will be afforded by support from: Core A, the Administrative Core, to coordinate the activities of the Program
Project at all levels, Core B, the Human Biological Sampling and Immunocytometry Core and Core C, the
RNA-Seq and Bioinformatics Core. Taken together, these projects will establish new concepts in immune-
epithelial interactions underlying asthma pathogenesis and ...

## Key facts

- **NIH application ID:** 10425153
- **Project number:** 2P01AI106684-06A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Anuradha Ray
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,878,574
- **Award type:** 2
- **Project period:** 2015-06-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425153

## Citation

> US National Institutes of Health, RePORTER application 10425153, Immune Airway-Epithelial Interactions in Steroid-Refractory Severe Asthma (2P01AI106684-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10425153. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*