# Mechanisms of Antigen-Induced Tolerance in the Lung

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $592,242

## Abstract

Repeated exposure to low doses of an allergen prevents adverse reactions upon subsequent exposure to the
same allergen. Allergen immunotherapy (AIT) has been effectively practiced to treat a broad spectrum of
allergic diseases although examples of AIT in asthma are rare because of safety concerns. There is hence an
unmet need for useful animal models for airway tolerance to common aeroallergens for future translation.
Many studies suggest a critical time window in early life for achieving tolerance (Tol) to prevent development of
allergic disease. We have established a new model of allergen-tolerance (Tol) initiated by repeated exposure
of newborn mice to a low dose of the common household allergen, house dust mite (HDM). Using older mice,
we previously demonstrated PPARg-mediated production of H2O2, a reactive oxygen species (ROS), from the
mitochondria of lung CD11c+ cells in the context of inhaled Tol to the model allergen ovalbumin. Since ROS
can be generated from mitochondria as well as from non-mitochondrial sources, using newborn MCAT
transgenic mice that overexpress the enzyme catalase specifically in mitochondria to selectively deplete
mitochondrial H2O2 (mt H2O2), we have recently published that Tol to HDM is abolished in MCAT mice.
Functionally, we observed an impact of Tol in constraining numbers of conventional dendritic cells (cDCs) in
the lung and correspondingly scRNA-seq data show a significant decrease in expression of the gene Marcksl1
implicated in cellular apoptosis and cell migration in Tol MCAT mice. Analysis of recently published human
scRNA-seq data of endobronchial biopsies from asthmatic individuals subjected to segmental allergen
challenge has revealed suppression of Marcksl1 expression relative to baseline in human lung cDC1s upon
allergen challenge. At the other end of the spectrum, in studies of asthma, we and others have identified tissue
resident memory (TRM) cells in the lungs of humans and mice. In our ongoing work we have found that the
TRMs can be reactivated after a prolonged period of rest highlighting the importance of suppressing allergen
sensitization in early life to minimize emergence of TRMs. These observations lead us to hypothesize that
persistent exposure to low doses of allergens such as HDM programs lung cDCs to express Marcksl1 requiring
mt H2O2 that is important for Tol establishment. Early life allergen Tol suppresses the development of TRMs to
provide long-term protection from disease. We propose the following 3 aims, to address these hypotheses:
Aim 1. To dissect the impact of cDC-specific deletion of Marcksl1 on loss of HDM-induced Tol.
Aim 2. To determine ROS production in the presence or absence of Marcksl1 and the role of fatty acid
oxidation in cDC1s in Tol induction.
Aim 3. To analyze scRNA-seq data from mice and humans to understand DC subset-specific
programming during Tol vs inflammation.

## Key facts

- **NIH application ID:** 10979940
- **Project number:** 1R01AI176632-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Anuradha Ray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $592,242
- **Award type:** 1
- **Project period:** 2024-06-12 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979940

## Citation

> US National Institutes of Health, RePORTER application 10979940, Mechanisms of Antigen-Induced Tolerance in the Lung (1R01AI176632-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10979940. Licensed CC0.

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