# Modulation of innate immune cells to create transplant tolerance

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $484,500

## Abstract

Project Summary
Macrophages as a key cell type in the innate immune system are involved in a wide spectrum of allograft
responses, but exactly what they do and by what mechanisms they affect diverse allograft outcomes
remains poorly understood. We recently reported the identification of Paired Ig-like Receptors (PIR) as an
innate allorecognition system that allows myeloid cells to acquire features of allospecificity and innate
memory in transplant models (Science 2020;368:1122), thus uncovering new opportunities in better
understanding and potentially targeting those cells in favor of transplant survival. However, outstanding
questions remain regarding the longevity of innate memory macrophages in vivo, how PIR-A/B receptors
are regulated, and the exact identity of macrophages in tolerized grafts. Now we have generated new
preliminary data showing that the chromatin structures at Pira and Pirb loci are strikingly different and that
they are controlled by distinct epigenetic mechanisms downstream of CD40 and PIR-A3 signaling
pathways. Furthermore, the anti-donor innate memory macrophages in vivo are incredibly stable as a result
of the concerted actions of CD40 and PIR-A3. The goal of this project is to dissect mechanistically how the
anti-donor innate memory macrophages are induced and maintained long-term, testing the hypothesis that
the “open” chromatin modifications at the Pira3 locus downstream of CD40 signaling pathways mediate
PIR-A3 expression via allelic exclusion and that the subsequent PIR-A3 signaling then programs stable
memory features of innate macrophages upon binding to MHC-I. We put together 3 Aims to test this
hypothesis. Aim 1 is to determine whether induction of anti-donor innate macrophage memory depends on
“open” chromatin remodeling at Pira3 locus downstream of CD40 signaling as well as the NF-kB pathways
involved (canonical vs. non-canonical). Aim 2 is to examine whether the long-term maintenance of anti-
donor innate memory macrophages requires PIR-A3 signaling, especially in driving epigenetic and
metabolic rewiring and cell survival. Aim 3 is to use a mouse heart transplant model to test whether
decommissioning the anti-donor innate memory macrophages is a fundamental mechanism of tolerance
induction upon targeting the CD40/PIR-A3 axis. We believe that studies in this application are addressing a
significant knowledge gap in transplantation, and the animal models, tools, and multi-omics approaches we
have developed in the lab put us in a unique position to carry out the proposed studies and move the field
forward.

## Key facts

- **NIH application ID:** 10975215
- **Project number:** 2R01AI080779-12A1
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Xian Chang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,500
- **Award type:** 2
- **Project period:** 2011-03-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975215

## Citation

> US National Institutes of Health, RePORTER application 10975215, Modulation of innate immune cells to create transplant tolerance (2R01AI080779-12A1). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10975215. Licensed CC0.

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