# Defining How Macrophage Allorecognition Impacts Tissue Repair After Transplantation

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic rejection (CR) after heart transplant (HTx) is the principal barrier to long-term graft survival that results
in nearly 50% graft rejection after 10 years post-transplant (Tx). The factors driving CR are complex, as current
immunosuppressive regimes targeting lymphocytes fail to prevent progressive fibrotic scarring and occlusion of
graft vasculature. However, a known protagonist to the development of CR is prolonged graft ischemia
reperfusion injury (IRI) that triggers robust early inflammatory responses of graft infiltrating monocytes that react
to local inflammatory signals. Recently, it was established that monocytes and macrophages (MΦs) distinguish
non-self from self MHCI via paired-immunoglobulin-like receptors (PIRs), and direct innate recognition of
allogeneic H2-Dd by PIR-A promoted HTx rejection. MΦs are essential for resolving inflammation to promote
reparative responses that re-establishes graft homeostasis to preserve organ function, yet how MΦ alloantigen
recognition shapes or dysregulates the repair of grafts is completely unknown. I tested how MΦ recognition of
self or non-self coordinates their differentiation and demonstrated that mono-derived MΦ recognition of
allogeneic materials locally transforms them into pro-inflammatory Ly6chiCD86hi MΦs in wildtype, Rag2-/-γc-/-, and
Pira-/--Rag2-/-γc-/ B6 recipients-. My preliminary data further settled that recombinant H2-Dd promotes pro-
inflammatory differentiation in bone marrow-derived MΦs (BMDMΦs) and there were again no differences
between wildtype and Pira-/- BMDMΦs. Therefore, I tested whether MΦs express other H2-Dd receptors and my
preliminary data shows that blocking the receptor Ly49d extinguished H2-Dd-associated pathways. Lastly, I
determined the functional consequences of this MΦ allorecognition, and show that MΦ exposure to allogeneic,
but not syngeneic, amplifies their repair of fibroblasts. Therefore, my hypothesis is that recipient MΦs differentiate
into a pro-fibrotic subset due to Ly49d-induced signaling triggered by donor H2-Dd MHCI leading to dysregulated
repair and accelerated CR. I will directly test this hypothesis by addressing the following Specific Aims: 1.
Define how MΦ recognition of non-self H2-Dd shapes the transcriptome and metabolome to induce pro-
inflammatory MΦ differentiation. 2. Determine if preventing MΦ non-self MHCI recognition limits CR after IRI in
heart grafts. Completion of these aims will establish if Ly49d is a fundamental MΦ allorecognition receptor and
define pathways mediating pro-inflammatory MΦ differentiation to H2-Dd. I will also precisely determine whether
MΦ recognition of H2-Dd amplifies their pro-fibrotic roles, and if abolishing MΦ responses to non-self MHCI limits
CR to deliver effective graft repair. Contribution to Training: This proposal entails an extensive training plan to
elucidate MΦ alloimmune responses combined with superb mentorship in bioinformatics and biochemistry.
Together, the ...

## Key facts

- **NIH application ID:** 10929377
- **Project number:** 5F31HL170514-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jordan Warunek
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929377

## Citation

> US National Institutes of Health, RePORTER application 10929377, Defining How Macrophage Allorecognition Impacts Tissue Repair After Transplantation (5F31HL170514-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10929377. Licensed CC0.

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