# Immunoregulatory Mechanisms of IL-33 in Heart Transplantation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $598,488

## Abstract

Early graft injury is the consequence of unavoidable transplant-associated events, such as donor brain death,
ischemia/reperfusion injury, and surgical trauma. Recipient responses to graft alloantigens will also produce graft
damage throughout the life of the graft. These injuries and stresses cause the release of self-molecules
containing damage-associated molecular patterns (DAMPs). It is well appreciated that DAMPs support pro-
inflammatory responses when they are sensed by cells of the innate immune system, particularly monocytes
and macrophages. Preclinical rodent heart transplant studies reveal that these released DAMPs initiate and
propagate alloresponses and targeting inflammatory DAMPs, or the signaling cascades they activate, reduce
alloimmunity and improve outcomes after transplantation. Yet, our recent research has provided compelling
evidence that these graft injuries also release reparative DAMPs (rDAMPs), such as Interleukin-33 (IL-33), which
limits local inflammation and initiates immune-mediated tissue repair after heart transplant. By assessing
pediatric heart transplant recipient samples and using a preclinical mouse heart transplant model, we identified
that IL-33 is upregulated in graft stromal cells and limits the development of allograft vasculopathy and graft
fibrosis that later culminates in chronic rejection (CR). Our published and preliminary data suggest that IL-33
mediates this protection by targeting infiltrating monocytes and macrophages, as well as regulatory T cells
(Tregs), to limit the generation of pro-inflammatory macrophages and then coordinate a Treg and reparative
macrophage-mediated response to injury. While these data are encouraging, our studies also suggest that the
processes that initiate repair of early tissue damage may become dysregulated over the graft's life. In preliminary
data, we show that vessel-associated Tregs become pathologic when their sustained secretion of repair factors
in response to IL-33 promotes the proliferation of local fibroblasts contributing to CR. In addition to having their
functions programmed by local rDAMPs, graft infiltrating recipient monocytes recognize allogenic molecules
causing them to mature into pro-inflammatory myeloid cells that stimulate T cell proliferation and IFNγ production
in the graft. We have established that monocytes and macrophages recognize and develop allospecific
cytotoxicity and memory to MHCI antigens via paired immunoglobulin-like receptors-A. These data lead us to
HYPOTHESIZE that rDAMP signals initiating the repair of tissue damage early after heart transplantation
become dysregulated around the vasculature due to a sustained inflammatory response by alloreactive immune
cells. We will test this hypothesis in two aims: In AIM 1, we will define how rDAMP and immune cell interactions
evolve in heart transplant microenvironments during CR development. In AIM 2, we will establish if innate
alloimmunity prevents effective injury resolution and repai...

## Key facts

- **NIH application ID:** 10880447
- **Project number:** 5R01HL122489-08
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Heth R Turnquist
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,488
- **Award type:** 5
- **Project period:** 2022-08-10 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880447

## Citation

> US National Institutes of Health, RePORTER application 10880447, Immunoregulatory Mechanisms of IL-33 in Heart Transplantation (5R01HL122489-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10880447. Licensed CC0.

---

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