# Hedgehog-Induced Activation of Alloimmune T Cells During Ischemia Reperfusion Injury

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2024 · —

## Abstract

Ischemia reperfusion injury (IRI) is a pathological process affecting solid organ allografts and occurs
when a transplanted organ subjected to prolonged disruption of blood flow undergoes tissue damage following
surgical implantation. IRI frequently occurs among deceased donors and predisposes to chronic antibody-
mediated rejection (CABMR), decreased graft survival, and worsened patient outcomes. This condition has no
effective medical treatments and is especially relevant to veteran transplant recipients who undergo higher
rates of deceased donor transplants and are thus at risk for developing IRI and its related complications.
 In recognition of the significant lifetime health burden and costs incurred by IRI to veteran patients and
to the VA Healthcare System, respectively, recent federal mandates have established mechanisms to
systemically improve care for veteran recipients of solid organ transplants, in particular renal transplants. This
mandate will increase the number of transplanting VA centers, institute systems-based changes to improve
pre- and post-operative access to care, and promote basic research to improve allograft survival.
 In this context, we submit this transplant immunology application to explore a role for Hedgehog (Hh)
signaling in CABMR, an IRI-associated complication in solid organ transplantation. Complement (C') are
immune proteins involved in host defense that are pathologically activated on endothelial cells (ECs) during
IRI, a process we have found selectively expands T peripheral helper (TPH cells), a recently discovered CD4+ T
cell subset specialized in provision of B cell help. Hh signaling is a widely studied pathway regulating wound
healing by eliciting vascular cell proliferation. We reasoned that Hh ligands are released by C'-injured ECs
during IRI as a signal for autologous wound repair, but concurrently these same ligands could expand
alloimmune TPH cells that go on to promote alloantibody responses and CABMR-related pathologies.
 To test this notion, we used humanized models in vitro and in vivo, and we used prospectively collected
patient samples to increase the clinical relevance of our findings. Our data showed that IRI-treated ECs
produced Hh ligands in a C'-dependent manner that selectively activated T peripheral helper (TPH) cells, a
newly described T cell subset specialized in provision of B cell help. Mechanistically, Hh induced ZFYVE21, a
novel Rab5 effector we discovered, to elicit Akt-mediated NRLP3 inflammasomes in TPH cells. This resulted in
IL-18 release and IL-18-mediated expansion of IL-18R1+TPH cells that promoted CABMR-like pathologies
including vascular inflammation, alloAb production, and vasculopathy. These exciting preliminary data address
an important and prevalent clinical problem that is a focus area of recent federal initiatives at the VA.
 From these data, we hypothesize that Hedgehog ligands released by C'-injured EC during IRI activate
CD4+ TPH cells to elicit CABMR-associate...

## Key facts

- **NIH application ID:** 10725136
- **Project number:** 5I01BX005117-04
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Dan Jane-Wit
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10725136

## Citation

> US National Institutes of Health, RePORTER application 10725136, Hedgehog-Induced Activation of Alloimmune T Cells During Ischemia Reperfusion Injury (5I01BX005117-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10725136. Licensed CC0.

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