# Cell Death Pathways and Heart Transplant Rejection

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $550,756

## Abstract

The long-term survival of allografts and patients receiving deceased donor organs remain poor. There
is evidence to suggest that cold ischemia (CI) and the subsequent reperfusion during transplants causes
cellular injury, which leads to an induction of T cell alloimmunity against donor tissue and ultimately graft
rejection. The mechanism by which ischemia reperfusion (IR) initiates cellular injury, the manner of the injury,
and how this injury impacts alloresponse are poorly understood. To better mimic human deceased donor
transplants, the Fairchild laboratory developed an allograft heart transplant model whereby the donor organ is
subjected to extended CI prior to transplantation followed by administration of an CTLA4Ig costimulatory
blockade. Allograft hearts subjected to CI were rejected whereas those not subjected to CI survived.
Preliminary studies using this model indicated that complement deficiency in the recipients prolonged the
survival of CI-treated allografts, correlating with reduced circulating TNFα. As TNFα is a known inducer of
necroptosis, an inflammatory cell death, additional studies showed that organs from CYLD-deficient donors,
(which are defective in necroptosis) survived longer than wild type organs whereas organs from SHARPIN-
deficient donors (which have accelerated necroptosis) were rapidly rejected. Based on these studies, we have
proposed and will test the unifying hypothesis that complement activation following CI/IR during transplants
leads to the induction of TNFα, which then induces necroptosis of cells in donor tissues. In turn, this
inflammatory cellular injury activates T cell alloimmunity to cause rejection. This collaborative study brings
together in a highly synergistic manner the unique strengths of three laboratories to address the above
hypothesis. (1) In Aim 1, we will examine the role of mannose-binding lectin (MBL)-initiated complement
activation in triggering TNF-dependent necroptosis in our allograft transplant model using MBL, TNF and
TNFRs knockouts/knockins. (2) In Aim 2, the role of the TNF cell death pathway in CI-initiated rejection will be
further dissected using donor organs derived from various knockouts/knockins of CYLD, RIPK1, RIPK3,
Caspase-8 and SHARPIN. (3) Necroptosis releases damage-associated molecular patterns (DAMPs) and thus
in Aim 3, we will examine how DAMPs are sensed by host antigen-presenting cells and how this leads to
induction of the T cell alloresponse. All three aims are highly significant, as they will provide insights into which
molecules during (1) initiation, (2) cellular injury and (3) effector phases of graft rejection may be targeted for
therapeutic blockade in transplants. The approach has strong potential to directly and positively impact
outcomes of transplant patients.

## Key facts

- **NIH application ID:** 10162490
- **Project number:** 5R01AI132405-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Peter Scott Heeger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $550,756
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162490

## Citation

> US National Institutes of Health, RePORTER application 10162490, Cell Death Pathways and Heart Transplant Rejection (5R01AI132405-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10162490. Licensed CC0.

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