# Requirements and mechanisms of alloantigen-induced cardiac allograft survival by cDC1s

> **NIH NIH F30** · NORTHWESTERN UNIVERSITY · 2023 · $43,243

## Abstract

PROJECT SUMMARY/ABSTRACT
Heart transplantation is currently the only treatment for advanced stage heart failure and as such, the volume of
transplants performed globally continues to increase. Advances in surgical technique and available
immunosuppression have improved patient survival acutely, however the same cannot be said years after
transplantation. Immune mediated pathologies such as chronic allograft vasculopathy result in graft failure and
significant morbidity from prolonged use of immunosuppressant medication including renal dysfunction, diabetes,
and malignancy, continue to be experienced by patients. Therefore, improved strategies to promote survival of
the cardiac allograft are necessary.
A great deal of research has sought to identify the cellular actors responsible for cardiac allograft rejection and
tolerance. In the setting of rejection, the adaptive immune response has emerged in a leading role, specifically
CD4+ and CD8+ T cells. Importantly, T cells are not solo performers but instead require instruction provided by
antigen presenting cells, predominantly dendritic cells (DCs). Once considered a homogenous population, DCs
are now recognized for their distinct ontogeny and functional roles which determine DC subset identity.
Conventional DC 1 cells (cDC1s) are powerful mediators of the immune response and have been shown to be
critical for the promotion of central tolerance. Yet no work on the subset specific role of cDC1s in solid organ
transplantation has been performed and our understanding of cDC1s in peripheral tolerance remains in its
infancy. Importantly, my preliminary data implicate cDC1s as necessary in donor-induced tolerization strategies
that result in long term cardiac allograft survival.
Tolerization strategies utilizing infused donor antigen and costimulation blockade (CoB) produce long term
cardiac allograft survival in murine and nonhuman primate models, though little is known as to how exposure of
donor alloantigen influences tolerance induction. This proposal hypothesizes that during a donor-induced
tolerance strategy, the cDC1 subset is necessary to promote peripheral immunological
hyporesponsiveness towards cardiac allografts through processing of alloantigen, modulation of
surface marker expression, and metabolic transcriptional reprogramming. This hypothesis will be tested
using mouse models of cDC1 deletion and heterotopic heart transplantation alongside functional (palpation,
echocardiography) and cellular (flow cytometry, histology) analysis. Additionally, single-cell transcriptomics of
splenic DCs after in vivo allo- and iso- infusion in the presence of CoB coupled with in vitro experimentation will
help unveil cDC1 specific programming that promote a tolerogenic allospecific response. Thus, the proposed
studies will identify targetable pathways to enhance immunologic tolerance and improve cardiac allograft survival.

## Key facts

- **NIH application ID:** 10744193
- **Project number:** 5F30HL162456-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Samantha Leigh Schroth
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $43,243
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744193

## Citation

> US National Institutes of Health, RePORTER application 10744193, Requirements and mechanisms of alloantigen-induced cardiac allograft survival by cDC1s (5F30HL162456-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10744193. Licensed CC0.

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