# Peptide-dependent mobilization of CD8 regulatory cells in cardiac transplantation

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $661,493

## Abstract

Project Summary
Antibody-mediated graft rejection (AMR) remains a major barrier to successful solid organ transplantation.
Establishing novel treatment strategies based on our understanding of underlying mechanisms may improve
long term graft outcomes. Although pathogenic allo-antibodies mediating AMR are produced mainly by GC B
cells after induction by follicular T helper (Tfh) cells, regulation of this response is poorly understood. Insight into
mechanisms that regulate these GC responses and dampen AMR to improve heart allograft outcomes are
needed.
We have uncovered and exploited a central role for Qa-1-/HLA-E-restricted CD8 regulatory T cells in the control
of Tfh-dependent DSA responses against donor allografts. Our published and preliminary experimental data
indicate that CD8 Treg that are restricted by class Ib MHC (murine Qa-1/human HLA-E) can be mobilized by
synthetic FL9 peptides to inhibit alloimmune Tfh cells, dampen Ab-mediated injury and prolong heart allograft
survival in fully mismatched heart transplant models. These findings open the possibility of HLA-E-targeted
vaccine strategies that exploit the limited polymorphism of this MHC class Ib gene and avoid problems of class
Ia MHC diversity.
The FL9−Qa-1 complex is upregulated by a subset of activated Tfh cells that drive alloantibody responses.
Identification of synthetic FL9 agonist peptides that mobilize Ag-specific CD8 Treg after a screen of a yeast
peptide library based on the FL9 self-peptide is outlined in SA1. Analysis of mechanisms that underpin peptide-
induced regulation of AMR against heart allografts are addressed in SA2. Targeting of co-receptors that
modulate CD8 Treg activation and function are the subject of SA3. These studies should allow new and effective
approaches to reduce AMR and improve allograft survival.

## Key facts

- **NIH application ID:** 10910998
- **Project number:** 5R01AI165870-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jamil Azzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $661,493
- **Award type:** 5
- **Project period:** 2023-08-21 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910998

## Citation

> US National Institutes of Health, RePORTER application 10910998, Peptide-dependent mobilization of CD8 regulatory cells in cardiac transplantation (5R01AI165870-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10910998. Licensed CC0.

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