# Mechanisms and promotion of immune regulation by CD4+ regulatory T cells within allografts

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $383,295

## Abstract

PROJECT SUMMARY
 Poor long-term graft survival rates despite continuous immunosuppression still plagues transplantation in
patients. This is primarily due to two undesired effects of chronic immunosuppression: 1) inadequate control of
memory T cells, which can attack and reject the graft at any time, and 2) inhibition of regulatory CD4+ T cells
(Tregs) that exhibit suppressor functions and can protect the graft from immune attacks by memory T cells. Thus,
improved therapeutics that promote Treg suppressor function are critically needed to enhance long-term graft
survival. However, the mechanisms of Treg suppressor function within allografts is unknown, and improved
therapeutics will originate from a better understanding of these mechanisms.
 In this regard, our data identified dendritic cells (DC) as the likely cellular promoter and/or target of Treg
suppression within allografts. Thus, we hypothesize that cognate interactions between Treg and DCs are
key to Treg function within allografts, and that these interactions can be manipulated therapeutically to
enhance Treg suppressor function in the graft. We will test this through the following AIMs:
 In AIM 1, we will investigate whether Treg-DC interactions are key to Treg function within allografts.
Specifically, we will determine whether Treg-DC cognate interactions promote Treg function, and whether Treg
then suppress effector T cells through the inhibition of DC function resulting in the inhibition of effector T-DC
cognate interactions. In AIM 2, we will investigate whether Treg suppressor function within allografts can be
enhanced by therapeutically promoting Treg-DC interactions. We recently showed that a tolerogenic agent (anti-
CD45RB antibody) specifically promotes Treg proliferation in lymphoid organs by enhancing cognate Treg-DC
interactions. However, it remains unknown whether anti-CD45RB would promote Treg-DC interactions within
allografts to promote Treg function. Thus, this will be specifically addressed here.
 The visualization of Treg suppressor function using multi-photon intravital microscopy is crucial to testing
these hypotheses. In addition, these AIMs will be accomplished through the collaborative efforts of an
interdisciplinary group of experts, which includes a world-renowned microscopy expert. Therefore, this grant
application is responsive to this RFA-AI-16-042: Emerging Science and Technology in Transplantation (U01) as
it will investigate intragraft Treg function using intravital imaging.
 Overall, new knowledge generated from this grant will: 1) identify – at the cellular level, in the living host,
and in real time – the mechanisms of action of Tregs in the setting of transplantation; and 2) identify cellular and
molecular targets to promote Treg suppressor function in transplant recipients.

## Key facts

- **NIH application ID:** 10159074
- **Project number:** 5U01AI132758-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Geoffrey Camirand
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,295
- **Award type:** 5
- **Project period:** 2017-06-26 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159074

## Citation

> US National Institutes of Health, RePORTER application 10159074, Mechanisms and promotion of immune regulation by CD4+ regulatory T cells within allografts (5U01AI132758-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10159074. Licensed CC0.

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