# Regulatory immune cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation

> **NIH NIH U19** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $1,468,504

## Abstract

Our long-range objective is to develop a CNI-free therapeutic approach to safely promote organ transplant
tolerance. Two promising complementary but interactive approaches to regulatory immune cell therapy for
transplant tolerance,- DCreg and Treg, comprise this U19 application. They will share a novel IS drug regimen,
rationally-designed to enhance the regulatory function of these cells in graft recipients. In Project 1, our
preliminary data show that donor-derived DCreg infusion before transplantation promotes renal allograft
survival in rhesus macaques receiving a short-term, minimal IS regimen of costimulation blockade (CoSB) and
tapered rapamycin. This effect is associated with selective attenuation of donor-reactive memory T cell (Tmem)
responses. Recent clinical data show that lymphodepletion followed by CoSB and rapamycin maintenance
prevents CoSB-resistant acute rejection and selectively inhibits recovery of donor-reactive Tmem, although
operational tolerance was not achieved. We therefore hypothesize that a regimen comprising ATG, CoSB and
rapamycin that (i) is more permissive to extended graft survival and that (ii) incorporates the
immunomodulatory function of adoptively-transferred DCreg, will promote IS-drug free, donor-specific
tolerance. In Project 2, we will address shortcomings of Treg therapy (Treg timing, specificity, instability or
conversion to Teff) recently underscored in a recent NHP study by our group. We will do so by building on our
success in expanding highly-suppressive, donor-alloreactive rhesus Treg (arTreg) ex vivo, and on the basis of
our recent finding that IL-2 + TGFβ1/Fc can selectively promote rhesus Treg, while inhibiting Th17 responses.
We hypothesize that delayed arTreg administration to ATG, CoSB and rapamycin-treated transplant
recipients, together with low-dose IL-2 and TGFβ1/Fc, will enhance their stability/persistence, promote their
suppressive function, overcome Tmem activity and promote transplant tolerance. Our Overall Aims are:
Project 1: To determine the capacity of DCreg infusion to promote operational renal transplant
tolerance in NHP given combined ATG (lymphodepletion) and CoSB (belatacept or αCD40 mAb) plus
rapamycin maintenance.
Project 2: To determine the capacity of alloreactive Treg to promote operational renal transplant
tolerance in NHP given combined ATG, CoSB (belatacept) plus rapamycin maintenance, together with
low-dose IL-2 ± huTGFβ1Fc.
Both projects will be accompanied by highly-interactive, mechanistic studies and assess novel biomarker
(eomesodermin) expression by alloreactive Tmem as a potential predictor of transplant outcome/tolerance.
They will be supported by an Administrative and Biostatistics Core (Core A) and a Transplant Pathology
and Tissue Imaging Core (Core B), and utilize agents from the NIAID NHP Reagent Resource.

## Key facts

- **NIH application ID:** 10217982
- **Project number:** 5U19AI131453-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Angus W Thomson
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,468,504
- **Award type:** 5
- **Project period:** 2017-08-17 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217982

## Citation

> US National Institutes of Health, RePORTER application 10217982, Regulatory immune cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation (5U19AI131453-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10217982. Licensed CC0.

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