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

> **NIH NIH U19** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $1,041,302

## Abstract

Our objective in this U19 is to develop a safe and effective therapeutic approach to promote organ transplant
tolerance in a clinically-relevant, nonhuman primate model. Two promising complementary but interactive
approaches to adoptive immune cell therapy for transplant tolerance,- regulatory dendritic cells (DCreg) and
regulatory T cells (Treg) and their combination, comprise this U19 application. Work already completed during
the award shows that, using a minimal immunosuppressive (IS) drug regimen of tapering calcineurin inhibition
(tacrolimus) combined with co-stimulation blockade (CTLA4Ig), MHC-mismatched renal allograft graft
survival can be prolonged using either cell therapy alone. Thus, administration of donor-derived DCreg a
week before transplant, or delayed administration of Treg commencing 7 weeks post-transplant, prolongs
median kidney graft survival time in rhesus macaques, although transplant tolerance is not induced. As in
the original funded award, we hypothesize that, using the same immunosuppressive drug regimen,
incorporation of the combined immunomodulatory functions of adoptively-transferred DCreg before
transplant and Treg post-transplant will promote IS drug-free, donor-specific tolerance. In this type-4
Extension, we will complete mechanistic studies (delayed as the result of institutional restrictions imposed
in response to the COVID-19 pandemic) designed to improve understanding of the in vivo fate of each cell
product and how each cell therapy affects anti-donor immune reactivity, with emphasis on their impact on
immune effector and regulatory cell functions. In addition, the Extension will allow us perform the delayed
combined cell therapy transplant experiments proposed in our funded award, in which we will (in Project 1)
test the combined DCreg + Treg approach and (in Project 2) the potential of the anti-inflammatory agent
anti-IL-6 receptor antibody to potentiate the therapeutic effect of the combined cell therapy regimen. In both
projects, mechanistic studies will be performed on peripheral blood and lymph node mononuclear cells and
graft biopsies to elucidate underlying mechanisms. The proposed studies will take advantage of the success
we have achieved during the U19 award in expanding highly-suppressive, donor-alloreactive rhesus Treg
(arTreg) ex vivo. The Aims of the two Projects for the Extension are:
Project 1
Aim 1: To complete mechanistic studies concerning the influence of pre-or post-transplant infusion
of donor-derived DCreg on rhesus renal allograft survival
Aim 2: To perform combined pre-transplant DCreg infusion with delayed post-transplant arTreg
infusion on rhesus renal allograft survival and accompanying mechanistic studies
Project 2
Aim 1: To complete mechanistic studies concerning the impact of IL-6R blockade on kidney graft
survival and the therapeutic efficacy of ex vivo-expanded arTreg
Aim 2: To determine the impact of IL-6R blockade on kidney allograft survival in conjunction with
combined...

## Key facts

- **NIH application ID:** 10518430
- **Project number:** 4U19AI131453-06
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Angus W Thomson
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,041,302
- **Award type:** 4C
- **Project period:** 2017-08-17 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518430

## Citation

> US National Institutes of Health, RePORTER application 10518430, Regulatory immune cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation (4U19AI131453-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10518430. Licensed CC0.

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