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

> **NIH NIH U19** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $619,189

## Abstract

Rodent studies have demonstrated critical roles of regulatory T cells (Treg) in transplant tolerance, raising
expectations that adoptive Treg therapy may eliminate the dependence of transplant patients on CNI-based
immunosuppression (IS),- a major cause of morbidity and mortality. Recent use of alternative therapy, in
particular the costimulation blocking (CoSB) agent belatacept, while improving long-term renal graft function,
has led to increased rates of rejection. While T cell depletion (ATG) at the time of transplant reduces
dependence on CNI, homeostatic T cell proliferation results in preferential expansion of memory T cells
(Tmem),- a major barrier to tolerance induction. Combined T cell depletion plus belatacept can prevent
rejection, but tolerance is not achieved.
While clinical trials are underway to evaluate Treg in organ transplantation, their functional plasticity and
potential conversion to pathogenic T cells raise valid concerns, Better understanding of the mechanisms that
may alter Treg function after their infusion in graft recipients is essential for safe and effective implementation
of Treg therapy. We have shown recently that early polyclonal Treg infusion into lymphodepleted NHP is
associated with enhanced graft injury and Tmem recovery. IL-2 and transforming growth factor beta 1 (TGFβ1)
are critical for Treg development and low dose IL-2 selectively expands endogenous Treg in NHP and humans.
Also, TGFβ1 signaling is essential for prevention of inflammatory responses in lymphopenic hosts. In rodents,
infusion of huTGFβ1/Fc in combination with rapamycin enhances graft survival. In collaboration with the NIAID
NHP Reagent Resource we have generated an agonistic TGFβ1/Fc protein for use in NHP. Our preliminary
data show that this TGFβ1/Fc reduces rhesus T cell proliferation synergistically with rapamycin and promotes
Treg in the presence of IL-2. Circulating TGFβ1/Fc can be detected for several days after its infusion into
lymphodepleted rhesus. Based on these findings, we propose to evaluate, the influence of donor alloractive-
reactive Treg (arTreg) therapy in combination with IL-2 and TGFβ1/Fc on renal graft survival in the rhesus
model. All three Specific Aims will be accompanied by mechanistic and biomarker studies and be
highly interactive with Project 1 and Cores A and B.
Aim 1: To determine the influence of ex-vivo expanded autologous arTreg on renal allograft survival in
rhesus macaques given ATG, belatacept and rapamycin (ABR) IS, and underlying mechanisms
Aim 2: To assess whether low-dose IL-2 can enhance the suppressive function and numbers of ex-
vivo expanded arTreg in graft recipients given ABR IS and further improve graft survival
Aim 3: To evaluate the influence of co-administered TGFβ1/Fc and IL-2 on the stability and
suppressive function of ex-vivo expanded arTreg in graft recipients given ABR IS and promote
operational tolerance

## Key facts

- **NIH application ID:** 9991741
- **Project number:** 5U19AI131453-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Mohamed B Ezzelarab
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $619,189
- **Award type:** 5
- **Project period:** 2017-08-17 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991741

## Citation

> US National Institutes of Health, RePORTER application 9991741, Regulatory T cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation (5U19AI131453-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9991741. Licensed CC0.

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