# Determinants of donor-specific T cell tolerance in kidney transplantation in non-sensitized recipients

> **NIH NIH U19** · DUKE UNIVERSITY · 2024 · $1,143,031

## Abstract

Studies from our current NHPCSG U19 revealed that induction with depletional thymoglobulin in
combination with maintenance with co-stimulation blockade plus rapamycin (ATG/CoB/Rapa) is a highly effective
regimen in repopulating the post-depletional lymphocyte repertoire with a naïve and CoB-sensitive phenotype.
In this application, we hypothesize that this newly repopulated repertoire is now susceptible to donor-specific
manipulation by an innovative cellular therapy using ECDI-treated, ex vivo expanded donor B cells to induce
donor-specific transplantation tolerance via donor-specific deletion, anergy and regulation. To test our
hypothesis, we will (1) deliver donor ECDI-B cells in the context of ATG/CoB/Rapa and determine its efficacy on
the induction of donor-specific tolerance; (2) apply the cutting-edge technology of rhesus macaque single cell
immune repertoire sequencing (scIRS) pioneered by our collaborator Dr. Peng at NCSU to investigate and
precisely quantify donor-specific deletion, anergy or regulation at a single cell level. As infections have been
brought into sharp focus by the recent SARS-CoV2 pandemic and have been shown to have a profound effect
on the susceptibility and stability of immune tolerance, we propose to further interrogate the interaction between
anti-viral immunity and donor-specific immune tolerance at a molecular level. We propose to use
cytomegalovirus (CMV) as a model pathogen as it is commonly encountered in transplant recipients. With these
goals in mind, we constructed three specific aims for this Project: Aim 1 will determine the efficacy of
transplantation tolerance by donor ECDI-B cell infusions in the presence of ATG/CoB/Rapa in rhesus kidney
transplantation, modeling both deceased donor as well as living donor kidney transplantation; Aim 2 will
determine the effect of CVM exposures on the induction and maintenance of transplantation tolerance in rhesus
macaques; and Aim 3 will employ cutting edge technologies including scIRS and the expertise in high-
dimensional data analytics provided by the CIC to examine lymphocyte repertoire and functionality under
tolerance conditions with or without concurrent CMV infection. At the completion of this project, we will: 1)
establish a clinically feasible and effective regimen for transplantation tolerance induction in rhesus macaques
using a combination of depletional induction and infusions of ECDI-fixed donor leukocytes; 2) understand the
cellular and molecular mechanisms of this tolerance approach; 3) determine the effective components of
therapeutic strategies to preserve transplantation tolerance in settings of unexpected viral infections. These
advances will ultimately position us to conduct a first-in-human kidney transplant tolerance trial testing the
optimized combinatorial regimen of donor ECDI-B cell infusions in the context of ATG/CoB/Rapa.

## Key facts

- **NIH application ID:** 10821472
- **Project number:** 5U19AI131471-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Xunrong Luo
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,143,031
- **Award type:** 5
- **Project period:** 2017-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821472

## Citation

> US National Institutes of Health, RePORTER application 10821472, Determinants of donor-specific T cell tolerance in kidney transplantation in non-sensitized recipients (5U19AI131471-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10821472. Licensed CC0.

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