# Apoptotic Donor Leukocytes to Promote Kidney Transplant Tolerance

> **NIH NIH U19** · UNIVERSITY OF MINNESOTA · 2024 · $974,638

## Abstract

PROJECT 2 SUMMARY
We demonstrated that two peritransplant infusions of apoptotic donor leukocytes (ADLs) and transient
immunosuppression (TIS) with α-CD40, rapamycin, sTNFR, and α-IL-6R induced long-term (>1 year) tolerance
to islet allografts in 5 of 5 nonsensitized, 1 MHC-II DRB allele-matched nonhuman primates (NHPs). Project 2
will examine the efficacy and mechanisms of the ADL+TIS regimen in a kidney transplant model and apply high-
dimensional immune profiling to guide protocol refinements, with the PRINCIPAL OBJECTIVE of developing a safe,
effective, and clinically translatable protocol for inducing stable tolerance in living donor kidney transplantation.
WE HYPOTHESIZE that the ADL+TIS regimen, with modifications deemed necessary to facilitate successful
translation to a solid organ transplant setting and with refinements informed by results of the overall U19 program,
promotes long-term graft survival in living donor kidney transplant models in NHPs through operational tolerance.
To test this hypothesis and facilitate the clinical translation of ADL+TIS, we propose two SPECIFIC AIMS:
AIM #1: To determine the efficacy and mechanisms of ADL infusions combined with transient
immunosuppression in inducing and maintaining tolerance in a NHP renal transplant model
Studies determining the efficacy of the ADL+TIS protocol in achieving operational tolerance of renal allografts in
NHPs will be accompanied by deep immune profiling of blood, graft, spleen, and urine to investigate the effects
of the protocol on the abundance and activation profiles of distinct effector, exhausted, and regulatory immune
cell subsets in various compartments and their spatial organization within graft and spleen.
AIM #2: To study the efficacy and mechanisms of inflammasome inhibition and IL-1b antagonism to
promote renal transplant tolerance induced by ADL infusions and transient immunosuppression in NHPs
Studies in this Aim will determine the ability of strategies inhibiting the inflammasome and its products to
synergize with ADL+TIS in promoting operational tolerance in a renal transplant model in NHPs. Mechanistic
studies will investigate how inflammasome inhibition and IL-1b antagonism modify the effects of ADLs + TIS on
frequencies and activation profiles of myeloid and lymphoid cell subsets in blood, urine, and spleen and their
recruitment to and spatial interaction within coordinated immune regulation domains in the renal allograft.
The SIGNIFICANCE & INNOVATION of the proposal lie in the efficacy of the ADL+TIS protocol to deplete and exhaust
allospecific T cells and to create potent immune regulation. The prospects for tolerance induction to renal
transplants in NHPs are high, based on documented tolerance to renal transplants in rodents and islet transplants
in NHPs and opportunities for rational refinements of the strategy created by system-level immune profiling.

## Key facts

- **NIH application ID:** 10830952
- **Project number:** 5U19AI174966-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Bernhard Josef Hering
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $974,638
- **Award type:** 5
- **Project period:** 2023-04-20 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830952

## Citation

> US National Institutes of Health, RePORTER application 10830952, Apoptotic Donor Leukocytes to Promote Kidney Transplant Tolerance (5U19AI174966-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10830952. Licensed CC0.

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