# Immune response and tolerance to liver transplants in NHP

> **NIH NIH R56** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $861,395

## Abstract

Although spontaneous tolerance after liver transplantation can be achieved in immunosuppression withdrawal
studies, its broad application is limited by the lack of knowledge about the mechanism of tolerance, markers for
tolerance, and therefore the lack of rational targets for immune induction therapy to increase the rate of tolerance.
To address these gaps, we developed the only nonhuman primate liver transplant model in the United States.
Preliminary data in rodent, human, and our primate liver transplant model indicate that memory CD8 T cells are
the greatest barrier to tolerance after stopping immunosuppression. We now propose to control the response of
memory cells by early deletion or by regulation at the time of immunosuppression withdrawal. Our long-term goal
is to develop clinically-applicable protocols for tolerance induction early after liver transplant and to define the
mechanism by which tolerance develops. Our central hypothesis is that control of anti-donor CD8 T cells through
deletion or regulation will lead to stable graft function with normal histology after immunosuppression withdrawal.
The rationale for defining the immune response to liver transplants is that this will allow us to optimize immune
induction for immunosuppression withdrawal. The proposed research is innovative because it utilizes a
translational animal model to develop a clinically-applicable tolerance induction protocol. It will also use
innovative techniques to characterize the donor-specific immune response to liver transplants, and the
interaction of graft-infiltrating lymphocytes and recipient antigen-presenting cells. In Aim 1, we will test the ability
of targeted memory T-cell depletion at the time of transplant to reduce donor-specific T-cell responses and thus
lead to tolerance. We will also test the ability of ex vivo expanded donor-specific Tregs given at the time of
immunosuppression withdrawal to suppress alloresponses. Finally, we will perform control transplants that
receive standard clinical immunosuppression prior to early withdrawal to ensure our interventions are achieving
their hypothesized results. In Aim 2, we will adapt our laboratory's high-throughput TCR sequencing platform to
the cynomolgus model to track donor-reactive effector and regulatory T-cell clones after transplant. Since mouse
studies suggest the liver participates in tolerance induction by inducing anergy or apoptosis of T cells, we will
also digest transplanted liver wedge biopsies to isolate and characterize graft-infiltrating T cells and APCs to
determine if (and how) the liver promotes tolerance. These mechanistic studies will have a positive impact by
revealing potential biomarkers of tolerance that could be used to withdraw immunosuppression on patients
currently maintained on standard medications. They will also allow us to refine our induction protocol to minimize
toxicities. Upon successful completion of the proposed research, we expect to have developed a tolerance...

## Key facts

- **NIH application ID:** 10240857
- **Project number:** 1R56AI150873-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Adam David Griesemer
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $861,395
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240857

## Citation

> US National Institutes of Health, RePORTER application 10240857, Immune response and tolerance to liver transplants in NHP (1R56AI150873-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240857. Licensed CC0.

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