# Infections and the Stability of Transplantation Tolerance

> **NIH NIH P01** · UNIVERSITY OF CHICAGO · 2020 · $1,587,598

## Abstract

PROGRAM SUMMARY
 Transplantation tolerance, a state of long-lasting immune unresponsiveness to donor antigens after
cessation of therapy, is an attractive approach for life-long graft acceptance without global
immunosuppression. Long-term follow up of tolerant patients has revealed that tolerance can be lost in some
individuals after years of graft stability, sometimes after infections, raising 2 possibilities: that tolerance at
induction was equally robust but some patients were exposed to more inflammatory events that eroded the
state of tolerance, or that tolerance at induction was metastable in some patients and robust in others.
 The first cycle of our Program Project addressed the first possibility using a mouse model of
transplantation tolerance that is robust and resistant to most inflammatory challenges with the exception of
Listeria monocytogenes (Lm). Importantly, we tracked alloreactive T cells by analyzing small numbers of
congenic TCR-Tg alloreactive T cells seeded before transplantation, or using fluorescent pMHC Class I and
Class II multimers to identify endogenous populations of T cells reactive to model donor antigens. By
comparing alloreactive T cells before (Project 1) and after (Project 2) Lm infection of tolerant mice, our
Program discovered that i) robust transplantation tolerance is maintained by multiple redundant mechanisms of
T cell tolerance, including constraining alloreactive T cell numbers, increasing the ratio of regulatory to
conventional T cells, inhibiting conventional T cells intrinsically and restraining alloreactive T cell populations to
clones with low avidity for alloantigen; ii) robust tolerance is resilient because it spontaneously returned in
animals that experienced Lm-dependent graft rejection; iii) tolerance after infection is eroded and dependent
on single mechanisms of T cell tolerance such that blockade of PD-L1 or depletion of Tregs was sufficient to
precipitate graft rejection in tolerant hosts post-infection but not in uninfected hosts. Globally, our Program has
demonstrated that transplantation tolerance is not an all-or-none state, but rather can exist at different levels of
robustness. These observations highlight the need to precisely define and monitor the mechanisms underlying
graft acceptance in each tolerant recipient and to devise strategies to improve tolerance when it becomes
eroded. For this Competitive Renewal, we will address the second possibility, that not all patients achieve
robust tolerance at induction. Globally, we hypothesize that the mechanisms restraining alloreactive T cell
subsets can distinguish robust tolerance established in naive hosts from eroded tolerance after infection, and
from metastable or failed tolerance in sensitized hosts. Project 1 will focus on 2 novel features of alloreactive
T cells that we recently discovered as characteristic of robust transplantation tolerance in naïve hosts, namely,
cell intrinsic hyporesponsiveness and the constraint of alloreact...

## Key facts

- **NIH application ID:** 9985697
- **Project number:** 5P01AI097113-09
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Maria-Luisa Alegre
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,587,598
- **Award type:** 5
- **Project period:** 2012-07-17 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985697

## Citation

> US National Institutes of Health, RePORTER application 9985697, Infections and the Stability of Transplantation Tolerance (5P01AI097113-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9985697. Licensed CC0.

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