# Tolerance Blockade by Immune Memory

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $388,750

## Abstract

Abstract
For many years, animal models have been greatly useful for dissecting basic mechanisms of allograft
rejection and tolerance. However, the translation of basic studies to clinical intervention has been an arduous
challenge. The majority of published small animal allograft studies utilize relatively young healthy animals,
both as transplant donors and recipients. One can argue that these models often do not reflect several
features of clinical transplantation that can impair the tolerance process. In response to this dilemma, many
more recent studies have focused on identifying key rate-limiting, clinically relevant obstacles to allograft
tolerance induction. This proposal focuses on identifying how a particular route of immune memory results in
the disruption of tolerance in a mouse model of islet transplantation. The prevailing view of immune memory
as a barrier to tolerance is that prior exposure to environmental antigens, pathogens, and vaccination
antigens generates a burden of antigen-experienced T and B cells that can spontaneously cross react to
allogeneic MHC molecules. However, our recently published studies indicate that vaccine-induced memory
with little if any cross-reactivity to donor MHC can nevertheless disrupt tolerance if the donor cells express the
vaccine-directed antigen. We refer to this type of reactivity as 'incognito' immune memory simply because it is
not readily detected by pre-transplant host monitoring for anti-donor MHC reactivity. As such, this scenario
models a common transplant setting in which the donor graft harbors non-MHC antigens that can be
recognized by host immunity generated through prior exposure to pathogens, vaccinations, or pre-existing
autoimmunity. We posit that this type of common host immunity can be disregarded and yet it can readily
impair tolerance induction without any requirement for cross-reactivity to donor MHC antigens. This project
will determine the mechanisms of how this form of immune memory disrupts tolerance by addressing the
general working model: Non-MHC-directed memory can disrupt tolerance by simultaneous 'linked' recognition
of alloantigens and vaccine- or virus-induced antigen specific memory in vivo. Implications of this overall
model will be addressed through the following three Specific Aims: Specific Aim 1: Determine the conditions
of memory-directed antigen expression required to disrupt tolerance. Specific Aim 2: Determine the impact of
memory cells on the activation of naïve, graft reactive T cells. Specific Aim 3: Determine the impact of
physiologically relevant host and donor gammaherpesvirus 68 (gHV68) infection on the subsequent capacity
to induce transplant tolerance. Taken together, the goal of this project is to dissect how this alternative form
of immune memory disrupts tolerance. We propose that understanding how such 'incognito' memory impacts
tolerance will identify key target pathways for future intervention and potentially expand how transplant
candid...

## Key facts

- **NIH application ID:** 9984181
- **Project number:** 5R01DK115745-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Ronald G Gill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2018-09-20 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984181

## Citation

> US National Institutes of Health, RePORTER application 9984181, Tolerance Blockade by Immune Memory (5R01DK115745-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984181. Licensed CC0.

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