# Advancing Transplantation Tolerance in Nonhuman Primates

> **NIH NIH U19** · UNIVERSITY OF MINNESOTA · 2024 · $3,635,295

## Abstract

While short-term outcomes following organ transplant have greatly improved with the development of more
effective immunosuppression, long-term outcomes remain problematic with a significant number of patients
developing diabetes, accelerated heart disease as well as increased rates of cancers and infections. For
decades transplant researchers and clinicians have sought to develop strategies to induce immune tolerance
to transplanted organs and avoid the requirement for life-long immunosuppression. It is likely that any
successful tolerance regimen will incorporate targeted immunosuppression strategies like costimulation
blockade. One of the most important interactions is the CD40-CD154 pathway. We will evaluate novel,
clinically relevant therapeutics targeting either CD40 or CD154 and explore their role in facilitating tolerance.
Based on our recent publication showing that CD11b is a novel alternate receptor for CD154 during
alloimmunity, we will also test novel nanotechnology to block the CD154:CD11b interaction, an important
mechanism of cross-talk between the innate and adaptive immune responses during transplantation.
Moreover, based on our published data showing that memory T cells are a potent barrier to transplantation
tolerance, we will determine the role of OX40-OX40L blockade to control alloreactive memory CD8+ T cells and
promote a pro-regulatory environment. In addition, we will assess the importance of the VISTA pathway on the
induction of donor-specific tolerance using an agonistic anti-human VISTA antibody. VISTA has a dual role in
negatively regulating antigen-specific T cell responses while also impacting the innate immune response by
inhibiting ischemia reperfusion injury, monocyte activation and neutrophil migration thereby suppressing the
early inflammatory response. We will also investigate the contribution of IL-1 and the inflammasome on
tolerance induction and employ clinically applicable therapeutics to control early inflammation during the
induction of tolerance. The combination of cellular therapy and costimulation blockade is a powerful strategy to
promote donor-specific tolerance. Myeloid derived suppressor cells (MDSCs) have inherent
immunosuppressive properties and have been used to facilitate tolerance. They modulate innate immunity and
inhibit T cell activation and effector cell function while also promoting regulatory T cell expansion for
maintenance of long-term donor specific tolerance. Apoptotic donor leukocytes (ADLs) represent another
promising cellular therapy that has been proven to control alloreactive T cells and promote donor specific T cell
deletion. We will use donor bone marrow derived MDSCs or ADLs in combination with the above novel
therapeutics to promote tolerance in nonhuman primate kidney transplantation.

## Key facts

- **NIH application ID:** 10830944
- **Project number:** 5U19AI174966-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Andrew B Adams
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $3,635,295
- **Award type:** 5
- **Project period:** 2023-04-20 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830944

## Citation

> US National Institutes of Health, RePORTER application 10830944, Advancing Transplantation Tolerance in Nonhuman Primates (5U19AI174966-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10830944. Licensed CC0.

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