# Promoting Kidney Transplantation Tolerance Through Novel Immunomodulation and Cellular Therapy

> **NIH NIH U19** · UNIVERSITY OF MINNESOTA · 2024 · $939,602

## Abstract

Transplantation is the preferred treatment for patients suffering from end-stage kidney disease. While short-
term outcomes have greatly improved with the development of more effective immunosuppression, the long-
term outcomes remain problematic with life-span limiting complications including 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. Transplantation
tolerance is typically defined as the lack of a donor-directed immune response while preserving protective
immunity in the absence of long-term immunosuppression. It is likely that any successful tolerance regimen
will incorporate targeted immunosuppression strategies like costimulation blockade. Two of the most
promising reagents are anti-CD154 and anti-OX40L, both of which are protolerogenic and supportive of
immunoregulation as part of their mechanism of action. We have partnered with industry to evaluate two
clinically relevant compounds, dazodalibep (HZN-4920) an innovative anti-CD154 nonantibody scaffold protein
and a high affinity, novel anti-human OX40L antibody. 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. 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. We will use donor bone marrow
derived MDSCs in combination with novel therapeutics to control naïve (anti-CD154, anti-VISTA) and memory
(anti-OX40L) T cell responses as well as the innate immune response (anti-VISTA) in combination with pro-
tolerogenic anti-inflammatory cellular therapy (repetitive MDSC infusions). We will test this strategy in a
clinically relevant nonhuman primate kidney transplant model.

## Key facts

- **NIH application ID:** 10830958
- **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:** $939,602
- **Award type:** 5
- **Project period:** 2023-04-20 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830958

## Citation

> US National Institutes of Health, RePORTER application 10830958, Promoting Kidney Transplantation Tolerance Through Novel Immunomodulation and Cellular Therapy (5U19AI174966-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10830958. Licensed CC0.

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