# Optimizing Strategies to Overcome Kidney Xenograft Rejection

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $801,413

## Abstract

With over 100,000 patients now on the waiting list for a kidney transplant it is obvious that there is a critical
shortage of available donor organs. Xenotransplantation represents a promising solution. While pigs are
viewed as the optimal non-human source of organs, the potency of the human immune response to pig organs
has prevented the clinical application of pig-to-human kidney transplantation. In this application we propose
using cutting-edge genetic engineering approaches in combination with the use of the next generation of
agents targeting critical T cell costimulatory pathways to reduce both the humoral and cellular immune
response of nonhuman primates (NHP) undergoing kidney transplantation as a preclinical model to inform
future human trials. The first and dominant obstacle is the robust humoral immune response of primates to pig
kidneys. Despite the gradual introduction of a number of genetic modification to pig donors including knocking
out α-1,3-gal, the presence of pre-formed, naturally occurring antibodies as well as the de novo formation of
xenoantigen-specific antibodies continues to result in early rejection. Here, we will use the powerful
CRISPR/Cas9 system of genome editing to eliminate novel carbohydrate xenoantigens generated by the
β4GAL-NT2 enzyme , and interrogate the impact of this gene deletion (layered onto GAL-/- hCD55 transgenic
animals) on the survival of pig kidneys transplanted into NHP recipients. Beyond the humoral barrier to
xenotransplantation, the robust cellular immune response to pig organs poses a second challenge to the
clinical application of xenotransplantation. The development of immunosuppressive strategies based on the
blockade of critical costimulatory signals that are required for T cell activation offers a potential strategy to
more effectively control the cellular immune response with less toxicity in comparison to standard
immunosuppressive regimens. However, current strategies targeting the two dominant costimulatory pathways,
CD28 and CD154 using CTLA4-Ig and anti-CD154 mAb have been associated with issues of efficacy and
safety. Importantly, our work has demonstrated the superior efficacy and safety of novel “next-generation
costimulation blockers” compared to current costimulation blockers in both mouse and NHP models. Thus we
will next interrogate the ability of these next generation reagents, or domain antibodies, to better control xeno-
reactive immunity and prolong kidney xenograft survival. Finally, we will employ additional strategies that are
synergistic with the blockade of T cell costimulation to consolidate graft acceptance: 1) genome-editing
strategies to delete SLA class I/ class II on donor tissue and thereby mitigate T cell responses elicited via direct
presentation following xenotransplantation, and 2) blockade of the cell adhesion molecule VLA-4 and cytokine
signaling through CD122 as adjunct immunotherapeutic strategies to control the xeno-reactive, costimulation-
independe...

## Key facts

- **NIH application ID:** 10371783
- **Project number:** 7R01AI126322-06
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Andrew B Adams
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $801,413
- **Award type:** 7
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371783

## Citation

> US National Institutes of Health, RePORTER application 10371783, Optimizing Strategies to Overcome Kidney Xenograft Rejection (7R01AI126322-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10371783. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*