# Overcoming humoral rejection after xenotransplantation in sensitized nonhuman primate recipients

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $797,199

## Abstract

Abstract
Xenotransplantation has long been proposed as a therapeutic strategy to address the ongoing organ shortage
in transplantation. In recent years, pig-to-primate xenotransplantation outcomes have dramatically improved
following advances in the genetic engineering of pig donors and utilization of costimulation blockade-based
immunosuppression, such that translation to the clinic appears within reach. Highly allosensitized patients,
those who have developed anti-donor antibody as a response to foreign HLA exposure, are potential first
candidates for xenotransplantation given their reduced chances of undergoing allotransplantation. However,
the impact of allosensitization in the setting of xenotransplantation has not yet been fully elucidated in pig-to-
primate models. Our preliminary data suggest that allosensitization promotes antibody-mediated rejection
(AMR) following kidney xenotransplantation and leads to early graft failure. Use of donor kidneys from highly
engineered pigs prolong xenograft survival yet do not fully alleviate AMR development. Additional therapeutic
strategies are thus needed to dampen the post-transplant humoral response following xenotransplantation in
sensitized recipients. This project aims to evaluate novel desensitization and immunosuppression strategies to
control the post-transplant humoral response and foster long-term xenograft survival in sensitized recipients.
Our overarching hypothesis is that both conditioning the host immune response ahead of xenotransplantation
through desensitization and continuous targeting of B cells, plasma cells, or complements following
transplantation, are necessary to control the post-transplant humoral response and alter the repopulating
xenoreactive immune repertoire to favor long-term graft acceptance. To explore this, we propose 3 specific
aims: Specific aim 1: We will define the effects of desensitization (costimulation blockade and proteasome
inhibitor) pre-transplant in rhesus monkeys undergoing kidney xenotransplantation. Specific aim 2: We will
define the impact of adjuvant therapies targeting downstream elements of the humoral response following
xenotransplantation. Specific aim 3: We will identify the functional phenotype of xeno-specific T and B cell
repertoires required to establish long-term AMR-free xenograft survival while preserving anti-viral/vaccinal
response. These advances will ultimately position us to conduct a first-in-human xenokidney transplantation in
sensitized patients testing this optimized immunosuppressive regimen. Our proposal involves many academic
and industry collaborations that are ongoing as attested by letters of support. The impact of this proposal has
broad implications that may benefit U.S. citizens affected by end stage renal failure or by immune-mediated
illnesses or infections.

## Key facts

- **NIH application ID:** 10778607
- **Project number:** 5R01AI175411-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jean Kwun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $797,199
- **Award type:** 5
- **Project period:** 2023-02-06 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10778607

## Citation

> US National Institutes of Health, RePORTER application 10778607, Overcoming humoral rejection after xenotransplantation in sensitized nonhuman primate recipients (5R01AI175411-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10778607. Licensed CC0.

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