# Development of novel strategies to modulate human NK cell response in xenotransplantation

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $237,750

## Abstract

PROJECT SUMMARY
Xenotransplantation (i.e. cross-species transplantation using pig organ in human) offers a potential solution to
address persistent organ shortage. Organ shortage more severely impacts minorities, such as African
Americans, Asians, and Hispanics. However, pig-human incompatibility results in destructive human immune
response and ultimate rejection of pig organs. The long-term goal of this proposal is to develop an effective
and safe method to prevent the human immune response to transplanted pig cells, tissues, and organs.
Human NK cell mediated-direct killing of porcine endothelial cells is one of the barriers in xenotransplantation.
A balance of signals from porcine cell ligands and human NK cell receptors interaction determines human NK
cell function. This proposal focuses on manipulation of porcine cell surface proteins to inhibit/block NK cells
recognition and activation. In our preliminary data, we have demonstrated that expression of HLA-G on porcine
cell inhibits NK cell activation and reduces pro-inflammatory cytokine production. An antibody mediated-
blocking of NKG2D receptor can diminish NK cell activation. We hypothesize that manipulation of porcine
ligands may abolish human NK cell-mediated cytotoxicity. Expression of inhibitory ligands and removal of
activating ligands on porcine cells may induce NK cell tolerance and inhibition. The hypothesis will be
addressed in the experiments of the following Specific Aims: 1) to determine the inhibition of human NK cell by
co-expression of HLA class I molecules HLA-C, HLA-E, and HLA-G on porcine cells; and 2) to determine
whether elimination of NKG2D porcine ligands blocks human NK cell recognition and activation. This
exploratory study will expand our understanding of the mechanism of cross-species immune recognition and
response, develop a novel approach to induce local immune tolerance/acceptance, and guide engineering of
pigs to meet xenotransplantation needs.

## Key facts

- **NIH application ID:** 10285145
- **Project number:** 1R21AI164002-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Ping Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $237,750
- **Award type:** 1
- **Project period:** 2021-05-21 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285145

## Citation

> US National Institutes of Health, RePORTER application 10285145, Development of novel strategies to modulate human NK cell response in xenotransplantation (1R21AI164002-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10285145. Licensed CC0.

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