# Tolerance of Adaptive and Innate Human Anti-pig Immune Responses in Humanized Mice

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $453,298

## Abstract

Project 3 addresses two approaches to inducing human immune tolerance to the pig, namely mixed
xenogeneic chimerism and porcine thymic transplantation, in a humanized (HU) mouse model. We have
demonstrated that each approach can centrally tolerize human T cells to the donor pig and we hypothesize
that the combination of both approaches will ultimately be optimal. During the current funding period, we have
obtained evidence that mixed xenogeneic chimerism leads to specific tolerance or global unresponsiveness of
human NK cells. We have obtained evidence that mixed xenogeneic chimerism tolerizes human T cell-
independent B cells producing anti-pig xenoantibodies. We have shown that human T cells developing in
human and porcine thymus grafts are functional and dependent on human APCs in the periphery for
homeostasis. Human T cells developing in porcine thymus grafts, while tolerant of the donor pig, have reduced
homeostatic expansion and reduced responses to antigen presented by HLA. We hypothesize that such
abnormalities may be corrected while optimal protective immunity and tolerance to the pig and the human will
be achieved by injecting autologous thymic epithelial cells (TECs) into the porcine thymic graft and combining
transplantation of this “hybrid” thymus with mixed xenogeneic chimerism. We will: 1) Engineer a pig/human
“hybrid” thymus to mediate positive and negative selection of human T cells on both pig and human
MHC molecules. We will evaluate the impact of a pig/human TEC-containing hybrid thymus and of
mixed xenogeneic chimerism on tolerance, homeostasis and function of human T cells. These studies
will be directly relevant to the baboon studies in Project 1 and are expected to achieve optimal tolerance and
protective immunity; and 2) Determine the impact of duration of mixed xenogeneic chimerism on
tolerance of human T, B and NK cells to the pig. We will determine the extent to which human CD47
expression on pig bone marrow prevents pig bone marrow rejection by human macrophages and enhances
porcine chimerism in HU mice. We will then separately examine the impact of the duration of chimerism on the
persistence of T cell, B cell and NK cell tolerance. We will examine the mechanism of persistent T cell
tolerance if observed after loss of chimerism. We will also determine the impact of duration of mixed
xenogeneic chimerism on human NK cell tolerance and of transgenic expression of HLA-E by pig bone marrow
cells on induction of mixed chimerism in HU mice and on tolerance and function of human NK cells.
Collectively, the studies will continue to guide the tolerance studies in Projects 1 and 2 and the development of
optimal transgenic pigs in Project 4.

## Key facts

- **NIH application ID:** 9987466
- **Project number:** 5P01AI045897-20
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Megan Sykes
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,298
- **Award type:** 5
- **Project period:** 2000-09-15 → 2022-01-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987466

## Citation

> US National Institutes of Health, RePORTER application 9987466, Tolerance of Adaptive and Innate Human Anti-pig Immune Responses in Humanized Mice (5P01AI045897-20). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9987466. Licensed CC0.

---

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