# A Tolerance Approach to Xenotransplantation

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $3,121,671

## Abstract

This is a renewal of a highly synergistic PPG exploring tolerance induction for xenotransplantation. Themes
include: 1) Tolerance of the adaptive immune system; 2) Overcoming innate immune barriers; and 3) Using
advanced genetic engineering techniques to improve genetically modified (GM) MGH inbred miniature swine.
In Project 1, “Achieving Xenograft Tolerance through Thymic Programming in Primates”, we will study and
attempt to avoid the proteinuria which limits GalT-KO pig kidney transplant survival in baboons; we will
optimize tolerance and protective immunity by transplanting a hybrid vascularized thymus (VT) containing pig
and baboon TECs and combine this with mixed xenogeneic chimerism with intra-bone injection of pig bone
marrow to simultaneously tolerize both adaptive and innate immunity. In Project 2, “Achieving Xenograft
Tolerance through Mixed Chimerism”, which also uses the pig-to-baboon model, we have achieved prolonged
mixed chimerism in baboon recipients of human CD47 (hCD47) Tg pig hematopoietic cells (HCs), resulting in
remarkably prolonged pig skin graft survival; we will combine this approach with intrabone injection of hCD47
Tg/hCD55 Tg/GalT KO pig hematopoietic cells and use ex-vivo expanded recipient Tregs to enhance engraftment,
aiming to achieve more durable chimerism and, with it, tolerance of B, NK and T cells; we will also test HCs from
new GM swine produced in Project 4. Project 3, “Tolerance of Adaptive and Innate Human Anti-Pig Immune
Responses in Humanized Mice”, combines mixed xenogeneic chimerism and porcine thymic transplantation in
humanized mice with robust human immune systems; we will combine engineered pig/human hybrid thymi with
mixed xenogeneic chimerism to achieve multi-faceted immune tolerance along with protective immunity for
both human and porcine tissues; we will determine the impact of the hCD47 Tg on induction of porcine mixed
chimerism in these mice and determine the impact of duration of this mixed chimerism on human T, B and NK
cell tolerance. In Project 4, “Improving Xenogeneic Chimerism and Tolerance through Genome Engineering
Technology”, advanced genetic engineering techniques will be used to generate two optimal GM pig lines, one
for tolerance induction and the other for organ transplantation, on a background of inbred miniature swine with
common GMs that will be needed for both purposes. Core A will provide administrative support for the PPG,
facilitating interactions between the primary and subcontract sites. Core B will support all large animal needs,
including non-human primates and GM MGH inbred miniature swine; provide support for infectious diseases,
coagulation and clotting issues of swine and baboons; and provide mAbs and antisera. The synergism of
these projects and cores and the fertile interactions among them should bring us closer to the goal of
clinical xenotransplantation.

## Key facts

- **NIH application ID:** 9987457
- **Project number:** 5P01AI045897-20
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** DAVID H SACHS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,121,671
- **Award type:** 5
- **Project period:** 2000-09-15 → 2022-01-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987457

## Citation

> US National Institutes of Health, RePORTER application 9987457, A Tolerance Approach to Xenotransplantation (5P01AI045897-20). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9987457. Licensed CC0.

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