# Intestinal allograft tolerance in large animals

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $201,065

## Abstract

Project Abstract: Despite recent improvements in immunosuppression, graft/patient survival of small intestinal
transplantation (ITx) remains suboptimal, limiting the broader application of this therapy. Induction of donor-
specific tolerance to any organ is desirable to eliminate co-morbidities associated with immunosuppressive
treatment. The induction of tolerance is particularly desirable for ITx due to: (1) the requirement for high levels
of immunosuppression to prevent rejection of small bowel grafts; (2) complications associated with heavy
immunosuppression; and (3) the young average age of the recipients. However, to our knowledge, tolerance of
intestinal allografts has not been extensively studied in preclinical models. Even in rodent models, there are few
reports demonstrating tolerance to small intestine, but one successful strategy has been through the induction
of durable mixed allogeneic chimerism. The overall goal of this proposal is to develop a large animal preclinical
model for tolerance induction following ITx and to develop a protocol appropriate for tolerance induction in parent
to child (living donor LD) ITx. We recently reported that rejection rates appear to be higher in clinical recipients
of isolated intestinal transplants (iITx) compared to multivisceral transplants (MVTx), which include donor liver,
stomach and pancreas. Notably we have found, for the first time, that T cell mixed chimerism which develops
without GVHD following iITx and even more commonly following MVTx, is associated with reduced rejection
rates. We hypothesize that the presence of graft-vs-host-reactive (GVHR) clones in these MVTx recipients
facilitates engraftment of donor progenitor cells contained within the grafts, and further hypothesize that
transplantation of additional hematopoietic stem cells (HSCs) during this period of the GVHR will augment
chimerism and tolerance induction even in iITx recipients. The early GVHR that migrates from the graft to the
recipient’s peripheral immune system (lymphohematopoietic GVH response, or LGVHR) makes hematopoietic
“space” for engraftment of these hematopoietic progenitors. In this proposal, we will utilize MHC inbred
miniature swine, the only large animal model that allows reproducible transplantation with defined GVH and
host-vs-graft (HvG) genetic barriers, to address the above hypotheses and develop a clinically relevant LD ITx
tolerance induction model. We will first establish a porcine model of orthotopic iITx and MvTx that parallels our
institution’s clinical protocol and determine the role of GVH and HvG alloreactivity in driving chimerism and
clinical outcomes (Aim 1). We will then utilize the LGVHR and donor HSCs to achieve tolerance in long-term
allograft acceptors in the models in Aim 1 (Aim 2). The studies in this proposal may have eventual clinical
applicability that could solve the most problematic issues in ITx and vastly improve the outcomes of this
therapeutic modality.

## Key facts

- **NIH application ID:** 10265649
- **Project number:** 3R01AI138547-04S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Megan Sykes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $201,065
- **Award type:** 3
- **Project period:** 2020-07-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265649

## Citation

> US National Institutes of Health, RePORTER application 10265649, Intestinal allograft tolerance in large animals (3R01AI138547-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10265649. Licensed CC0.

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