# Lymphocyte reconstitution and responses in intestinal transplantation

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $368,000

## Abstract

Project 3 Summary
The intestine is a rich lymphoid organ. The success of intestinal transplantation (ITx) for the treatment of
intestinal failure is limited by high rates of rejection and risks of graft-vs-host disease (GVHD) and infection. On
the funded grant (Project 4), we addressed the hypothesis that these outcomes were largely determined by the
exchange of lymphoid tissue and hence the balance of graft-vs-host (GVH) and host-vs-graft (HvG)-reactive T
cells. By combining multiparameter FCM, including allele-specific mAbs to distinguish donor and recipient-
derived cells, with high-throughput TCR β chain CDR3 sequencing to track alloreactive T cells in the GVH and
HvG directions in the graft and circulation, we obtained data consistent with this hypothesis. High-level
multilineage donor hematopoietic chimerism was common in the recipient blood after transplant, often persisted
>1 year and usually was not associated with clinical GVHD. Increased blood chimerism in recipients of
multivisceral transplants (MvTx) was associated with reduced donor-specific antibody (DSA)-positive rejection
and slower replacement of donor graft T cells by the recipient compared to recipients of isolated intestinal
transplants (iITx), demonstrating interrelationships between lymphocytes in the graft and the circulating T cell
pool. Our data suggest that GvH-reactive tissue resident memory (TRM) cells in the graft expand locally in
response to rapidly infiltrating recipient APCs, then enter the recipient’s peripheral circulation and possibly the
bone marrow, where they may promote engraftment of donor graft-derived hematopoietic stem cells (HSCs) and
progenitors that contribute to multilineage donor blood chimerism. Early rejection is associated with graft mucosal
infiltration by recipient T cells with a non-TRM, circulating T cell phenotype, in which HvG T cell clones
predominate. These HvG clones persist within the graft, acquire the TRM phenotype after the rejection resolves,
and apparently seed the entire gut, potentially posing a constant threat of rejection. Our data suggest that GVH-
reactive clones may counteract HvG reactivity both locally within the graft, thereby protecting it from rejection,
and systemically. In this renewal, we will build on these findings and those of Projects 1 and 2 to address the
central hypothesis that local antigen responses establish and maintain the intestinal lymphocyte
resident memory pools, that TRM and effector T cells (Teff) may be interconvertible and that graft
TRM/Teff can enter the circulation and recipient bone marrow. We propose to: 1) Determine the functional
and spatial regulation of alloreactive T cell responses in the graft, circulation and bone marrow; and 2)
Assess the homeostasis, specificity and genesis of B cell responses in the graft, bone marrow and
circulation. Project 3 will provide unique insights into the temporal development of human tissue resident
lymphocyte populations that complement the spatial ana...

## Key facts

- **NIH application ID:** 10176374
- **Project number:** 5P01AI106697-09
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Megan Sykes
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,000
- **Award type:** 5
- **Project period:** 2013-06-25 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176374

## Citation

> US National Institutes of Health, RePORTER application 10176374, Lymphocyte reconstitution and responses in intestinal transplantation (5P01AI106697-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10176374. Licensed CC0.

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