# T cell invasion of the stem cell compartment during immune-mediated GI damage

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $573,014

## Abstract

Despite the importance of intestinal stem cells (ISCs) for epithelial maintenance in the gastrointestinal (GI) tract
and the clinical significance of inflammatory intestinal disorders and immune-mediated GI damage, the
potential of the immune system to directly engage with the ISC compartment remains poorly understood. GI
graft vs. host disease (GVHD) is one of the greatest challenges for allogeneic hematopoietic/bone marrow
transplantation (allo-BMT), causing severe toxicity, necessitating deeply immunosuppressive interventions, and
limiting the wider usage of allo-BMT for potentially curable conditions. We have found that acute GVHD leads
to substantial reduction of Lgr5+ ISCs and the Paneth cells providing their epithelial niche. While there is limited
understanding of the precise mechanisms by which immune responses induce ISC compartment damage and
regeneration, it is not possible to fully understand BMT-related complications in the GI tract or how immune
cells may impact specific epithelial components without examining the three-dimensional (3-D) tissue
environment of the intestines and the proximity of immune responses to the ISC compartment. We seek to
understand the fundamental interactions occurring between the immune system and the ISC compartment,
how these interactions are engaged in the context of hematopoietic transplantation, and how the underlying
biology may be manipulated therapeutically for clinical intervention. To address these goals, we have
developed a research proposal emphasizing 3-D imaging of immune effectors within GI tract, mechanistic ex
vivo modeling of murine and human immune cell recruitment to the ISC compartment, and in vivo validation in
experimental transplant models. We have also assembled a multi-disciplinary team of collaborators at the
forefront of basic and translational immunology, ISC biology, and advanced microscopic imaging. Our
preliminary findings indicate that the ISC compartment is the first site of allogeneic T cell invasion within the
intestinal mucosa after BMT and thus the initial target of GVHD. Furthermore, we have found that co-cultures
of immune cells and intestinal organoids can be used to model and mechanistically dissect these processes.
Using 3-D confocal and 2-photon intravital imaging, we have developed the capacity to accurately quantify loss
of ISCs, specific invasion of the ISC compartment, and localization of T cell homing ligands during
homeostasis and during active immunity. We have also developed strategies for analysis of in vivo lineage-
specific gene expression within the ISC compartment. This study will thus test the hypothesis that lymphocyte
recruitment to and regulation of the ISC compartment are central features of GI damage post-transplant,
impacting both physiologic and pathologic mucosal responses, and we will evaluate approaches to modulate
lymphocyte homing and promote recovery of injured epithelium. This project will lead to a mechanistic
understanding of fundam...

## Key facts

- **NIH application ID:** 10322754
- **Project number:** 5R01HL145631-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Alan M Hanash
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $573,014
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322754

## Citation

> US National Institutes of Health, RePORTER application 10322754, T cell invasion of the stem cell compartment during immune-mediated GI damage (5R01HL145631-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10322754. Licensed CC0.

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