# Control by Beta 7 integrins of the bacterial triggers of IBD

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2024 · —

## Abstract

7. Project Summary/Abstract
The blockade of lymphocyte surface integrins (i.e. natalizumab (α4), vedolizumab (α4β7)) is an FDA-approved
strategy for the treatment of inflammatory bowel disease (IBD). Our understanding of their mode of action is
incomplete and little emphasis has been placed on their effect on B cells. However, a single dose of vedolizumab
in healthy volunteers lowers secretory immunoglobulin (Ig)A (SIgA) and weakens the immunization response to
oral cholera vaccine. To address the role of β7 integrins for the migration, localization and function of B cells in
IBD, we crossed tumor necrosis factor (TNF)-overproducing mice (TNFΔARE, which develop Crohn’s-like ileitis)
and IL10-/- (colitic-prone) with β7-deficient (β7-/-) mice. Unexpectedly, double mutant (TNFΔARE/β7-/-) mice
developed accelerated ileitis (earlier onset and worse severity), whereas IL-10-/-β7-/- develop lethal colitis. This
phenotype could additionally be induced by an anti-MAdCAM-1(α4β7-ligand) antibody. The accelerated
phenotypes were not due to a deficiency of retinoic acid-producing αE(CD103)+ dendritic cells, regulatory T
cells, regulatory B cell-derived cytokines or defensins. There was, however, markedly decreased lamina propria
(CD19+) B cells, poor localization of IgA+ plasma cells, luminal IgA deficiency, and differences in microbiota
composition in co-housed siblings. Furthermore, fecal microbiota transplants from β7-/- mice induced colitis in
IL-10-deficient mice, suggesting that an Ig deficit may allow transmissible proliferation of colitogenic pathobionts.
Thus, there is a critical need to understand whether sustained blockade of integrins or their ligands may have
implications for mucosal immunity. We hypothesize that the acceleration of ileitis and colitis in β7-deficient mice
is mediated by impaired B cell migration and suboptimal IgA transcytosis leading to an intestinal immunoglobulin
deficit and proliferation of pathobionts. To test these hypotheses, we will examine: 1. the role of B cell recruitment
and survival to maintain luminal IgA. 2. How do changes in microbiota composition alter the course and severity
of IBD? and 3. Further examine the role of β7 integrin (i.e., αEβ7) for docking of IgA-producing plasma cells with
epithelium and optimal IgA transcytosis. This investigation is significant as it begins to address the role of B cells
and their unique critical dependence on β7 integrins to home to the intestine and optimally transcytose IgA to
maintain the required IgA levels that control certain pathogenic elements of the microbiota during homeostasis
and IBD. Understanding the role of lymphocyte integrins at the interface between the microbiota and its host
may lead to a better understanding of how do current anti-integrin therapeutics work and even lead to new
interventions to prevent initiation of the dysregulated immune response to the microbiota that triggers IBD.

## Key facts

- **NIH application ID:** 10721820
- **Project number:** 5I01BX005951-02
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Jesus Rivera-Nieves
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721820

## Citation

> US National Institutes of Health, RePORTER application 10721820, Control by Beta 7 integrins of the bacterial triggers of IBD (5I01BX005951-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10721820. Licensed CC0.

---

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