The Role of CD4+ T Cell Subsets in the Mechanism of Action of Vedolizumab in Ulcerative Colitis

May 15, 2024 updated by: Brian Bressler, University of British Columbia

The cause of Inflammatory Bowl Disease (IBD) is not known, but studies from patients with IBD have found that these patients make unusually strong immune responses to their own intestinal tissues and to bacteria that normally live in the healthy gut. These overactive immune responses might result from an imbalance of T-lymphocytes, which are a type of white blood cell that recognize and respond to threats like infection or damaged tissues. In healthy tissues, a type of T-lymphocytes called T-regulatory cells control excess inflammation by preventing other T cells, called T-effector cells from responding. We believe that T-regulatory cells are somehow less active in IBD, resulting in damage to intestinal tissues by the T-effector cells.

T-lymphocytes, including both T-regulatory and T-effector cells, are guided to different parts of the body by 'alpha4beta7-integrin' molecules. Vedolizumab or Entyvio works by blocking this homing molecule so that T cells do not reach the intestine, but stay in the blood where they cannot aggravate your IBD. This study will help in understanding how Vedolizumab helps to heal or decrease the symptoms of your Ulcerative Colitis.

The effect of Vedolizumab on different types of T cells in the human intestine has not yet been studied. However, the investigators think that Vedolizumab will shift the balance of T cells in the intestine towards more healing T-regulatory cells and less damaging T-effector cells. The purpose of this study is to measure the different types of T cells in participants' blood and intestinal tissue before and during Vedolizumab treatment.

Study Overview

Status

Active, not recruiting

Conditions

Detailed Description

Inflammatory bowel disease (IBD) is an umbrella term for Crohn's disease and Ulcerative Colitis (UC), which are thought to be caused by disruption of the intestinal epithelial cell barrier, leading to changes in the intestinal flora and a consequent aberrant activation of the mucosal immune system. The resulting chronic intestinal inflammation is highly dependent on different subsets of CD4+ T helper (Th) cells. For example, correlative data suggest that Crohn's disease is driven by exaggerated Th1 and Th17 cell responses, since inflamed lesions contain increased levels of cytokines associated with these cells including IFNγ, IL-12, and IL-17 and IL-18. In contrast, although Ulcerative Colitis is in the same family of diseases, it is typically associated with Th2 cells since patients have high levels of IL-13 in the intestinal mucosa compared to patients with Crohn's disease or healthy individuals. Recent evidence implicates the newly emerging Th9 subset of Th cells in the pathology of UC. The development and function of Th cells with pathogenic potential is kept in check by another subset of CD4+ T cells, which is known as the regulatory T cell, or Treg. In healthy individuals, the intestinal lamina propria has a large proportion of Tregs, and evidence that simply lacking Tregs leads to IBD, suggests Tregs have a critical role in controlling intestinal homeostasis. Indeed, work in animal models and early phase clinical trials have shown that restoration of Treg function can ameliorate IBD. These data suggest that effective therapies need to promote the function of Tregs. Hence in order to understand the mechanism of action of new therapeutics it is critical to assess their impact on the balance between effector and regulatory CD4+ T cells.

Homing of effector and regulatory T cells to the intestine is controlled by a variety of integrins and chemokine receptors, with evidence that expression of alpha4beta7-integrin molecules (α4β7) on T cells has a key role in this process. Since Vedolizumab (Entyvio) specifically blocks the interaction between α4β7 and its ligands, which are expressed in mucosal tissue, its therapeutic effects in IBD are presumed to be related to a reduction in T cell trafficking to the intestine. However, how this biologic agent specifically affects the homing of Tregs versus effector T cells is unknown. In humans, Tregs in the peripheral blood are reported to express lower levels of α4β7 compared to effector T cells, but the relative expression on different subsets (i.e. Th1, vs. Th2, vs. Th17) of CD4+ T cells is unknown. Interestingly, in the intestine there is also a subset of Tregs that produces IL-17 and expresses high levels of α4β7, but the functional relevance of these cells in IBD is unknown. In addition, in mice, expression of α4β7 on CD4+ T cells is unstable under inflammatory conditions, suggesting that studies with circulating T cells in healthy individuals may not accurately reflect integrin expression in states of inflammation. Understanding how Vedolizumab affects the localization of circulating versus tissue-localized subsets of CD4+ T cells is key to understanding how this therapy works.

Also unknown is how signaling by α4β7 affects the development and/or function of different subsets of CD4+ T cells. In T cells, integrins not only mediate homing, but they also provide tissue-specific signals. For example, they can act as costimulatory molecules 10-12 and influence cytokine production. The molecular basis for the effects on T cells has not been well characterized, but in other cells integrins activate the PI3K pathway, providing a pro-survival signal 16. Since we have shown that activation of the PI3K pathway regulates the balance of effector versus regulatory T cells 17, it is possible that blockade of α4β7 may reduce PI3K signaling and favor the development of Tregs. In support of this possibility, we have shown that fibronectin, which is a ligand for α4β7, inhibits the development of Tregs.

This is an observational study to determine the expression pattern and function of α4β7 on effector and regulatory CD4+ T cells, and to define how treatment with Vedolizumab affects the homing and function of these cells. We hypothesize that that treatment with Vedolizumab will shift the balance of effector and regulatory T cells through two mechanisms: 1) altered migration of different subsets of CD4+ T cells to the intestine; and 2) promoting Treg stability as a consequence of reduced PI3K signaling downstream of α4β7.

Study Type

Observational

Enrollment (Actual)

50

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z4H4
        • Child and Family Research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Group 1: Healthy human volunteers who respond to our advertising poster (put up around CFRI and Vancouver General Hospital).

Group 2: Patients who are undergoing endoscopy at the Pacific Gastroenterology Associate's endoscopy clinic for indications other than Inflammatory Bowel Disease (such as colon cancer screening or polypectomy).

Group 3: Participants who are about to undergo Vedolizumab treatment from Pacific Gastroenterology Associate's clinic (affiliated with St. Paul's Hospital) as part of their standard of care treatment. Physicians will identify these patients when they undergo medical consultation for treatment of their Ulcerative Colitis.

Description

Inclusion Criteria:

  • Group 1: Healthy adults who have not donated blood within the past two months and who have no history of blood-borne diseases.
  • Group 2: Adult patients undergoing endoscopy for indications other than Inflammatory Bowel Disease or other inflammatory conditions of the bowel (such as colon cancer screening or polypectomy)
  • Group 3: Adults with an established diagnosis of Ulcerative Colitis (≥ 6 months preceding involvement in study) who are both scheduled for an endoscopy and are about to receive Vedolizumab as part of their standard of care treatment. Former anti-TNF treated Ulcerative Colitis patients will not be excluded, however, only 50% of the group 3 patient cohort can be on anti-TNF medications 12 weeks before Vedolizumab initiation.

Exclusion Criteria:

  • Less than 19 years of age or greater than 80 years of age
  • Known or suspected inflammatory conditions of the bowel (such as irritable bowel syndrome, celiac disease)
  • Known or suspected transmissible infectious disease such as HIV, Hep B or C or a hemorrhagic disorder
  • Known hematologic malignancy
  • Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Healthy Adults
[Not receiving Vedolizumab] Healthy adults who have not donated blood within the past two months and who have no history of blood-borne diseases.
Adults with no Inflammatory Bowl Disease
[Not receiving Vedolizumab] Adult patients undergoing endoscopy for indications other than Inflammatory Bowel Disease or other inflammatory conditions of the bowel (such as colon cancer screening or polypectomy)
Donors with Ulcerative Colitis
[Set to receive Vedolizumab] Adults with an established diagnosis of UC (≥ 6 months preceding involvement in study) who are both scheduled for an endoscopy and are about to receive Vedolizumab treatment (standard of care).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Differences in CD4+ T cell subsets in the blood and colonic tissue of IBD patients before and after Vedolizumab treatment; relative CD4+ T cell numbers will be determined by immunofluorescent detection of subset specific markers.
Time Frame: Two years
Two years

Secondary Outcome Measures

Outcome Measure
Time Frame
Differences in the stability of T regulatory cells with and without alpha4beta7 integrin binding as measured by maintenance of the Treg-specific-demethylation region in the FoxP3 promoter.
Time Frame: Two years
Two years
Differences in the suppressive capacity of T regulatory cells with and without alpha4beta7 integrin binding as measured by ability to suppress the proliferation of CD4+CD25- T effector cells.
Time Frame: Two years
Two years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of British Columbia

Investigators

  • Principal Investigator: Brian Bressler, MD, FCRP(C), University of British Columbia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2016

Primary Completion (Actual)

December 1, 2023

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

March 8, 2016

First Submitted That Met QC Criteria

March 22, 2016

First Posted (Estimated)

March 29, 2016

Study Record Updates

Last Update Posted (Actual)

May 17, 2024

Last Update Submitted That Met QC Criteria

May 15, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H15-01034

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Ulcerative Colitis

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Egypt

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe