Ignite Creation Date:
2024-05-06 @ 8:23 AM
Last Modification Date:
2024-10-26 @ 11:59 AM
Study NCT ID:
NCT02721719
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-05-17
First Post:
2016-03-08
Brief Title:
The Role of CD4 T Cell Subsets in the Mechanism of Action of Vedolizumab in Ulcerative Colitis
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
The Role of CD4 T Cell Subsets in the Mechanism of Action of Vedolizumab in Ulcerative Colitis
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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
Detailed Description:
Inflammatory bowel disease IBD is an umbrella term for Crohns 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 Crohns 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 Crohns 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 ie 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 andor 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
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 ie 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 andor 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None