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.
