Crohn’s immunomodulators (anti-TNF), however efficient outcomes appear to

Crohn’s
disease (CD) is an Inflammatory Bowel Disease (IBD) distinguished by
discontinuous excessive inflammation along the gastrointestinal tract (GI). Advanced
or untreated CD, commonly leads to scar formation or ulcers, further resulting
in intestinal stricture and bowel obstruction. 
In such cases, surgery is required to remove the affected region of
either small or large intestine.  Currently,
the most prevalent treatments against CD include anti-inflammatory drugs
(corticosteroids) and immunomodulators (anti-TNF), however efficient outcomes
appear to a proportion of patients. 
Additionally, CD approximately affects 2.5 million individuals of any
age in the Western world and has an accelerating increase in incidence in the
developing world.  The above evidence
illustrate the necessity of discovering novel therapies in order to bear a
spectrum of alternative treatments that can be implemented according to the
individual. 

The
aetiology as well as pathogenesis of CD, and more generally of IBD is ambiguous
and complicated.  The most accepted
hypothesis suggests that the synergy between genetic and environmental factors
trigger disease onset by stimulating continuous expression of pro-inflammatory
cytokines.  Under normal conditions, the
intestinal mucosal barrier is essential for preventing invasion of commensal bacteria
in the epithelial cells.  This is
achieved through maintaining immune self-tolerance. However, the aforementioned
risk factors of CD cause imbalances of the gut microenvironment, leading to
increase of intestinal permeability which results in dysfunction of mucosal
barrier and subsequent breakdown of tolerance (Wang et al, 2016).  Therefore,
the breakdown of tolerance elicits excessive immune responses.  According to this, GWAS-studies indicated
that genetically susceptible individuals may carry specific genetic
polymorphisms related to bacteria recognition, further promoting tolerance
impairment. CD is considered a cell-mediated disease, as Th1 and Th17 responses
are predominantly associated with its pathogenesis, illustrated in Figure 1. 

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The
balance between Treg/Th17 cells is significant for mucosal homeostasis, through
sustaining the equilibrium among pro- and anti-inflammatory cytokines.  Dependent on the microenvironment, the pro-inflammatory
responses of Th17 cells are restricted by the activity of Tregs, and vice versa
(Ziegler and Buckner, 2009).  This is achieved in the presence of TGF?, a common mediator significant for Th17
and Treg differentiation.  Th17 cells are
thought to be originated from a subset of naïve T cell expressing the lectin
receptor, CD161 as well as the transcription factor ROR?t (Cosmi
et al, 2008).  Their differentiation depends
on the presence of the pro-inflammatory cytokines, IL-1?, IL-6, IL-21 and TGF?. Following activation, Th17 cells express
high levels pro-inflammatory of IL-17, IL-21, and IL-22 which have an essential
role in host defences against extracellular pathogens by triggering further
recruitment of innate immune cells (Galvez,
2014).  In contrast, regulatory T
cells (Tregs) are divided into two categories; natural and induced.  Natural Tregs (nTreg) arise from the thymus
already expressing FOXP3, while induced Treg (iTreg) develop from mature CD4+
effector T cells in the periphery.  Treg
differentiation in the periphery is achieved upon exposure to high
concentrations of TGF?.   FOXP3+ Treg’s main function involves regulation
of excessive immune responses as well as maintenance of self-tolerance to
prevent autoimmune disease development. 
This is achieved through TGF?
and IL-10 anti-inflammatory cytokine secretion at the site of inflammation (Yadav, Stephan and Bluestone, 2013).

 

During
CD, mucosal barrier dysfunction alters the Th17/Treg commitment towards Th17-induced
inflammatory response, and thus significantly eliminating iTreg within the
intestinal lamina propria.  As mentioned
before, even if these both subtypes exhibit contradictory functions, TGF? is required
for their differentiation.  At low
concentrations, TGF? synergizes with IL-6 and IL-6-dependent IL-21 to promote
IL-23 receptor expression, and thus Th17 differentiation.  On the other hand, at high concentrations of
TGF? and absence of IL-6 or IL-21, IL-23R is supressed resulting in inhibition
of ROR?t and induction of iTregs (Omenetti
and Pizzaro, 2015).  This suggests,
that Th17 cells can inhibit Tregs by the expression of IL-21, while Tregs through
IL-10 production (Raza et al, 2012).  However, in CD even if TGF? levels are elevated, the downstream signalling
pathway is destructed by the blockage of smad3 phosphorylation.  This is achieved by the up-regulation of a natural
intracellular inhibitor of smad signalling, known as smad7 which acts as a negative
feedback.  Interestingly, both iTreg and
Th17 cells illustrated of being instable with a degree of trans-differentiation
into other CD4+ subtypes.  To illustrate this,
a fraction of FOXP3+ Tregs showed high-degree of plasticity towards IL-17-producing
cells as well as loss of FOXP3 expression. 
This is caused due to the accumulation of Th17-generating cytokines, as
plasticity may be an adaptive mechanism (Ueno
et al, 2015).  Oppositely, a research
indicated that under homeostatic conditions, Th17 cells can be converted into CD4+
Foxp3- type1 Tregs (Tr1) in the presence of TGF? and aryl hydrocarbon receptor (AhR) (Gagliani et al, 2015).  As Tregs expressing IL-17 were found
up-regulated in IBD patients, trans-differentiation can be utilised as a
potential therapeutic target.

IL-35 is a novel
anti-inflammatory cytokine, member of IL-12 family.  It is a heterodimer containing p35 and
Epstein-Bar virus-induced gene 3 (EBI3) subunits while the IL-35 receptor
requires the dimerization of gp130 and IL1R?2 domains.  A recent study, illustrated that this
cytokine is essential for Tregs to achieve their maximum regulatory activity,
both in vitro and in vivo. IL-35 was found to be mainly
produced by Tregs and B regulatory cells (Bregs) but not from effector cells.  Once IL-35 engagement to the receptor, STAT1
and STAT4 form a unique heterodimer which results in a continuous
feedback-loop, promoting IL-35 expression. 
Research has also observed expression of IL-35 in a population of IL-35-only
induced CD4+ Tregs, referred as iTr35 cells (Collison et al, 2010).  IL-35-induced cells were indicated of being
able to supress both CD4+ and CD8+ T cells proliferation, as well as their
differentiation into Th17 cells.  Ebi3
deficient mice have a significant increase in the production of IL-17.  This is achieved through Treg expansion and
increased production of IL-10. (Oslon,
Sullivan and Burlingham, 2013).  In
models of inflammatory bowel disease, IL-35 gene therapy and the adoptive
transfer of IL-35-expressing Tregs have been shown to cure colitis
symptoms.  According to the ability of
IL-35 of inducing the autologous Breg, IL-35+ Breg cells, as
well as, iTr35 can be utilised to eliminate excessive immune responses and
allow mucosal healing