Clinical Science (2010) 118, 707715 (Printed in Great Britain) doi:10.

1042/CS20100027 707

R E V I E W

T-cell-directed therapies in inflammatory

bowel diseases

Giovanni MONTELEONE and Flavio CAPRIOLI

Department of Internal Medicine, University Tor Vergata of Rome, Rome, Italy, and Unit of Gastroenterology 2.
Fondazione IRCCS Ca Granda - Ospedale Maggiore Policlinico, Milan, Italy

A B S T R A C T

Gut inflammation occurring in patients with IBDs (inflammatory bowel diseases) is associated with
exaggerated and poorly controlled T-cell-mediated immune responses, which are directed against
normal components of the gut flora. T-cells accumulate in the inflamed gut of IBD patients as
a result of multiple mechanisms, including enhanced recruitment of cells from the bloodstream,
sustained cell cycling and diminished susceptibility of cells to undergo apoptosis. Activated T-cells
produce huge amounts of cytokines, which contribute to amplify and sustain the ongoing mucosal
inflammation. Strategies aimed at interfering with T-cell accumulation and/or function in the gut
have been employed with clinical success in patients with IBDs. In the present article, we review the
available results showing that T-cell-directed therapies are useful to dampen the tissue-damaging
immune response in IBDs.

INTRODUCTION an active cross-talk between immune and non-immune

CD (Crohns disease) and UC (ulcerative colitis) are the
major chronic IBDs (inflammatory bowel diseases) in
humans. Although the aetiology of both CD and UC
is unknown, evidence has accumulated to demonstrate
that IBD-related mucosal inflammation develops in
genetically predisposed individuals as a result of an
exaggerated mucosal immune response directed against
luminal antigens [1]. Detailed analysis of the immuno-
inflammatory molecules produced in the inflamed gut
of IBD patients has, however, revealed that CD and
UC have considerably different pathophysiologies, even
though non-specific mediators of tissue damage are
produced in excess in both diseases. It is also becoming
evident that, during IBDs, tissue damage is mediated by
cells, and that T-cells are key players in this pathogenic
process [2]. This concept is supported by several lines
of evidence. First, in both CD and UC, the tissue
injury occurs in areas that are heavily infiltrated with
activated CD4+ and CD8+ T-lymphocytes. These cells
are recruited from the bloodstream as a result of enhanced
production of chemoattractants within the inflammatory
microenvironment and regulated expression of adhesion
molecules on vascular endothelium and integrins on T-
cells [3] (Figure 1). The increased mucosal accumulation
of CD4+ T-cells also relies on a sustained cell cycling and
diminished susceptibility of cells to undergo apoptosis,
the programmed cell death that follows activation and
helps maintain immune homoeostasis by preventing
expansion of effector cells [4,5] (Figure 1). Secondly,

Key words: Crohns disease, cytokine, inflammatory bowel disease (IBD), interleukin, T-cell, ulcerative colitis, tumour necrosis
factor (TNF).
Abbreviations: APC, antigen-presenting cell; AZA, azathioprine; CD, Crohns disease; IBD, inflammatory bowel disease; ICAM-1,
intercellular adhesion molecule-1; IFN- , interferon- ; IL, interleukin; Flip, Fas-associated death domain-like IL-1-converting
enzyme-inhibitory protein; IL-6R, IL-6 receptor; LFA-1, leucocyte function-associated antigen-1; MAdCAM-1, mucosal addressin
cell adhesion molecule-1; 6-MP, 6-mercaptopurine; MS, multiple sclerosis; NFATc, nuclear factor of activated T-cells, cytoplasmic;
NF-B, nuclear factor B; STAT, signal transducer and activator of transcription; TCR, T-cell receptor; Th, T-helper; TNF-,
tumour necrosis factor-; UC, ulcerative colitis; VCAM-1, vascular cell adhesion molecule-1.
Correspondence: Dr Giovanni Monteleone (email Gi.Monteleone@Med.uniroma2.it).


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708 G. Monteleone and F. Caprioli
Figure 1 Putative mechanisms involved in the accumulation of T-cells in the gut of patients with IBDs
T-cells (T) are recruited from the bloodstream as a result of enhanced synthesis of chemokines by epithelial cells, APCs and stromal cells, and interaction between
adhesion molecules (e.g. MadCAM-1 and ICAM-1) on vascular endothelium and integrins (e.g. 47 and LFA-1) on T-cells. In the gut lamina propria, T-cells undergo
proliferation and become resistant against apoptotic stimuli.
studies conducted in various mouse models of IBDs have
shown that most immunoregulatory events in mucosal
inflammation are controlled by T-cells, that mucosal
T-cell activation is antigen-dependent and the responsible
antigens originate from intestinal bacteria [68]. Thirdly,
reductions in CD4+ T-cell numbers may favour clinical
remission in IBD patients. This can occur, for example,
in patients undergoing bone-marrow transplantation or
infected with HIV [9,10]. Fourthly, IBDs may associate
with other T-cell-mediated diseases [e.g. psoriasis, MS
(multiple sclerosis), rheumatoid arthritis and celiac
disease], raising the possibility that these diseases may
share the same T-cell-mediated pathogenic mechanism(s)
[11,12]. Finally, therapeutic interventions targeting
T-cells or T-cell-derived cytokines have already shown
great promise in the treatment of IBD patients [13].
In the present article, we will review results
showing that compounds interfering with mucosal
T-cell accumulation and/or T-cell functions are useful
in attenuating gut inflammation and in halting the
progression of the inexorable tissue damage and loss of
function associated with IBD.
INHIBITORS OF T-CELL TRAFFICKING IN
THE GUT MUCOSA
T-cell trafficking in mucosal surfaces is mostly mediated
by interactions between integrins (e.g. 47), a family of

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transmembrane glycoproteins expressed on the leucocyte
surface, and cognate endothelial ligands, which include
members of the immunoglobulin superfamily of adhesion
molecules, VCAM-1 (vascular cell adhesion molecule-1),
MAdCAM-1 (mucosal addressin cell adhesion molecule-
1) and ICAM-1 (intercellular adhesion molecule-1)
[14]. Compounds that inhibit the interaction between
lymphocyte integrins and endothelial adhesion molecules
have been used to reduce homing of T-cells into the gut
lamina propria of IBD patients [3]. One such inhibitor
is natalizumab, a humanized IgG4 monoclonal antibody
directed against the 4 integrin subunit which was
initially used commercially for treatment of MS [15]. In
two large Phase III studies, natalizumab was effective
in inducing and maintaining remission in patients with
active luminal CD, regardless of whether patients were
or were not refractory to anti-TNF- (tumour necrosis
factor-) antibodies [16,17]. Since some patients receiving
natalizumab treatment developed progressive multifocal
leucoencephalopathy, a rare opportunistic infection
of the central nervous system caused by the JC virus [18],
the drug was temporarily withdrawn from the market.
In 2008, the FDA (Food and Drug Administration)
reapproved natalizumab for the treatment of moderate-
to-severe active CD in patients who have had an
inadequate response to, or are unable to tolerate,
conventional therapies. More recently, vedolizumab
(formerly MLN0002), a humanized 47 antibody, and
rhuMAb Beta7, a humanized IgG1 monoclonal antibody

targeting the 7 integrin subunit, have been introduced
for the treatment of active IBDs. Two Phase II studies
showed that vedolizumab is significantly more effective
than placebo in inducing short-term clinical responses
in patients with UC and patients with CD [19,20].
Two Phase III trials evaluating vedolizumab therapy in
inducing and maintaining remission in both UC and CD
are currently in progress. A Phase I trial evaluating safety
of rhuMAb Beta7 in patients with active ulcerative colitis
is currently ongoing.
Alicaforsen (ISIS-2302) is an antisense oligonucleotide
designed to inhibit the expression of ICAM-1,
an endothelial molecule that selectively binds the
integrin LFA-1 (leucocyte function-associated antigen-
1) expressed on the leucocyte surface. Despite initial
and promising results [21], a large randomized placebo-
controlled study demonstrated that alicaforsen is ineffect-
ive in inducing clinical remission in patients with CD [22].
CCX282-B is a small molecule that has been
developed to selectively antagonize the activity of CCR9
(chemokine receptor 9), a T-cell-surface molecule that
promotes lymphocyte homing to small intestinal mucosa
upon its binding with epithelial cell-derived CCL25
(chemokine ligand 25). Oral administration of this drug
has been evaluated in a Phase II trial in patients with
moderate-to-severe CD, with encouraging preliminary
results [23]. Phase III trials of this compound in patients
with CD are currently ongoing.
INHIBITORS OF T-CELL PROLIFERATION
TCR (T-cell-receptor) engagement by antigen/MHC
ligand initiates a complex signalling cascade, which
triggers the activation of various transcription factors [e.g.
NF-B (nuclear factor B)] and promotes the release
of calcium from the endoplasmic reticulum into the
cytoplasm. Increases in calcium levels lead to the acti-
vation of calmodulin, a calcium-sensor protein, which,
in turn, activates the serine/threonine phosphatase
calcineurin [24]. Activated calcineurin then rapidly
dephosphorylates and promotes the nuclear translocation
of the transcription factor NFATc (nuclear factor of
activated T-cells, cytoplasmic) [25]. Once in the nucleus,
NFATc initiates the transcription of several genes
involved in T-cell activation (e.g. cell proliferation and
cytokine production) [26]. It is noteworthy that pharma-
cological inhibitors of calcineurin (i.e. cyclosporin and
tacrolimus) have been shown to have some efficacy in
IBDs. In particular, cyclosporin, a cyclic non-ribosomal
peptide originally extracted from the fungus Beauveria
nivea, is effective in the control of CD-related perianal
fistulas; however, a very high rate of recurrence occurs
after drug withdrawal [27]. More convincing results were
seen in UC, where cyclosporin is effective as a rescue
therapy in steroid-intolerant or steroid-resistant patients
T-cells in inflammatory bowel diseases 709
with severe disease [28]. However, cyclosporin treatment
associates with a very high rate of adverse events,
such as opportunistic infection, hypertension, electrolyte
imbalances, paraesthesiae, tremor and renal dysfunction,
which limit its long-term use [29]. Tacrolimus, a
macrolide lactone, has been successfully employed in the
treatment of patients with fistulizing CD and patients
with severe steroid-refractory UC [30,31]. As with
cyclosporin, tacrolimus administration can have serious
adverse effects (e.g. nephrotoxicity).
More recently two monoclonal antibodies directed
against the chain of the IL (interleukin)-2 receptor
(namely CD25) have been developed to antagonize IL-2
biological effects and mimic the activity of calcineurin
inhibitors. Findings obtained with daclizumab, a
humanized anti-CD25 antibody, showed no clinical and
endoscopic effect of this antibody over placebo in patients
with moderately active UC [32]. By contrast, two small
uncontrolled trials showed that basiliximab, a chimaeric
anti-CD25 monoclonal antibody, can be effective in active
steroid-resistant UC [33,34]; a Phase II trial is currently
in progress to assess the efficacy of basiliximab in UC.
Whether basiliximab is effective in CD remains unknown.
INDUCERS OF T-CELL APOPTOSIS
There is evidence that in IBDs, and particularly in CD,
mucosal T-cell accumulation is partly dependent on a
reduced rate of programmed cell death (apoptosis) [35].
The molecular mechanisms underlying this phenomenon
are complex and not fully understood; however, there
is evidence that some cytokines over-produced in IBD
tissue can prolong T-cell survival by enhancing the
expression of various anti-apoptotic factors [e.g. Bcl-
2, Bcl-XL and Flip (Fas-associated death domain-like
IL-1-converting enzyme-inhibitory protein)] [3539]
(Figure 2). Therefore restoring the susceptibility of
T-cells to apoptosis is a major goal in the therapeutic
armamentarium of IBD patients. In this context,
several studies have shown that the clinical benefit
of various pharmacological agents commonly used in
the treatment of IBDs is linked to their ability to
enhance mucosal CD4+ T-cell apoptosis. One such
compound is AZA (azathioprine). Both AZA and its
derivative 6-MP (6-mercaptopurine) are currently used
to induce and maintain remission in patients with
CD as well as in patients with UC [40,41]. AZA
treatment has steroid-sparing effects, and associates
with the attenuation or resolution of the mucosal
inflammation. It has been shown that treatment of CD
patients with AZA led to a marked increase in apoptotic
T-cells in the intestinal lamina propria [42]. Interestingly,
AZA-induced lymphocyte apoptosis requires T-cell
co-stimulation with CD28, and is mediated by the
specific blockade of the activation of the GTPase

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710 G. Monteleone and F. Caprioli
Figure 2 Possible mechanisms implicated in the resistance of gut T-cells to apoptosis
Inflammatory cytokines (e.g. IL-6, IL-12 and TNF-) activate transcription factors, such as STAT and NF-B, and enhance the expression of anti-apoptotic molecules
[e.g. Bcl-2, Bcl-XL and Flip) with the downstream effect of promoting T-cell accumulation.
Rac1. This inhibits, in turn, the transcription of Rac1
target genes, such as MEK (mitogen-activated protein
kinase/extracellular-signal-regulated kinase kinase), NF-
B and Bcl-XL , and activates the mitochondrial path-
way of apoptosis [42]. More recently, additional mechan-
isms of action of thiopurine derivatives in controlling
IBD-related inflammation have been proposed. In
particular, it was shown that AZA/6-MP significantly
inhibited both T-cell proliferation and memory response
respectively in vitro and in vivo [43].
Antibodies to TNF- are second-line agents for the
treatment of patients with IBDs. Clinical trials have
demonstrated that intravenous therapy with infliximab,
an anti-TNF- human/mouse chimaeric monoclonal
antibody, is able to induce and maintain the clinical
response in adult and paediatric patients with moderate-
to-severe active luminal CD [44,45], and patients with
moderate-to-severe active UC [46]. There is also evidence
that infliximab induces and maintains remission in
patients with CD-related perianal fistulas [47,48]. More
recently, it has been reported that adalimumab, a fully
humanized anti-TNF- monoclonal antibody, displays
clinical efficacy in adult patients with luminal and
fistulizing CD [49,50]. Clinical trials for adalimumab
in UC are currently ongoing. Several reports have
demonstrated that treatment with anti-TNF- increases
the rate of apoptosis in the intestinal lamina propria
compartment and that this effect associates with mucosal
healing [51]. However, the mechanisms by which
anti-TNF- antibodies induce T-cell death is still a
matter of debate. In a preliminary report, Scallon
et al. [52] showed that infliximab binds transmembrane
TNF- and kills TNF--expressing cells via both
complement activation and antibody-dependent cell-
mediated cytotoxicity. More recently, two independent
groups reported that infliximab-induced T-cell death
was completely prevented by the broad caspase inhib-
itor Z-VAD-FMK (benzyloxycarbonyl-valyl-alanyl-dl-
aspartyl-fluoromethane), thus suggesting that this drug
activates the caspase-dependent pathway of apoptosis
after binding to surface TNF- [53,54]. It has also been
shown that infliximab promotes accumulation of toxic

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ROS (reactive oxygen species) in lymphocytes and up-
regulates the pro-apoptotic factors Bax, Bak and p21
proteins [55].
Visilizumab is a humanized IgG2 monoclonal antibody
that specifically binds to the invariant CD3 chain of
the TCR. This antibody has been selectively engineered
in the Fc region to decrease binding on surface Fc
receptors located on immune cells [56]. As a result
of these changes, visulizumab reduces T-cell activation,
complement fixation, cytokine release and recruitment of
APCs (antigen-presenting cells). Visilizumab can induce
dose- and time-dependent apoptosis of lamina propria
T-cells isolated from patients with UC or patients
with CD through a caspase 3/8-dependent mechanism
[57]. The therapeutic efficacy of visilizumab has been
evaluated in patients with severe UC. In a preliminary
study, 32 patients with severe steroid-refractory UC
were assigned to receive two intravenous infusions of
visiluzumab. More than 80 % of patients demonstrated
a clinical response, and 41 % achieved clinical remission
[58]. In another study, patients were randomly assigned
to receive intravenous visilizumab at 5, 7.5, 10 or
12.5 g kg1 of body weight day1 for 2 consecutive
days. For all treatment groups, response and remission
rates ranged between 50 % and 71 %, and 5 % and
35 % respectively [59]. Results from ongoing Phase
III trials in patients with UC and in patients with
both luminal and fistulizing CD are currently pending.
However, visilizumab administration has been associated
with a very high rate of infusion-related side effects,
the most common of which is the cytokine-release
syndrome, characterized by fever, headache, chills,
arthralgias, nausea and vomiting. Initial experiences have
demonstrated that this syndrome, which is linked to
polyclonal T-cell activation, may occur in up to 90 %
of subjects and frequently leads to dose reduction and
even to a premature halting of the therapy [58,59].
Another cytokine involved in the control of lamina
propria T-cell apoptosis is IL-6 [60]. To induce its bio-
logical effects, IL-6 needs to bind a circulating receptor
(IL-6R); the IL-6IL6R complex is then recognized by
the membrane-bound receptor subunit gp130. This
 T-cells in inflammatory bowel diseases 711

Figure 3 Distinct patterns of cytokines are made by Th cells in IBD tissue

In CD, nave T-cells differentiate along the Th1 pathway under the stimulus of IL-12; however, additional signals, such as those provided by IL-23 and IL-21, are
necessary to expand Th1 cell responses. Th1 cells make IFN- , TNF- and IL-21. By contrast, in the inflamed colon of patients with UC, there is a predominant
accumulation of Th2 cells that make IL-4, IL-5 and IL-13. Factors involved in the differentiation of Th2 cells are not fully understood, but IL-4 synthesized by
non-T-cells could contribute. In both CD and UC, the intestinal mucosa is massively infiltrated with Th17 cells, which make IL-17 (both IL-17A and IL-17F), IL-21
and IL-22. Th17 cells differentiate from nave T-lymphocytes under the stimulus of TGF-1 (transforming growth factor-1) and IL-6; IL-23 and IL-21 contribute to
maintain/expand Th17 cell populations.

interaction triggers the activation of the transcription
factor STAT3 (signal transducer and activator of
transcription 3), and the production of several intracell-
ular anti-apoptotic factors, such as Bcl-2 and Bcl-XL
(Figure 2). Consistently, blockade of IL-6 activity en-
hances gut lamina propria lymphocyte apoptosis and, in
vivo in mice, injection of an anti-IL-6R antibody reduces
colonic inflammation [38]. A small placebo-controlled
Phase I/II randomized clinical trial showed that a
humanized anti-IL-6R monoclonal antibody (MRA, also
known as tocilizumab) was effective in inducing remis-
sion in patients with moderate-to-severe active luminal
CD. Interestingly, the therapeutic benefit of MRA was
associated with a significant increase in the percentage of
apoptotic lamina propria mononuclear cells [61].
INHIBITORS OF T-CELL ACTIVATION AND
DIFFERENTIATION
T-cell activation in response to TCR engagement relies
on the concomitant delivery of co-stimulatory signals
provided by binding of lymphocyte surface molecules
[e.g. CD28 and CD40L (CD40 ligand)] to their cognate
receptors on the APC surface (e.g. CD80, CD86
and CD40). TCR engagement without co-stimulation
leads to a state of profound T-cell unresponsiveness,
known as T-cell anergy [62]. Thus selective inhibition
of T-cell co-stimulation could be a novel therapeutic
approach to limit T-cell activation and dampen mucosal
inflammation in patients with IBDs. Abatacept is a
recombinant fusion protein composed of a fragment of
IgG1 and the extracellular domain of CTLA-4 (cytotoxic
T-lymphocyte antigen-4), a molecule which binds the
APC receptors CD80 and CD86 with high affinity,
thus preventing CD28-mediated co-stimulation of T-cells
[63]. Abatacept is approved in the U.S.A. for patients
with rheumatoid arthritis who failed any other type of
disease-modifying drug, and in Europe for those who
failed other disease-modifying drugs including TNF
antagonists. Phase III studies of abatacept are in progress
in CD and UC. No Phase I or II studies have been
performed in patients with IBDs.
Several studies indicate that lamina propria T-cells
derived from patients with CD and patients with UC
have distinct functional phenotypes and exhibit different
patterns of cytokine production. For example, CD tissue
contains high levels of TNF- and IFN- (interferon- ),
two cytokines predominantly synthesized by activated
Th1 (T-helper type 1) cells and involved in macrophage
activation [64] (Figure 3). By contrast, in UC tissue,
there is a predominant synthesis of IL-5 and IL-13,


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712 G. Monteleone and F. Caprioli
two cytokines made by Th2 (Th type 2) cells [65,66]
(Figure 3). However, mounting evidence suggests that
this classic Th1/Th2 paradigm in IBDs may be overly
simplistic, and the hypothesis that these two pathways are
always mutually exclusive has recently been challenged.
Additionally, in the last few years, work from many
laboratories has contributed to show that in both CD
and UC there is exaggerated synthesis of additional
cytokines, which are produced by a distinct subset of
Th lymphocytes, known as Th17 cells [67] (Figure 3).
Polarization of Th cells along the Th1, Th2 or Th17
pathway relies on the activity of additional molecules that
are released within the inflammatory microenvironment
(Figure 3). For example, differentiation of Th1 cells
is strictly dependent on the presence of IL-12, a
heterodimeric cytokine that is produced by APCs mostly
in response to bacterial stimulation [68]. IL-12 shares
the p40 subunit with IL-23, a cytokine involved in the
expansion of both pathogenic Th1 and Th17 cells
responses [69] (Figure 3).
The importance of the IL-12-driven Th1 signalling
pathway in immuno-mediated injury in the gut was
initially supported by studies in murine models of IBDs
showing that administration of a monoclonal antibody
directed against the IL-12/p40 subunit reduced the
ongoing Th1 cell response and ameliorated CD-like
colitis induced in mice by intrarectal administration
of 2,4,6-trinitrobenzene sulfonic acid [70]. These
observations led to the hypothesis that antibodies to
IL-12 could also be beneficial in patients with active CD.
To address this issue, two large placebo-controlled phase
II clinical trials have been carried out, with the purpose
of evaluating the safety and efficacy of monoclonal
antibodies directed against the p40 subunit of IL-12
(ABT-874 and ustekinumab) in patients with active CD
[71,72]. The clinical response and remission rates after
7 weeks of treatment with ABT-874 were 75 % and
38 %, respectively, compared with 25 % and 0 % for
the group receiving placebo. Treatment with anti-IL-12
was associated with decreases in the secretion of IL-12,
IFN- and TNF- by mucosal cells and with significant
improvement in mucosal histological scores [73]. The
other study showed that ustekinumab was more effective
than placebo in inducing a clinical response in patients
with moderate-to-severe CD [73]. No relevant adverse
effects were observed after treatment with anti-IL-12
antibodies. As pointed out above, IL-12 shares the p40
subunit with IL-23. Thus, at the present time, it is difficult
to establish whether the therapeutic effect of anti-IL-
12/p40 antibody is due to either the selective blockade of
IL-12/IL-23 or concomitant neutralization of both IL-12
and IL-23. Indeed, IL-23, rather than IL-12, appears to be
required for the development of some forms of intestinal
inflammation in mice [74].
Apilimod mesylate, formerly known as STA-5326,
is an oral inhibitor of IL-12 and IL-23 production.

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This compound has been shown to reduce the Th1
cell response and experimental intestinal inflammation
induced by transfer of pathogenic CD4+ CD45RBhigh
T-cells in SCID (severe combined immunodeficiency)
mice [75]. On the basis of these results, a randomized
double-blind placebo-controlled clinical trial has recently
been carried out to evaluate the efficacy of apilimod
mesylate in patients with moderate to severe active
CD [76]. Apilimod was well-tolerated but did not
demonstrate efficacy over placebo in patients with CD
[76].
In the last few years, various antibodies directed against
the signature Th17 cytokine IL-17A have been developed
and tested in models of inflammation [77]. AN417, a
monoclonal antibody against IL-17, is currently being
studied in Phase II clinical trials in patients with
moderate-to-severe CD and the results are currently
pending.
CONCLUSIONS
In recent years, progress in basic and translational
research has led to a better understanding of the role of
T-cells in the pathogenesis of IBDs. This has also fostered
the advent of novel therapeutic strategies to attenuate
T-cell-driven inflammation and to halt the progression
of the inexorable gut damage and loss of function
associated with IBDs. Blockade of T-cell recruitment
in the gut and/or T-cell function is at the forefront
of this new era with the success of several biological
compounds, including immunosuppressors and anti-
cytokine antibodies. These therapies are, however, not
effective in all patients and efficacy may wane. Moreover,
the use of some T-cell-directed therapies has been partly
hampered by the occurrence of serious adverse events,
and the therapeutic effect seen in pre-clinical studies has
not been always confirmed by studies in humans. Thus
a new challenge is to identify additional T-cell targets
which could be selectively regulated from a therapeutic
point of view, as well as to establish which patients will
benefit from which therapy.
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