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REVIEWS

Advances in the treatment of coeliac disease:


an immunopathogenic perspective
Katri Kaukinen, Katri Lindfors and Markku Mäki
Abstract | Coeliac disease is a common and fairly well-characterized systemic disorder that mainly affects the
small intestine, but also has extraintestinal manifestations. The environmental trigger (gluten derived from
wheat, rye and barley), the genetic predisposition conferred by the HLA‑DQ2 and HLA‑DQ8 haplotypes and
many steps in the disease pathogenesis are known. This knowledge has enabled researchers to suggest novel
alternative treatments or adjunctive therapies to the gluten-free diet, which is currently the only available and
effective treatment for the condition. This Review focuses on emerging and potential treatment strategies
that are based on the current concept of the disease pathophysiology. The search for novel future treatment
modes, including nonpharmacological and pharmacological approaches, is also outlined. The potential pitfalls
associated with the various research avenues are also discussed.
Kaukinen, K. et al. Nat. Rev. Gastroenterol. Hepatol. advance online publication 6 August 2013; doi:10.1038/nrgastro.2013.141

Introduction
Patients with coeliac disease report that their condi- Before the discovery of gluten as the causative agent
tion is “tricky to find, hard to treat and impossible to in coeliac disease, a number of cumbersome attempts
cure”. 1 However, a new understanding has emerged were made to treat the condition.4 For instance, systemic
of the mechanisms that produce the characteristic cortico­steroids have been tried, but they are no longer
dietary g­luten-induced damage to the small bowel used routinely owing to their association with systemic
mucosa, which has enabled improvements in the adverse events.5 The concept of a gluten-free diet as a valid
diagnosis and treatment of coeliac disease. The disor- treatment for coeliac disease dates back to the 1950s; since
der occurs in response to the digestion of wheat, rye then, this method has been the only available and effective
and barley that contains gluten in individuals carry- approach.4 Strict adherence to the diet results in recovery
ing either HLA‑DQ2 or HLA‑DQ8. 2 Therefore, the of the small bowel mucosa and alleviat­ion of symptoms
development of villous atrophy in the small bowel and might also prevent the development of complications
mucosa and crypt hyperplasia with substantial T-cell- related to coeliac disease such as osteo­porotic fractures
mediated and humoral responses in coeliac disease are and small bowel lymphoma.6 However, adherence to the
promoted by both genetic and environmental factors. diet can remain inadequate as the g­luten-free diet is costly
Such immune-mediate­d enteropathy is characterized and particularly restrictive in nature, and the replacement
by a variety of symptoms, including a wide range of products are often less palatable than gluten-containing
abdominal complaints and extraintestinal manifest­ food and have poor availability.7 Patients who are unable
ations such as short stature, infertility, osteoporosis to adhere to the gluten-free diet are at risk of continu-
and neurological problems. The advent of highly accu- ous gluten-induced health problems. 7 Furthermore, a
rate serological tests (such as endomysial and trans­ small subgroup of patients with coeliac disease do not
glutaminase 2 [TG2] autoantibody assays) has enabled respond to the gl­uten-free diet and thus need additional
the identification of the increasing incidence of coeliac immuno­therapy.7 In view of these obvious problems with Department of
disease. Historically, the prevalence of coeliac disease the gluten-free diet, patients with coeliac disease feel that Gastroenterology and
Alimentary Tract
was 0.01%, but according to current data it is 1–2% an unmet need exists for alternative therapies to treat Surgery, Tampere
in Western countries. 3 This percentage means that their condition.1 This article reviews the current knowl- University Hospital and
~7–14 million people in Europe have coeliac disease and edge regarding the disease pathogenesis and the latest School of Medicine,
(K. Kaukinen), Tampere
that ~3 million people in the USA have the condition. advances towards developing novel t­ reatment options Center for Child Health
Coeliac disease would then be one of the most common for coeliac disease. Research, University of
Tampere and Tampere
food-related lifelong disorders worldwide. University Hospital,
Luminal processing of gluten (K. Lindfors, M. Mäki),
University of Tampere,
Cereals, including wheat, rye and barley, are staple
FI‑33014 Tampere,
Competing interests foods and important sources of nutrients, dietary fibre Finland.
M. Mäki declares associations with the following companies:
Alvine Pharmaceuticals, BioLineRx, Flamentera AG, ImmusanT.
and other health-promoting compounds. Gluten is
Correspondence to:
See article online for full details of the relationships. The other the major structural component of these cereals and K. Kaukinen
authors declare no competing interests. has unique viscoelastic properties that are essential for katri.kaukinen@uta.fi

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Key points lumen, even in individuals without coeliac disease. 11,12


Incomplete degradation of gluten in the gastro­intestinal
■■ As the knowledge of the pathogenesis of coeliac disease has increased, new
tract leads to fairly long peptides entering the small
alternative treatment modes (such as detoxification of gluten) to replace the
burdensome gluten-free diet have been suggested
intestinal lumen, where their first contact is with the
■■ Several investigational approaches exist to detoxify gluten in the lumen of the mucosal epithelium. In patients with coeliac disease,
small intestine, including glutenase therapy and polymeric gluten sequestrants this e­ncounter launches deleterious downstream effects.
■■ Suggested treatment options that prevent gluten-induced effects at the
intestinal epithelium include blockers of intestinal permeability and IL‑15 Food production
■■ Other therapeutic options (such as transglutaminase 2 inhibitors and HLA Gluten can be detoxified before it is digested, for
blockers) are based on the prevention of the gluten-induced immunological example, during food production (Figure 1). In practice,
cascade in the lamina propria
this strategy would require the development of strains
■■ Currently, the most advanced drug candidates are in phase II clinical trials
of gluten-containing grains that lack the proteins that
activate coeliac disease. Such detoxification could be
Gut lumen attained by several routes using selection, breeding and
Cereal
gluten 2 genetic engineering by silencing or deleting harmful
Gluten gluten sequences.13 One important point to consider,
1 digestion
Nontoxic during food however, is that wheat varieties with increased crop yield
cultivars production
Insufficiently digested gluten and improved characteristics for food production have
been developed over the cent­uries, and these character­
3
Gluten digestion 4 istics are associated with increased gluten content of
with probiotics Gluten the grains.10 This point raises the question of whether
or oral enzymes sequestration
modification of the current gluten-rich wheat cultivars to
remove the harmful components would result in a loss of
Epithelium Binding of P(HEMA-co-SS) the character­istics that make gluten-containing products
preferable for food processing. Moreover, the techniques
required to modify the grains, especially genetic engi-
neering, would probably considerably increase the cost of
Figure 1 | Investigational approaches that work in the lumen of the small intestine the gluten-free diet, which is already economically more
that could be used to treat coeliac disease in the future. Gluten is highly resistant burdensome than a diet that contains gluten.
to degradation by gastrointestinal enzymes and thus fairly long peptides enter Another way to develop gluten-free food products,
the intestinal lumen. In patients with coeliac disease, these peptides launch especially bread, is to use sourdough fermentation
deleterious downstream effects. (1) Cereal products from nontoxic cultivars during baking. During this ancient process, the gluten
produced by selection, breeding and genetic engineering would lack the harmful
concentration in the wheat flour is reduced by the lacto­
peptides that induce coeliac disease and thus the activation of the deleterious
bacilli and yeast in the sourdough. 14 Findings from
cascade could be avoided. (2) Sourdough fermentation leads to gluten degradation
during food processing; ingestion of foods produced by this technique should be studies published in the past 4 years, suggest that goods
safe for patients with coeliac disease. (3) Alternatively, the degradation of harmful baked using sourdough fermentation are not harmful for
gluten peptides into nontoxic fragments can be accomplished after ingestion by patients with coeliac disease.15,16
probiotics such as bifidobacteria or by individual oral enzymes or their
combinations. (4) The binding of P(HEMA-co-SS) gluten in the gastrointestinal Bacterial and fungal degradation
lumen can prevent the production of harmful gluten peptides and their downstream The gluten-degrading capacity of various bacteria and
effects, this option is emerging as an alternative therapeutic strategy. Abbreviation:
fungi have also been exploited to develop novel drug-
P(HEMA-co-SS), poly(hydroxyethyl methacrylate-co-styrene sulfonate).
based therapies for coeliac disease (Figure 1).17 Per oral
protease supplementation therapy, which is based on
dough formation and gives bread its distinctive texture further digestion of gluten peptides into small nontoxic
and taste.8 Gluten-containing flours are therefore used peptides before they reach the intestinal epithelium, is the
in preparing our most common foods, including bread, most widely studied approach for alternative treatments
pastries, biscuits, cakes and pasta. Furthermore, the of coeliac disease.12 As the high proline content of gluten
technological qualities of gluten have been exploited in makes it resistant to gastrointestinal digestion, prolyl
widely consumed manufactured foods such as sausages, endopeptidases (PEP) have been considered as a poten-
instant soups and confectioneries. Consequently, the tial treatment mode for coeliac disease, as this family of
daily gluten intake in Western countries is high, often enzymes are able to cleave peptides at internal proline resi-
ranging between 15 g and 20 g per day.9 dues.12 PEP are widely expressed in different microbial and
The term ‘gluten’ refers to the main storage proteins mammalian species, including humans.18,19 Interestingly,
of all three grains that illicit an immunological response the usual level of PEP in humans seems to be insufficient
in patients with coeliac disease. Wheat gluten has two to assimilate dietary proteins in the gut.18,19 By contrast,
main components, the gliadins and the glutenins, which microbial PEP from species of fungus and bacteria such
both consist of considerable amounts of the amino acids as Aspergillus niger, Flavobacterium meningosepticum,
proline and glutamine.10 This characteristic means that Sphingomas capsulata and Myxococcus xanthus are able to
food-derived gluten is highly resistant to digestion by hydrolyse gliadin peptides in various in vitro and in vivo
gastric and pancreatic proteases in the gastrointestinal conditions.20,21 Moreover, all of these microbial enzymes

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are also able to exert their proteolytic function in the pH obtained from patients with coeliac disease, pretreated
range present in the human gastrointestinal tract, and they gliadin had less harmful effects than untreated gliadin.34
are all at least moderately resistant to the prevailing harsh All these data suggest that this approach might be
environment.18,22 The treatment of gluten peptides in vitro s­uccessful and should be further developed and optimized.
with PEP from either A. niger or F. meningosepticum leads
to a reduced response of intestinal T cells from patients Probiotics
with coeliac disease.23,24 Furthermore, in a randomized, The knowledge that various microbes are able to degrade
double-blind, cross-over clinical study, pretreatment with or alter gluten, together with data demonstrating dys-
PEP prevented gluten-induced malabsorption in over half biosis in the lumen of patients with coeliac disease, have
of patients with coeliac disease.25 prompted consideration of the use of probiotics as a non-
dietary therapy.36,37 Interestingly, data show that levels of
Enzyme therapy Bifidobacterium are lower in both the faeces and small
In addition to the aforementioned microbes, cereal seeds intestinal mucosa of patients with coeliac disease than
also contain a mixture of endogenous proteases capable in patients without coeliac disease.36,37 In cell culture and
of degrading gluten during germination to provide animal experiments, bifidobacteria reduce the severity
nutrients for the growing seedling. One such enzyme of the toxic effects of gluten seen in patients with coeliac
present in barley is cysteine proteinase EP‑B2. The suit- disease.38–40 Together, the above-mentioned insights have
ability of cysteine proteinase EP‑B2 as a candidate drug opened up prospects of developing an alternative therapy
for coeliac disease lies in its stability and activity in the for coeliac disease based on bifidobacteria. An explora-
conditions of the gastrointestinal tract.26 An early proof- tory, randomized, double-blind, placebo-controlled
of-concept study demonstrated that cysteine proteinase clinical study has concluded that the administration of
EP‑B2 can effectively digest gluten in the rat stomach the Bifidobacterium infantis natren life start strain to
in a dose and time-dependent manner.27 Similar results untreated patients with coeliac disease might alleviate
have also been obtained in experiments carried out using symptoms, but has no effect on increased intestinal per-
gluten‑sensitiv­e rhesus macaques.28 meability or active coeliac-type immune response.41 The
As PEP and cysteine proteinase EP‑B2 have comple- applicability of bifidobacteria as an alternative treatment
mentary sequence specificities, researchers have surmised for patients with coeliac disease thus clearly warrants
that a combination of these enzymes would actually be a further investigations. For instance, such studies could
dramatically superior therapeutic approach for the treat- be performed with VSL#3® (Sigma-Tau Pharmaceuticals,
ment of coeliac disease than either enzyme being used on Gaithersburg, MD, USA), a commercially available pro-
its own.29 To this end, a combination enzyme product, biotic product that contains four different bifidobacteria
ALV003 (Alvine Pharmaceuticals, San Carlos, CA, USA), and Lactobacillus species that hydrolyse gliadin.42
consisting of a 1:1 mixture of barley cysteine proteinase
EP‑B2 and S. capsulate PEP, has been formulated.30 A Polymeric binders
clinical study found that ALV003 was safe and well toler- Quite distinct from the approaches mentioned earlier
ated; no serious adverse events or allergic reactions were seeking novel treatments for coeliac disease are the poly-
observed during the 4‑week follow-up after a single dose.31 meric binders, which sequester gluten in the small intesti-
Moreover, the drug has been reported to prevent the nal lumen and in so doing prevent its harmful downstream
gliadin-induced T‑cell response in patients with coeliac effects (Figure 1). One such gluten-binding molecule is
disease ex vivo.32 On the basis of these encouraging results, poly(hydroxyethyl methacrylate-co-styrene sulfonate)
this drug candidate has entered phase IIa clinical trials. (P[HEMA-co-SS]), which reduces digestion of gluten
Although the results await publication in a peer-reviewed in vitro, thereby decreasing the formation of toxic pep-
journal, preliminary data suggests that the compound can tides associated with coeliac disease.43 The polymer is able
attenuate gluten-induced small bowel mucosal injury in to reverse gliadin-induced alterations in epithelial cells43
patients with coeliac disease.33 and to reduce the secretion of proinflammatory cytokines
Following up on the concept of combination enzyme ex vivo in mucosal biopsy specimens from patients with
therapy, an entire array of enzymes found in germinating coeliac disease.44 Moreover, in different mouse models
cereals has been tested for the ability to degrade gliadin.34,35 used in coeliac disease research, the sequestrant can atten-
The major advantage of such an approach is that the pro- uate gliadin-induced changes in the intestinal barrier and
tease preparation contains all the enzymes evolutionarily T‑cell activation.43,44 However, a potential concern about
selected for total cleavage of storage proteins in germinat- this approach is the question of whether P(HEMA-co-SS)
ing kernels. Studies have shown that a solution prepared also binds nutrients other than gluten and could thus pre-
from wheat, rye or barley that contains all germinating dispose patients to nutritional deficiencies. Nevertheless,
cereal enzymes is able to degrade gliadin in vitro to short this binding might not be a major issue, as the therapeu-
peptides that are probably <10 amino acids in length.34,35 tic approach using P(HEMA-co-SS) is suggested as an
Moreover, gliadin pretreated with such an enzyme cocktail adjunctive therapy for coeliac disease to detoxify traces
has a reduced capacity to induce harmful effects on intest­ of gluten contamination in the diet. Before proceeding
inal epithelial cells and to activate the T cells of patients to clinical trials in patients with coeliac disease, the drug
with coeliac disease.34 Similarly, ex vivo experiments in BL‑7010 that is based on this polymer needs to undergo
an organ culture of small bowel mucosal biopsy samples safety assessments in healthy volunteers.

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Lumen Gliadin as type 1 diabetes mellitus, that involve loss of intestinal


peptides
2 barrier function (Figure 2).
Blocking transcellular
Zonulin CXCR3 gliadin transport
CD71
slgA Tight-junction modulation
Larazotide acetate is an octapeptide derived from the
zonula occludens toxin from Vibrio cholerae that con-
3 tains a motif shared by zonulin. 49 This compound
Intraepithelial
Blocking lymphocyte prevents the opening of the intestinal epithelial
Epithelial IL-5
junction IL-15 tight junctions, presumably by antagonizing zonulin
action, and thus prevents gliadin-induced permeabil-
ity ex vivo and in vivo.50,51 Moreover, larazotide acetate
Tight-junction Transcellular
1 modulation gliadin peptide prevented the development of gluten-induced intestinal
permeability
permeability in a 1‑week phase I randomized placebo-
MICA NKG2D controlled study in which patients were challenged
Epithelial layer Apoptosis with gluten either with or without larazotide acetate.52
However, contrasting results have been obtained
Paracellular gliadin from two clinical randomized, double-blind, placebo-
peptide permeability
controlled trials of larazotide acetate. In these 2‑week
Lamina propria phase IIa and 6‑week phase IIb studies with 86 and 184
treated patients with coeliac disease on a gluten-free diet,
Figure 2 | Suggested treatment options that prevent gluten-induced effects at respectively, gl­uten-induced intestinal permeability was
the intestinal epithelium. (1) A characteristic feature of untreated coeliac disease
not affected, although treatment with larazotide acetate
is compromised epithelial barrier function caused by abnormal expression of
epithelial junction proteins, which enables paracellular passage of gluten peptides did reduce the severity of gastrointestinal symptoms.53,54
into the subepithelial compartment. This process, promoted by zonulin, has been This avenue of research nonetheless continues and a
proposed as a suitable future drug target in coeliac disease. (2) In addition to 14-week phase IIb clinical study is currently recruiting
the paracellular route, intact gliadin peptides can pass through the epithelium 320 patients with coeliac disease who have persistent
transcellularly by a mechanism involving gliadin–sIgA complexes binding to symptoms despite being on a gluten-free diet.55
transferrin receptor CD71. Blocking transcellular entry of gliadin peptides into the
intestinal mucosa could be the basis of a novel therapeutic strategy in coeliac
Blocking transcellular gliadin transport
disease. (3) Toxic gliadin peptides induce epithelial and other cells to secrete IL‑15,
which results in an increase in the number of intraepithelial lymphocytes. These
In addition to the paracellular route, intact gliadin pep-
intraepithelial lymphocytes become activated via epithelial MICA–NKG2D tides can pass through the epithelium transcellularly by
interaction stimulating cytotoxic effects on epithelial cells and thus increased a mechanism involving secretory IgA (sIgA).56,57 This
epithelial permeability. Blocking IL‑15-mediated effects has thus been suggested transcellular passage seems to involve gliadin–sIgA
as a therapeutic option for coeliac disease. Abbreviation: sIgA, secretory IgA. complexes binding to transferrin receptor CD71, which
is upregulated in intestinal epithelial cells of patients
with active coeliac disease.57 Although still in the dis-
Gluten at the intestinal epithelium covery phase, the inhibition of the sIgA–CD71-mediated
After gluten is partially digested in the gastrointestinal gliadin-peptide transport pathway has been proposed as
lumen into various peptides that are harmful in patients a new therapeutic option for coeliac disease (Figure 2).
with coeliac disease, these peptides come into contact with
the epithelial layer, which under usual circumstances is Blocking IL‑15
almost impermeable to macromolecules. However, clinical Gliadin, specifically the nonimmunogenic toxic gliadin
and experimental studies have indicated that the perme- peptides, has another effect on the intestinal epithelium.
ability of the epithelial cell layer is increased in untreated Upon encountering the epithelium, the toxic gliadin
patients with coeliac disease as a result of abnormal peptides induce the expression of IL‑15 by different cell
expression of epithelial junction proteins.45,46 Such com- types, including epithelial cells.58 Augmented expres-
promised barrier function would enable gliadin peptides sion of IL‑15 induces an increase in the number of intra­
to cross the intestinal epithelium paracellularly into the epithelial lymphocytes, which is characteristic of coeliac
lamina propria. One molecule suggested to contribute to disease.59 Moreover, IL‑15 upregulates the expression of
the opening of the epithelial tight junctions is zonulin, MICA in epithelial cells and triggers direct activation and
subsequently called prehaptoglobin 2.47 Intestinal epi- costimulation of the numerous intraepithelial lympho-
thelial cells are thought to release zonulin in response to cytes via the binding of MICA to NKG2D, which leads to
binding of gliadin peptides to the chemokine receptor an innate-like cytotoxicity toward epithelial cells.60 This
CXCR3.48 This engagement of gliadin with the recep- IL‑15-mediated enterocyte apoptosis also contributes
tor results in the activation of the zonulin pathway with to the compromised epithelial barrier function that is
an immediate reduction in intestinal barrier function and characteristic of coeliac disease. The importance of IL‑15
passage of gliadin into the subepithelial compartment. The during the pathogenesis of coeliac disease is highlighted
increased paracellular permeability caused by zonulin has by the finding that transgenic mice over­e xpressing
been proposed as a suitable future drug target in coeliac IL‑15 in intestinal enterocytes develop inflammation
disease as well as in other autoimmune disorders, such with villous atrophy in the small intestine.61 In view of

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the prominence of IL‑15 in the development of atrophy Intraepithelial


in the small bowel and inflammation in the context of lymphocyte
coeliac disease, blocking the actions of this cytokine has
emerged as a novel potential therapeutic strategy for the Epithelium Increased permeability
disorder (Figure 2). Lamina
In organ culture experiments using mucosal biopsy propria Gliadin peptides
samples from the small bowel of patients with coeliac 4
Anticytokine
disease, anti-IL‑15 monoclonal antibodies abro- therapy
gate upregulation of MICA by epithelial cells that is Anti-TG2-antibodies
1
induced by gliadin peptides60 and neutralize enterocyte TG2 Inhibition
of TG2
a­poptosis.62 In addition to these results, blocking IL‑15 Deamidated IFN-γ
downregulates the adaptive immune response in the gliadin peptides and TNF

lamina propria,63 thus further supporting the suitability of 2 5


Targeting B cells
anti-IL‑15-based therapy as a future treatment for coeliac Blocking
or autoantibody
HLA-DQ2 or
disease. Such a therapeutic approach is particularly suit­ HLA-DQ8
able for severe cases of refractory coeliac disease58 because T B
cell cell
blocking IL‑15 is expected to induce the apoptosis of the TCR
HLA-DQ2
malignant cells and prevent their further transformation or 6
HLA-DQ8 Tolerance induction
into invasive lymphoma.64 3
by vaccine or
Suppression Necator americanus
of T cells
Lamina propria immunological cascades 7
Other
The access of the gliadin peptides to the lamina propria approaches
after passing through the epithelial layer either para­
cellularly or transcellularly launches a strong adaptive Figure 3 | Therapeutic options based on prevention of immunological cascades in
immune response in susceptible patients with coeliac the lamina propria. (1) After gaining access to the lamina propria, relevant gliadin
peptides are deamidated by TG2. TG2 inhibitors have therefore emerged as
disease. The coeliac disease autoantigen TG2 is readily
candidate drugs for coeliac disease. (2) Deamidated gliadin peptides bind to
expressed below the epithelial layer on the basement HLA‑DQ2 and HLA‑DQ8 molecules on APCs. HLA-blocking compounds could thus
membrane, even in healthy individuals.65 TG2 is a multi­ inhibit the presentation of gliadin peptides to T cells, thus preventing downstream
functional enzyme and can catalyse a wide variety of T‑cell activation. (3) T‑cell response in the mucosa could be suppressed by
post-translational modifi­cations of proteins, including exogenous IL‑10, anti-CD3-antibodies or by blocking the homing of T cells into the
protein–protein cross-linking, glutamine deamidation small intestinal mucosa. (4) Activated T cells secreting inflammatory cytokines
and incorporation of primary amines into proteins. 66 such as IFN‑γ and TNF have been suggested as therapeutic targets. (5) Selective
Interestingly, certain gliadin peptides are substrates B‑cell depletion by anti-CD20 therapy and blockage of the binding of coeliac
disease autoantibodies to their target have emerged as future therapeutic
of TG2.67 The TG2-mediated enzymatic modification of
strategies. (6) A further means to prevent or treat coeliac disease in the future is
immunogenic gliadin peptides includes conversion of dis- the induction of tolerance by vaccinations or modifying the inflammatory immune
tinct glutamine residues to negatively charged glutamic acid response by hookworm infection. (7) Other therapies include steroid therapy, which
residues via a deamidation reaction.68 Deamidated gliadin are used in refractory coeliac disease. Abbreviations: APC, antigen-presenting cell;
peptides have an increased affinity for HLA‑DQ2 and IFN‑γ, interferon γ; TCR, T‑cell receptor; TG2, transglutaminase 2.
HLA‑DQ8 (which predispose carriers to coeliac disease)
that are expressed on antigen-presenting cells.68,69 Antigen-
presenting cells then present the peptides to gluten-reactive from patients with coeliac disease and organ culture
CD4+ T cells, thereby activating them. Subsequently, the of mucosal biopsy samples from the small intestine of
numerous activated T cells increase the secretion of pro- patients with coeliac disease.71–73 Currently, the available
inflammatory cytokines such as interferon γ (IFN‑γ) and TG2 inhibitors lack tissue specificity and it is thus pos-
TNF, all of which contribute to the development of lesions sible that the inhibitors might have an effect outside the
in the small bowel mucosa with villous atrophy and crypt gastrointestinal system, potentially leading to serious
hyperplasia.2 In parallel, the activated T cells are thought to adverse events in patients. This issue needs to be taken
induce the production by B cells of coeliac disease-specific into account when additional studies are designed.
autoantibodies against TG2.2
Blocking HLA‑DQ2 or HLA‑DQ8
Inhibition of TG2 Another potential means to prevent the adaptive immune
In view of the role of TG2 enzymatic activity in the response that occurs in coeliac disease is use of HLA-
pathogenesis of coeliac disease, it has been suggested blocking compounds to prevent the presentation of gliadin
that inhibition of this enzyme would offer a suitable peptides by antigen-presenting cells (Figure 3). As a pre-
therapeutic approach (Figure 3).70 This strategy is still disposition for coeliac disease is attributable to HLA‑DQ2
in the discovery phase and only a few preclinical proof- and HLA‑DQ8, blockers for both haplotypes need to be
of-concep­t studies are available (Figure 4). These studies developed. Currently, efforts have focused on designing
show that inhibition of TG2 prevents gliadin-induced optimal compounds for HLA‑DQ2, the more frequent
adaptive and innate immune-driven effects in vitro and haplotype, and a variety of gluten peptide analogues have
ex vivo in intestinal epithelial cells, intestinal T cells been developed for this purpose.74–77 Before proceeding

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Gluten-free diet complicated coeliac disease, without much success.81,83


Despite a few auspicious reports, large-scale controlled
Gut luminal Blocking effects in Processing in lamina
processing intestinal epithelium propria and elsewhere clinical trials are called for. Only a limited number of
studies have tested the general efficacy of using anti-IFN‑γ
Inhibition of ■ HLA-DQ2 or HLA-DQ8
Gluten- slgA–CD71-mediated blockers
antibodies; for example, in Crohn’s disease, fontolizumab
Discovery sequestering
polymers gliadin-peptide ■ TG2 inhibitors has failed to show clinical efficacy.84 So far, no data have
transport ■ Blocking B cells been published and no ongoing clinical trials have been
and autoantibodies
registered on the use of fontolizumab in patients with
Phase I Vaccine coeliac disease.
Alternatively, suppression of activated gluten-specific
■ Glutenase ALV003 T cells could be accomplished by antibodies targeting the
■ CCR9 antagonist
Phase II
■ Glutenase STAN1 Larazotide
■ Immune modulation
CD3 molecule, which is a co-receptor for the T‑cell recep-
■ Glutenase AN-PEP acetate
■ Probiotics
with parasite tor. As outlined earlier, effector T cells have an important
role in the pathogenesis of coeliac disease and thus their
Phase III elimination by anti-CD3 therapy might prove effective as
a nondietary treatment. Anti-CD3 therapy is thought to
Approved
promote oral tolerance by inducing the action of regula-
Figure 4 | Overview of the therapeutic pipeline in coeliac disease. Drugs are
tory T cells;85 therefore, this approach might prove benefi-
categorized based on the site of action. Abbreviation: TG2, transglutaminase 2. cial in coeliac disease. However, it has been reported that
effector T cells from patients with active coeliac disease
become resistant to suppression by regulatory T cells thus
from discovery phase studies to clinical trials with these making this mode of therapy questionable.86
compounds, researchers need to obviate the possibilit­y
that such blockers might also interfere with other Targeting B cells
responses dependent on HLA class 2 that are i­mportant In addition to T‑cell-mediated effects, B cells could be a
for immunosurveillance. suitable drug target in coeliac disease.78 Selective B‑cell
depletion by anti-CD20 therapy has been successfully
Anticytokine therapy used to treat autoimmune disorders such as rheumatoid
As coeliac disease is characterized by high levels of T‑cell arthritis and multiple sclerosis.87,88 In coeliac disease, the
activation, including an extensive cytokine response, disease-specific autoantibodies could be involved in
therapies that either amplify regulatory cytokines or the pathogenesis of the disease89 and the anti-CD20 anti-
inhibit inflammatory cells or cytokines have also been body approach might thus be useful. However, this strat-
suggested for the treatment of coeliac disease (Figure 3).78 egy has been questioned in the context of coeliac disease
Interestingly, such approaches have already been tested as anti-CD20 therapy does not abrogate the generation
in other severe autoimmune disorders, including rheu- of IgA plasma cells in the gut mucosa,90 a process that
matoid arthritis, psoriasis and IBD.78 However, many of also applies to TG2-autoantibodies specific to coeliac
the drugs in this category have not been effective in the disease. A study published in 2012 identified the epitope
context of coeliac disease and adverse events have limited of coeliac disease TG2-targeted autoantibodies on TG2.91
their large-scale use. The authors of this paper report that a distinct monoclonal
antibody that recognizes part of the main coeliac disease
Suppression of T cells epitope can release deposited coeliac disease antibodies
IL‑10 is an immunoregulatory cytokine in the intestinal from patient tissues. Moreover, the same antibody was
tissue that suppresses gliadin-induced T‑cell activation able to antagonize the harmful effects of autoantibodies
ex vivo in organ cultures of biopsy samples from the small from patients with coeliac disease in cell culture experi-
bowel of patients with coeliac disease.79 However, in a clini- ments.91 Thus, interfering with a­utoantibody–autoantigen
cal pilot study conducted in patients with coeliac disease binding in coeliac disease might prove to be an attractive
who did not respond to a gluten-free diet, the cytokine was therapeutic target in the future, although the efficacy of
not effective in managing this condition,80 thus q­uestioning such a therapy might be diminished by the gluten-induced
its potency as a future treatment for coeliac disease. T‑cell-mediated effects during the disease pathogenesis.
A further plausible approach in treating coeliac disease
by suppressing gluten-induced T‑cell-mediated immune Blocking of intestinal homing
responses might lie in monoclonal antibody-based thera- Upon activation with an antigen in the presence of
pies. Anti-TNF therapies (such as infliximab, certolizumab costimul­atory molecules, immune cells undergo specific
and adalimumab) and anti-IFN‑γ therapies (for example, changes in their microenvironmental positioning and
fontolizumab) have been suggested as suitable biologic eventually accumulate at effector sites. Lymphocytes use
agents in this context.78,81 Regardless of the fact that anti- integrin α4β7 and the chemokine receptor CCR9 to localize
TNF monoclonal antibodies are effective and widely used to the gastrointestinal mucosa in a process aided by their
in the treatment of IBD,82 infliximab is the only drug that respective ligands, chemokine CCL25 and MADCAM1.92
has been tested in patients with coeliac disease so far. Interestingly, in patients with coeliac disease, the number of
Infliximab was tested in a small number of patients with CCR9-expressing T cells in peripheral blood is increased,

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whereas their number in the small intestine is reduced.93 could be further developed and tested in future clinical
In addition, the expression of MADCAM1 is aug- trials.106 This organ culture response probably occurs via
mented in the duodenum of patients with coeliac disease.94 switching off the CD4+ type 1 T helper response. However,
Altogether, these data suggest that lymphocyte homing to it remains unclear how increasing the type 2 T helper
the small intestine could be a suitable drug target in coeliac response will prevent the activation of intraepithelial
disease, similarly to IBD (Figure 3).95 A phase II clinical lympho­cytes, which probably has a major role in epithelial
trial with a CCR9 antagonist96 has been completed, but the damage2 or inducing tolerance.
results have not yet been published.
No studies targeting either integrin  α4β7 or Conclusions
MADCAM1 in coeliac disease have been published. Intense research efforts to develop alternative treatments
However, some studies do suggest a cause for concern with for coeliac disease to replace or at least supplement the
this approach. Firstly, it has been reported that the expres- g­luten-free diet are ongoing (Figure 4). Suggested thera-
sion of integrin α4β7 and CCR9 is required for the induc- peutic approaches range from enzyme supplementation
tion of oral immune tolerance in mice.97 Secondly, in the therapy to blockers of intestinal permeability, TG2 and
absence of functional CCR9, intestinal inflammation HLA‑DQ molecules to lymphocyte blocking. Moreover,
(other than coeliac disease) has been exacerbated in mice efforts have also been made to manage coeliac disease by
and interestingly, this phenomenon parallels a deficiency vaccination or suppression of the inflammatory immune
of regulatory T cells in the intestinal lamina propria, response with hookworm infections. Some of the novel
which leads to a weakened immune defence.98,99 A further treatment and/or management options have already
aspect of this strategy to be taken into consideration is that entered clinical trials, but before marketing (presumably
blocking lymphocyte homing to the small intestine is not initially as supplemental therapy), more testing in large
antigen-specific and might thus predispose patients to phase III clinical trials is called for. Whilst choosing new
­gastrointestinal infections in general. treatment strategies, one must consider the possible risks
versus benefits of the various treatments for a disease
Vaccination and other strategies that is generally benign and reversed by a gluten-free
As discussed earlier, the majority of approaches aimed diet that causes no major recognized adverse events. For
at the development of novel treatment options for instance, it would be ethically (and economically) accept-
coeliac disease are based on the inhibition of a specific able to treat refractory coeliac disease with antibodies and
d­eleterious event or a cascade occurring during the patho­ immune modulators, which will at best temporarily inhibit
genesis. Nonetheless, other means have also been sought, the migration or the local activation of immune cells. Such
including the induction of tolerance by vaccinations or an aggressive and costly approach in an uncomplicated
suppression of the inflammatory immune response by benign disease would be unrealistic, whereas the use of
hookworm infection.100,101 The identification of major enzymes (as safely used for many years to treat pancreatic
T-cell gluten epitopes100,102 has made the vaccination insufficiency) seems to be a much more reasonable option,
approach possible. A vaccine is already in phase I clinical at least to alleviate the restrictions of the gluten-free diet.
trials, where the safety and tolerability of the first peptide Prevention strategies by vaccination might be even
vaccine based on HLA‑DQ2 recognition of gluten pep- more attractive than novel treatment modalities of a
tides, Nexvax2® (ImmusanT, Cambridge, MA, USA), will manifest disease if proven safe and effective. In addition,
be tested.103 This trial notwithstanding, unsolved issues patients with coeliac disease and most clinicians treating
related to this strategy include the lack of information the patients will want to be convinced that the new drug
on the capacity of peptide injections to spread to involve for coeliac disease is able to prevent the development of
other subdominant epitopes that also probably exist in the gluten-induced damage to the small bowel mucosa.
gluten. Moreover, it is assumed that the peptide vaccines Such treatment trials will require large numbers of
induce tolerance through regulatory T cells,104 but it is patients. In this respect, the development of reliable non-
currently not known whether the potential vaccine for invasive surrogate markers for gluten-induced damage
coeliac disease could overcome the unresponsiveness to to the small bowel and effective patient-related outcome
suppression by regulatory T cells of the effector T cells of measures would be of help. The development of a novel
patients with coeliac disease.86 medication that is as effective and safe as the gluten-free
The rationale behind the hookworm approach is that diet is still in its early days and the conventional dietary
parasitic helminth infections, which have decreased world- treatment will thus hold its place for the time being.
wide over time, are thought to have an important role in
modulating the host’s immune system. Interestingly, a
phase II clinical trial with Necator americanus has been Review criteria
completed in coeliac disease. However, inoculating A search of the MEDLINE database was performed
patients who have coeliac disease with N. ameri­canus did using the search terms “celiac disease”, “gluten”,
not reduce the severity of symptoms and did not prevent “gluten-free diet”, “novel treatment”, “drug”, “therapy”,
deterioration of the small bowel mucosa.101 Regardless “pathogenesis” and “histopathology”. Only English
of this finding, the infection did suppress inflammatory language full-text articles and abstracts were considered.
responses in organ cultures of small bowel samples,105 Articles included reviews and original publications, no
implying that a strategy using N. americanus infection publication data restrictions were applied.

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containing gluten peptides to suppress CD4+ receptor 9 on intraepithelial lymphocytes in the manuscript.

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