Celiac Disease New Approaches to Therapy : A Review

Review article: coeliac disease, new approaches to therapyS. Rashtak & J. A. Murray

Celiac Disease Research Program,Division of Gastroenterology andHepatology and Department ofImmunology, Mayo Clinic, Rochester,MN, USA.

Correspondence to:Dr J. A. Murray, Celiac DiseaseResearch Program, Mayo Clinic, 2001st St SW, Rochester, MN 55905, USA.E-mail: [email protected]

Publication dataSubmitted 10 March 2011First decision 3 April 2011Resubmitted 18 January 2012Accepted 18 January 2012EV Pub Online 13 February 2012

This commissioned review article wassubject to full peer-review.

SUMMARY

BackgroundCoeliac disease is managed by life-long gluten withdrawal from the diet.However, strict adherence to a gluten-free diet is difficult and is not alwayseffective. Novel therapeutic approaches are needed to supplement or evenreplace the dietary treatment.

AimTo review recent advances in new therapeutic options for coeliac disease.

MethodsA literature search was performed on MEDLINE, EMBASE, Web of Sci-ence, Scopus, DDW.org and ClinicalTrial.gov for English articles andabstracts. The search terms used included, but not limited to, ‘Celiac dis-ease’, ‘new’, ‘novel’, ‘Advances’, ‘alternatives’ and ‘Drug therapy’. The citedarticles were selected based on the relevancy to the review objective.

ResultsSeveral new therapeutic approaches for coeliac disease are currently underdevelopment by targeting its underlying pathogenesis. Alternative therapiesrange from reproduction of harmless wheat strains to immunomodulatoryapproaches. Some of these therapies such as enzymatic cleavage of glutenand permeability inhibitors have shown promise in clinical studies.

ConclusionsGluten-free diet is still the only practical treatment for patients with coeliacdisease. Novel strategies provide promise of alternative and adjunctiveapproaches to diet restriction alone for patients with this disorder.

Aliment Pharmacol Ther 2012; 35: 768–781

ª 2012 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2012.05013.x

768

Alimentary Pharmacology and Therapeutics

INTRODUCTIONSensitivity to gluten results in a wide spectrum of mani-festations triggered by ingestion of the gluten-containinggrains – wheat, barley and rye. As the most commonpresentation of this disorder in genetically predisposedindividuals, coeliac disease presents with a set of diverseclinical features, which typically includes fatigue, weightloss, diarrhoea, anaemia, osteoporosis and depression.Intestinal damage is the main component of coeliac dis-ease and is characterised by intraepithelial lymphocytosis,crypt hyperplasia and villous atrophy.1 These pathologi-cal changes develop in the intestinal mucosa of sensitiveindividuals in response to gluten or the other relatedpeptides2 and improvement is usually observed by glutenwithdrawal from the diet.3 Currently, the prevalence ofcoeliac disease is estimated to be approximately 1% inwestern countries and increasing incidence of both diag-nosed and undiagnosed cases has been reported.4–6 Coe-liac disease is also commonly seen in association withextraintestinal manifestations, such as the typical skinlesions known as Dermatitis Herpetiformis, and the neu-rological disorders that primarily present with ataxia orneuropathy.7, 8 In addition, patients with longstandinguntreated coeliac disease may develop serious complica-tions such as osteoporosis, refractory sprue and malig-nant lymphoma that are potentially preventable withearly diagnosis and treatment.9 However, due to thebroad spectrum of presenting symptoms, the diagnosismay not be so obvious or easy.10 Thus, it is important tohave a greater awareness and lower threshold for testingfor this disorder. When coeliac disease is suspected, sero-logical testing and subsequently duodenal biopsies arerequired to confirm the diagnosis.11 Antibodies to tissuetransglutaminase of the IgA isotype (IgA anti tTg) andanti endomysial antibody testing have been repeatedlyshown to be highly sensitive and specific for identifica-tion of coeliac disease;12, 13 however, as assay perfor-mance is mainly dependent on pretest probability of thedisease,14 histological studies are still being considered asthe gold standard for establishing the diagnosis.

Currently, adherence to a gluten-free diet is consid-ered as the first line and indeed only therapy for coeliacdisease, which has been proven to relieve the symptomsin most cases and effectively prevent potential complica-tions.15–22 The availability of a readily applicable and safetherapy in the gluten-free diet has reduced the impetusfor alternative therapies. However, the costly and restric-tive aspect of complying with a life-long gluten-free regi-men may have a significant adverse impact upon the

quality of life of the patients.23, 24 Human nature indealing with temptation, motivation to resume regulardiet especially with milder disease, and the hidden glutenin the diet are the main issues. In many cases, whatshould be naturally considered as gluten-free foods arewidely contaminated with wheat.25, 26 Moreover, evenwith achieving and maintaining a truly gluten-free diet,especially in adults, there might be a lack of completerecovery in the intestine which may impact survival.27, 28

All these concerns along with ineffectiveness in somecases have warranted the development of alternative andcomplementary approaches to dietary treatment.Improved understanding of pathogenic pathways thatunderlie coeliac disease has led to development of multi-ple new therapeutic approaches, some of which havereached clinical studies. It may be especially importantto provide optimum aids and eventually alternatives tothe gluten-free diet for those with mild or no symptomsfor whom the motivation to be gluten-free may be less.

As a chronic autoimmune disorder, both adaptive andinnate immune responses are involved in pathogenesis ofcoeliac disease.29 In genetically susceptible individualswho express HLA DQ2 or DQ8, gluten consumptionleads to the recognition of gliadin by T lymphocytesthrough antigen presentation process.30 At the intestinelevel, tissue transglutaminase interacts with gliadin pro-teins, resulting in selective deamidation of certain gluta-mine residues. The deamidated gliadin peptide-TTGcomplexes presented by antigen presenting B cells pro-voke augmented activation of specific gluten-responsiveT cells. Similarly, transient T-cell response has beenshown with gluten challenge in the peripheral blood ofpatients with coeliac disease.31, 32 Interaction betweenactivated T cells and the B cell response together lead tostimulation of antibody-secreting cells and produce aninflammatory process that results in destruction of intes-tinal mucosa29 and presentations of the disease.

It is well recognised that the role of the T cell-basedadaptive immunity, i.e. HLA restricted, is required forcoeliac disease and also specific to the disease. However,the innate response to gluten, which may not be specificto coeliac disease, is nonetheless required.33 Hence,approaches that target either arm of the immune systemmay be helpful in the containment of their response togluten. Although directed at the specific T cell, responsesto gluten are more likely to have a degree of specificitynot seen with blocking the innate response. It is alsoimportant to preserve particularly innate responses toinfections within the intestine.

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Review: new therapies for coeliac disease

In this article, we aim to review the recent advancesin novel therapeutic options that have been suggested asadjuvant therapy for dietary restriction as well as thepotential true alternatives to gluten-free diet in coeliacdisease. Therapies that focus on detoxification of glutenare briefly discussed as they have been recently reviewedelsewhere.

An extensive literature search through August 2011for English articles and abstracts was performed onMEDLINE, EMBASE, Web of Science, Scopus, DDW.organd ClinicalTrials.gov. A combination of controlledvocabulary (MeSH, EMTREE) was used for MEDLINEand EMBASE. The terms ‘Celiac disease’, ‘Coeliac dis-ease’, ‘diet therapy’, ‘drug therapy’, ‘prevention and con-trol’, as well as text-words; ‘new’, ‘novel’, ‘strategies’,‘developments’, ‘advances’, ‘alternatives’, ‘compared’,‘comparison’, ‘comparative’ and ‘gluten-free’ were appliedin the searching process. Subject headings and publica-tion types, including ‘clinical trials’, ‘case reports’, ‘caseseries’, ‘controlled trials’, ‘randomised controlled trials’,‘cohort studies’, ‘retrospective/prospective studies’, ‘majorclinical studies’, ‘meta-analysis’, and ‘systematic review’,were used to identify the relevant literature. Cited articleswere selected based on the novelty and the relevancy tothe purpose of this review.

GLUTEN-FREE DIET AND NECESSITY FOR NOVELTHERAPIESThe association of coeliac disease with wheat consump-tion and similar cereals was first reported by Dicke, andsince then, gluten withdrawal has been considered as thecornerstone for the treatment of this condition.33 How-ever, the gluten-free diet, despite being safe and mostlyeffective, is not ideal. United States FDA and EuropeanUnion allow ‘Gluten free’ labelling only on the foodproducts that contain less than 20 part per million(PPM) of Gluten. In addition, daily amount of tolerablegluten is variable among people, but intake of less than10 mg of gluten per day has been reported to be safe forpatients with coeliac disease.34

Strict adherence to gluten-free diet is frequentlyaffected by patients’ compliance and gluten contamina-tion is a matter of concern, which leads to increased bur-den of the disease. Furthermore, the gluten-free diet isexpensive and not widely available in many countries,which makes it even more difficult for the patients tocomply with such a treatment.35–37 In addition, despitehigh risk of morbidity and mortality in a significantnumber of patients with coeliac disease, dietary treat-ment is not completely effective, as many of these

patients could be either unresponsive or require combi-nation therapies.38 Histological improvement is notalways achievable even in the adult patients with typicalcoeliac disease who are desirably responsive to a gluten-free diet in terms of symptoms and serological mark-ers.27, 39–41 This lack of complete healing common inadults is not benign and may be associated with negativelong-term consequences.

A recent study from England documented dissatisfac-tion with a gluten-free diet by the great majority ofpatients with coeliac disease. Patients were also asked todescribe their preference for three different potentialtherapeutic approaches, of which patients preferred avaccine approach over an antizonulin and peptidaseapproach by a moderate amount. In addition, patientswith coeliac disease also use complementary and alterna-tive medicine approximately one-fifth of the time.41

Therefore, investigation for developing novel therapeuticapproaches seems to be justified as alternative treatmentoptions are desired. Generation of new therapies isneeded for the patients who have difficulty being gluten-free as well as those compliant patients afraid of inadver-tent gluten contamination. Alternative therapies couldfree diagnosed individuals from the restrictive diet andprovide a passport to eat gluten with impunity. It is pos-sible that some regimens even prevent coeliac disease inindividuals with genetic susceptibility, such as those witha history of the disease in their family.

It is, of course, difficult to predict what regulatoryagencies will require of treatments for a disease whichhas not had drug therapy before. However, for a condi-tion such as coeliac disease, it is likely that we will haveto prove both safety and efficacy. The threshold forsafety will be particularly high, given that the currenttherapy, i.e. a gluten-free diet, can be considered particu-larly safe. Approaches that involve interruption of theimmune response, such as potent biological therapies,may pose unacceptable risks in this context other thanwhen being applied to severe disease. It would be hopedthat most topically or luminally active agents would havea very low potential for toxicity. Obviously, before anyagent would be used in humans, extensive toxicologytesting is necessary. With regard to efficacy, much devel-opmental work incorporates the use of cell-based systemsusing cells particularly derived from the small intestineof patients with coeliac disease or peripheral blood lym-phocyte of patients who have received gluten challenges.It is likely that efficacy of any agent for the treatment ofcoeliac disease will require both objective and subjectiveoutcome measures. Potential outcome measures could

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S. Rashtak and J. A. Murray

include healing or protection from histological worseningof the small intestine, the development of positive sero-logical tests for coeliac disease, or possibly other mea-sures of inflammation – for example, intestinal fatty acidbinding protein or antiactin immunity. There are nowclear guidelines provided by the FDA on how patient-reported outcome measures need to be generated, andsuch efforts are underway. Once complete, these willprovide a powerful tool with which to study patientresponses to therapy. Inherent in the evaluation of anyagent may require either deliberate or inadvertent chal-lenge with gluten. One can only speculate whether theregulatory authorities will require a natural state experi-ment or whether they would permit a study that wouldinclude a measured spiking of the diet with gluten. It isalso possible that regulatory agencies may differ on theirapproach to both safety and efficacy estimations for coe-liac disease treatments.

Recent advances in biomedical science have led to abetter insight into the molecular mechanisms behindcoeliac disease and identification of the pathogenicevents that can be targeted by potential medications.37, 42

These novel therapeutic strategies can be classified to thefollowing categories based on the site of effects and themechanism of actions (Table 1).

DIETARY MODIFICATION

Wheat variantsAlthough baking tactics, such as binding agents like xan-than gum or lactic acid-producing bacteria residing inthe ‘sourdough’, has been suggested for fermentation ofgluten-free products to increase baking quality, gluten-free bread generally lacks the desirable mechanical prop-erties that gluten provides for industrial baking.43, 44

Modified wheat strains which lack immunogenic pep-tides of gluten while maintaining satisfactory bakingquality have been considered as a desired therapeuticoption for patients with coeliac disease as this mightprovide an ideal replacement for gluten containing bread.These strains can be developed either by reproduction ofwheat species lacking harmful gluten epitopes or bygenetically altering the immunogenic peptides.

In the course of wheat evolution, the contribution oftwo ancient wheat strains, tetraploid Triticum Turgidum(AABB) and diploid Triticum tauschii (DD), has led todevelopment of the hexaploid Triticum aestivum(AABBDD), which is currently used globally as the breadwheat.45 Screening of extracted gluten proteins by usingisolated T lymphocytes from the intestine of coeliac

patients has revealed the immunogenicity of specificalpha gliadin sequences that are exclusively encodedby DD genomes and thus lacking in the AA and BBspecies.46, 47

Some specific wheat strains which have very low alphaand beta gluten content may have reduced toxicity. Simi-larly, genetic modification by deletion of alpha gliadinlocus from the D genome has been shown to reduceT-cell stimulatory epitopes, but it also affects bakingquality.48 Obviously, this only applies when wheat isconsumed and other toxic peptides from barley (horde-ins) or rye (secalins) if ingested could be potentiallyharmful.49 Therefore, by enhancing baking quality,reproduction of non-immunogenic wheat strains wouldbe a possible alternative for gluten exclusion, whichcould be very attractive for patients suffering from coe-liac disease. Recently, psyllium has also been suggestedas a gluten replacement with the least effect on odourand texture of the bread. Data of a sensory analysisstudy have shown the bread prepared from psylliumdough had a high acceptance rate among patients withcoeliac disease and healthy controls.50

Although these approaches are still at the preclinicalstages, they theoretically lead to elimination of harmfulgluten from foods which, along with increased quality oflife for the patients, could even prevent coeliac disease inthe community (Figure 1a). The economics of such anapproach is limited as commercial wheat is a very cheapand robust industrial commodity and it is unlikely thatthese specifically modified grains would ever replacecommercial wheat strains.

Gluten detoxificationSeveral strategies have been considered for detoxificationof dietary gluten and reduce immunogenicity of gliadinpeptides. These approaches are mainly at the preclinicalstage with a few in early clinical trials. These include,but are not limited to, probiotic preparations by lactoba-cilli,51 enzymatic cleavage of gliadin fragments by prolylendopeptidase (PEP) from microorganisms,52, 53 degra-dation of toxic peptides by germinating cereal enzymes,54

and the sequestration of stimulatory epitopes by poly-mers designed to inactivate them.55, 56 The strategies todetoxify gluten will be discussed in detail in another sec-tion (Figure 1a).

PERMEABILITY MODULATIONIn healthy individuals, tight junctions between the epi-thelial cells protect and control the exposure of submu-cosal tissues to the macromolecules that may induce a




toxic effect by passing through the intestinal barriers.They are also an important component of the cell-to-cellsignalling pathways.57 It has been shown that patientswith active coeliac disease have a defect in the epithelialbarriers that leads to increased permeability and possiblypassage of immunodominant gluten peptides and likelyother immunostimulatory luminal antigens, especiallybacterial components.58 These changes in the mucosalpermeability have been hypothesised to be an early path-ogenic event in the development of coeliac disease byexposing the immune system of susceptible individualsto the immunostimulatory gluten peptides.59 Previousstudies have identified the human protein Zonulin, a

precursor of prehaptoglobin-2, as a regulator of epithelialpermeability highly expressed in coeliac diseases and alikely contributor to its pathology.60, 61 This protein issimilar in effect to that of Zonula Occludens Toxin(ZOT) expressed by vibrio cholerae, which impairs epi-thelial tight junctions integrity.62 A recent study hasshown that gliadin binds to the chemokine receptorCXCR3 releasing Zonulin and subsequently increasingthe intestinal permeability via the My-D88 dependentpathway.63 An octapeptide derived from ZOT (AT-1001)that antagonises Zonulin action via receptor blockadeand therefore prevents mucosal impairment has beengenerated.64 As a part of Phase I clinical trial, the safety

Table 1 | New therapeutic approaches for coeliac disease

Underlying pathology Therapeutic approach Compound/Organism Development stage

Immunodominant GlutenPeptides

Dietary Modification

Wheat VariantsNon-immunogenic ancient wheatspeciesGenetically modified harmlesswheat strains

Gluten DetoxificationEnzymatic cleavage of gluten fragmentsInactivation by polymeric bindersProbiotic preparation

Prolyl EndopeptidasesP (HEMA-co-SS)Lactobacilli

PreclinicalPreclinical/phaseI clinical trial

Impaired MucosalBarrier

Permeability inhibition and mucosalreconstruction

Zonulin/ZOT receptor BlockadeMitogenic compounds

AT-1001R-spondin 1

Phase IIb clinical trialPhase III clinical trialfor Crohn's Disease

Adaptive Immunity Antigen Presentation SuppressionTissue Transglutaminase2 Inhibition

HLA DQ2/DQ8 blockade

KCC009, L-682777 Preclinical

PreclinicalInflammatory Response Cytokine therapy and Anti

InflammationAnti Inflammatory compoundsRegulatory Cytokines augmentationIL-10

Inflammatory Cytokine blockadeAntagonist peptidesAnti INF- gammaAnti TNF –alphaAnti IL-15

Budesonide

InfliximabAMG 714

Preclinical

PreclinicalPreclinical

Lymphocyte Recruitment Adhesion BlockadeAnti a4b7/MAdCAM-1Anti CCR9/CCL25

NatalizumabCcx282-B,CCX025

PreclinicalPreclinical

Overreactive AutoimmuneResponse

Immunomodulation

Tolerance InductionGluten VaccinationParasite InfectionChemotherapy and stem cell Transplant

Nexvax2Necator Americanus

Phase I clinical trialPhase II clinical trial




Intestinal lumen

ZonulinZonulin antagonist

(AT-1001)

Tight junction

ZOT receptor

Lamina propria

IELIEL

Intestinal lumen

Endopeptidase Modified dietary gluten

Gluten peptide

Gluten binder

Lamina propria

IELIEL

Intestinal lumen

Lamina propria

α4β7

Blocking antibody

Blocking antibody

MAdCAM-1

CCR9

CCL25

IELIEL

T-cellT-cell

Intestinal lumen

Gluten peptide

Lamina propria

Tr1Tr1cellcell

IL-10

AnergyAnergy

APCAPC

IELIEL

T-cellT-cell

Intestinal lumen

Lamina propria

E

TG-2TG-2TG-2

TG-2

Q

Q

inhibitor APC

TCR

HLA

HLA DQ2/DQ8

blocker

IELIEL

EEEE

QQ

QQT-cellT-cell

Intestinal lumen

Lamina propria

Apoptosis

MICA

Anti IL-15antibody

antibody

NKG2D Anti INF-Y

antibodyAnti TNF-α

INF-Y Fibroblast

TNF-α

IL-10

IL-15

IELIEL

Th-1Th-1

APCAPC

(a) (b)

(c) (d)

(e) (f)

Figure 1 | New therapeutic approaches for coeliac disease. (a) Detoxification of gluten. Polymeric binders or endopeptidaseenzymes act in the intestinal lumen to reduce immunogenicity of harmful gluten peptide. Nontoxic wheat strains lackingimmunostimulatory gluten peptides can be an alternative for gluten-free diet. (b) Permeability Modulation. Zonulinantagonist (AT-1001) binds to ZOT Receptors and reduces mucosal permeability by prevention of tight junction impairment.(c) Antigen Presentation Blockade. Inhibition of adaptive immunity by use of TG 2 inhibitors and HLA-blocking compounds(d) Cytokine Therapy. Monoclonal antibodies against inflammatory cytokines such as INF-gamma, TNF-alpha and IL-15reduce mucosal injury in coeliac disease. Regulatory cytokines such as IL-10 can be used for suppression of Th1 activation.(e) Inhibition of T-cell recruitment. Anti adhesion compound such as anti a4 antibodies block immune cell migration to theintestinal tissues. (f) Oral tolerance induction. Low-dose tolerance is driven by regulatory T cells via IL-10 secretion. Highdose of antigen mediates lymphocyte anergy via interaction between effector T lymphocyte and Antigen presenting cells.




and efficacy of this orally administrated medication wasinvestigated in a randomised controlled trial.65 In thisstudy, 14 patients with coeliac disease challenged by asingle dose of gluten while receiving AT-1001 for threeconsecutive days were compared with seven patients inthe placebo group. Intestinal permeability was measuredin the two groups by calculating fractional excretions oflactulose and mannitol to evaluate the efficacy of thetreatment. Interestingly, intestinal permeability remainedintact after gluten challenge in the subjects who receivedthe treatment, while adverse effects, gastrointestinalsymptoms and inflammatory markers were not observedto be more frequent when compared with the placebogroup. Based on these observations, use of Zonulinantagonists, which has recently completed phase IIb ofclinical trial, presents a complementary therapeuticapproach that is undergoing further clinical trials(Figure 1b).

ANTIGEN PRESENTATION BLOCKADE

Inhibition of tissue transglutaminaseIn the pathogenesis of coeliac disease, gluten peptidesneed to be introduced to T cell by binding to HLA mol-ecules located on the surface of antigen presenting cells.Native gliadin peptides have very few negatively chargedamino acids and that is while coeliac predisposing HLADQ2 or DQ8 preferably binds to negatively charged resi-dues. Interestingly, through a deamidation process,which is mainly due to effect of intrinsic tissue transglu-taminase 2 (TG2), conversion of specific glutamine resi-dues to glutamate results in increased affinity of HLAmolecules to gluten peptides, the process that leads tomore effective antigen presentation and exaggerated T-cell response.29 Thus, selective inhibition of TG2 andsubsequent blockade of the deamidation process couldbe an effective therapeutic approach for coeliac disease.To date, several types of competitive, reversible and irre-versible inhibitors of TG2 have been suggested as apotential compounds for the treatment of coeliac disease,neurological disorders and some types of cancers. Activecompounds with high potency for inhibition of TG2have been designed to be used in experimental studiesfor treatment of coeliac disease.66 However, as Glutamineresidues are partly modified to the deamidated form byenvironmental enzymes prior to absorption and someimmunogenic peptides illicit their T-cell stimulatoryeffect independent of deamidation process,49, 67 the prac-tical role of TG2 inhibitors in treating patients with coe-liac disease is uncertain.

A previous study on the isolated T lymphocytes fromthe intestinal biopsies of patients has shown that cysta-mine acts as a TG2 inhibitor and consequently leads toreduced T-cell response after gluten challenge.68 Othershave also suggested 2-[(2-oxopropyl)thio] imidazoliumderivatives, such as L-682777 and R-283, as potentialtherapeutic agents that inhibit human TG2 and blockactivation of gliadin-specific T cells. However, undesiredinteraction with biologically crucial macromolecules (e.g.Factor XIIIa blockade by L-682777) has made some ofthese agents unsuitable for in vivo studies.69, 70 It hasbeen shown that, although compatible with life, knock-out of TG2 mouse models develop systemic disorders,such as autoimmunity and immune complex glomerulo-nephritis.71 Therefore, even selective inhibition of TG2could be associated with adverse complications, especiallywhen it targets the tissues beyond intestinal level.Recently, dihydroisoxazole compounds (e.g. KCC009)have been shown to be promising in animal studies; theyappear well tolerated and effective inhibitors of TG2,with excellent bioavailability when given orally, but ashort serum half-life with minimal systemic effect.72, 73

Generally, despite looking beneficial, the potentiallybroad effects of TG2 inhibitors are concerning, and havelimited the evaluation in human studies. Clinical trialshave not been undertaken as yet in coeliac disease dueto the similarity in the catalytic sequences of differentsubtypes of transglutaminases and the risk of potentialinteraction with vital biological pathways (Figure 1c).

Coeliac-specific HLA inhibitionCoeliac disease almost exclusively occurs in subjects withthe HLA subtypes (DQ2 and DQ8).74 Presentation of gli-adin peptides that bind to HLA DQ2 and/or DQ8located on the surface of antigen-presenting cells leads toactivation of T lymphocytes and consequent adoptiveimmune response involved in coeliac disease.29 There-fore, blocking the binding site of these HLA moleculesby gliadin antagonist peptides could suppress the presen-tation process and consequently provide anotherapproach to treatment of coeliac disease. Whilst coeliac-specific HLA inhibition would be particularly attractive,a substantial challenge in terms of the avoidance of rapiddegradation of peptide agents and access to the bindinggroove of the DQ2/8 on antigen-presenting cells needsto be overcome. In addition, it cannot interfere with thenecessary class 2-dependent responses so important forimmunosurveillance.

The analogous gliadin peptide, generated by alterationin peptide structure via insertion of bulky groups or




using cyclic or dimeric peptides, developed enhancedaffinity for DQ2 and effectively inhibited HLADQ2-med-iated antigen presentation.75, 76 Recently, use of posi-tional scanning nonapeptide library has resulted ingeneration of high affinity binders to HLADQ2 by com-bining the optimal residues in each position of HLAbinding frame.77 Overall, if active locally in the gut andspecificity for gluten, HLA-blocking compounds may bea potential treatment for coeliac disease (Figure 1c).

MODULATION OF INFLAMMATIONCytokine therapies with either amplification of regulatorycytokines or inhibition of inflammatory cytokines havebeen used for severe autoimmune diseases such as IBDand rheumatoid arthritis. As such, several strategies tar-geting the involved cytokines and chemokines as well asthe associated chemokine receptors, are being developedand have been tested for coeliac disease (Figure 1d). Thisapproach, however, may be less applicable to typical coe-liac disease due to the associated side effects. On theother hand, patients with refractory coeliac disease whofail to respond to dietary treatments may benefit fromthe use of immunomodulators for inhibition of underly-ing inflammatory process.

Anti-inflammatory compoundsThere is persistent inflammation due to lack of response,in some patients with coeliac disease. Treatment with cor-ticosteroids and immunosuppressive agents has been con-sidered in these cases, despite the associated side effects. Ina cohort of 30 patients with collagenous sprue, a combina-tion of gluten-free diet and corticosteroids was found to beeffective in terms of treating the symptoms and healing ofmucosal injury.78 Budesonide, a locally acting corticoste-roid with minimal systemic side effects, inhibits the in vitrooverexpression of DR-molecules and blocks adhesionmolecule ICAM-1 and cyclo-oxygenase pathway. Theaddition of budesonide to gluten-free diet significantlyimproved malabsorptive symptoms of the patients withcoeliac disease compared with dietary treatment alone.79

There is also an anecdotal report of the use of mesalamineto treat refractory sprue patient.80 However, the applica-tion of topically active drugs for coeliac disease may be lessthan ideal when the particular formulation is designed tobe delivered in the distal small intestine or colon beyondwhere coeliac disease occurs.

Anti-interferon-gamma and TNF alphaThe activation of gluten-sensitive CD4+ T cells leads tosecretion of IFN-c, which triggers pro-inflammatory

responses including activation of metalloproteinases(MMPs) that results in mucosal injury and villous atro-phy. In a similar fashion, TNF-a also triggers a proteo-lytic cascade mediated by MMPs secretion fromintestinal myofibroblasts and results in intestinal archi-tectural alteration.42 Therefore, blockade of these cyto-kines may prevent the activation of proteolytic MMPsand ultimately resume the intestinal haemostasis. IFN-c-blocking antibodies prevented damage to healthy intesti-nal mucosa exposed to the inflammatory cytokinesreleased by the gliadin-specific T-cell lines.81Anotherstudy has demonstrated that gliadin induced- IFN-csecretion increases gliadin influx through the intestinalbarrier. Thus, IFN-c-blocking agents may stop thisvicious cycle; however, the baseline permeability to glia-din in the absence of inflammation may remain unaf-fected.82 Phase II clinical trial of anti IFN-c monoclonalantibodies has been just completed for Crohn's disease.Similarly, use of monoclonal antibodies against TNF–a(infliximab), which is beneficial for patients with IBD,has been described in case reports of patients with severerefractory coeliac disease and uncontrolled sprue.83, 84

Immunomodulatory peptides are another attractivetherapeutic option for regulation of the immune systemand antagonising the inflammatory process that underliescoeliac disease.

Altered peptide ligands are modified versions of im-munostimulatory epitopes that have been applied in anumber of mouse models of human disease and havebeen tested against peripheral blood T-cell responses togluten. By targeting specific amino acids for substitution,it is theoretically possible and has had some proof ofconcept supported by in vitro studies that altered peptideligands could provide a potential not only to block apro-inflammatory response to gluten but also provide anatural suppressive effect by enhancing the productionof IL10 from gluten-responsive T cells within the gut.85

However, coeliac disease has several challenges to thesuccess of such an approach. First, there is a broad rep-ertoire of T cells that can react to various gluten pep-tides, some of which may escape inhibition by thisapproach. However, it is possible that bystander suppres-sion may be elicited in such a way as to inhibit the Tcells that are not directly inhibited. Secondly, even theseAPLs could drive a TH2 effect, which theoretically couldproduce dermatitis herpetiformis or even extragastroin-testinal manifestations of coeliac disease that are perhapsdriven by humoral response. There are challenges in theeffective delivery of APLs to the intestine in a mannerthat can effectively prevent inflammatory T-cell




responses to gluten. APLs can directly target the TCR or,by binding with DQ2, could inhibit DQ binding to pep-tides. One approach has been the use of substitutingthreonine for certain amino acids in the immunodomi-nant alpha gliadin peptide 57–73. These ligands have an-tagonised the T-cell response to gluten in vitro usingELSPOT and, when combined with deamidation, seemto drive the normally gliadin-responsive T cells to pro-duce IL10 instead of interferon. This approach mayovercome the issue of specificity by providing a potentbystander effect within the intestine.86 A naturally occur-ring decapeptide sequence [QQPQDAVQPV] was identi-fied from durum wheat and appeared to shift a TH1 toTH2 type of response, although the mechanism of thiseffect is not entirely clear. This apparently also inter-rupted apoptosis of epithelial cells in coeliac diseasebiopsies ex vivo.87

Anti IL-15Interleukin-15 (IL-15) secreted from the intestinal epithe-lium and antigen-presenting cells plays a key role in theunderlying innate immunity of coeliac disease. It inducesthe secretion of epithelial MICA that binds to NKG2Dreceptor located on the surface of intraepithelial lympho-cytes.88–91 This ligand receptor interaction is enhanced byIL-15, leading to stimulation and proliferation of cyto-toxic T lymphocytes that induce epithelial apoptosis andresults in development of refractory coeliac disease andthe associated malignant transformation.92 A study ontransgenic mouse models with overexpression of IL-15and consequent development of autoimmune enteropathydemonstrated that blocking antibody against IL-15 wascapable of efficiently reversing the intestinal damage.93

IL-15 also prevents apoptosis of the cytotoxic intraepithe-lial lymphocytes that play a central role in refractory coe-liac disease via the Jak3/STAT5 signalling pathway. IL-15blocking antibodies were able to induce IEL apoptosisand reduce the number of intraepithelial lymphocytesaccumulated in the intestinal epithelium of human IL-15transgenic mouse models.94 To date, anti-IL 15 humanmonoclonal antibody has been evaluated in clinical trialstudies on patients with other autoimmune disease suchas rheumatoid arthritis, but despite the promising find-ings, a human study for coeliac disease is still awaited.Theoretically, targeting IL-15 could treat both responsiveand refractory coeliac disease.

IL-10Interleukin-10 (IL-10) is considered to be an immuno-regulatory cytokine in the intestinal tissue by suppression

of inflammatory cytokine secretion from TH1 cells.Thus, it has been suggested as a candidate for the treat-ment of TH1-mediated autoimmune disorders such asIBD and coeliac disease. A phase I clinical trial onpatients with Crohn's disease has been successfully con-ducted by using transgenic bacteria expressing humanIL-10; however, more advanced studies failed to provethe therapeutic role of IL-10 for these patients.95

Although IL10 was shown to be able to suppress gliadin-induced T-cell activation in an ex vivo study of culturedintestinal biopsies for coeliac disease,96 a pilot study onpatients with refractory coeliac disease did not show anypharmacological efficacy in managing this condition.97

LYMPHOCYTE RECRUITMENT BLOCKADE

Alpha 4 beta 7 and MAdCam-1T cells express the integrin a4b7 which permits gut hom-ing by binding to mucosal addressin cell adhesion mole-cule 1 (MAdCAM-1) located on vascular endothelialcells and is necessary in migration of lymphocyte to theintestinal mucosa.98, 99 MAdCAM-1 could be a potentialtherapeutic target in coeliac immunity and is signifi-cantly upregulated in untreated patients with active coe-liac disease.100 Moreover, Natalizumab a monoclonalantibody against a4 integrin, has been shown to be effec-tive in Crohn's disease,101 thus suggesting that it may beworthy of evaluation in only select cases of coeliac dis-ease, considering its potential side effects includingimmune suppression-related infections. Other compo-nents of the integrin could also be targeted, but a num-ber of concerns remain (Figure 1e).

CCR9 and CCL25Chemokine ligand 25 (CCL25) secreted by the intestinalepithelial cells binds to the CCR9 located on the surfaceof T lymphocyte and results in selective recruitment ofthese cells from peripheral blood to the intestinal tis-sue.102 Using a mouse model of chronic ileitis, blockingthe interaction between CCL25 and CCR9 effectivelyimproved the intestinal pathology that was treated on itsearly stages.103 A blocking agent has shown therapeuticefficacy in studies for patients with Crohn's disease104;and effectiveness of this approach in coeliac disease isunder investigation, although results of a completed trialare awaited (NCI # NCT01318993) (Figure 1e).

CXCL10 and CXCR3CXCL10 is another T-cell recruiting chemokine that elic-its its effects by binding to the receptor CXCR3 that is




primarily expressed by T lymphocyte.105 Recently, gliadinstimulation of human monocytes was shown to increasethe expression of CXCL10, suggesting a key role forthis chemokine in the recruitment of T cells to the epi-thelium as part of the HLA-independent innate responseto gliadin. These findings support the role of T cell-recruiting chemokines as a future therapeutic target notonly for coeliac disease but also for gluten sensitivity ingeneral.106

TOLERANCE INDUCTION ANDIMMUNOMODULATIONPrevious observations have reported that some patientswith coeliac disease or the associated skin disorder donot present with any immunological or histological evi-dence of the disease activity on resuming a gluten-con-taining diet. This is indicative of tolerance developmentthat can occur in some cases and introduces anotherpotential approach for treatment or even cure of coeliacpatients.107, 108

Mucosal tolerance inductionGenerally, mucosal tolerance to specific antigens occursby two different mechanisms, which include exposure ofimmune system to low doses of antigen that leads to tol-erance induction by the regulatory T cells and produc-tion of anti-inflammatory cytokines such as IL-10 andTGF-b. On the other hand, high-dose tolerance usuallyresults from lymphocytic anergy or clonal deletion thatis driven by T cell/APC interaction or FAS-mediatedapoptosis respectively.109

One of the early studies of tolerance has shown in-teranasal administration of a-gliadin in a mouse modelinhibited T-cell proliferation and IFN-c secretion, andit effectively suppressed the immune response to glu-ten.110, 111 With a different approach for induction oftolerance in a previously sensitised transgenic DQ8mouse model, oral administration of Lactococcuslactis with capability of secreting deamidated DQ8gliadin epitope resulted in activation of Foxp3(+) regu-latory T cells and significant inhibition of systemicimmune responses.112 Tolerance induction with thesemethods still lacks human studies; however, clinical tri-als for nonspecific immunomodulation with parasiteinfection have been conducted (Figure 1f) (NCI #NCT00671138). Infection with parasites has been sug-gested for treatment of autoimmune diseases via regula-tion of host immune system. Interestingly, a pilot studyon nine patients with Crohn's disease has revealed theeffect of hookworm infection in reduction of disease

activity.113 Furthermore, the potential role of infectionwith hookworm Necator Americanus in inhibition ofimmune response to gluten challenge as well as the safetyand feasibility of this method has been studied in arandomised double-blind study, which did not show anysignificant effect on gluten-induced enteropathy.114, 115

VaccinationVaccination was chosen as the preferred option amongalternative treatments to GFD by patients with coeliacdisease when compared with genetically modified wheat,peptidases and antizolulin.41 This could be explained bythe prophylactic aspect of immunisation and single-doseadministration as opposed to daily intake of otherpotential options that may raise the issue of compliance.Immunisation of a mouse model with repeated adminis-tration of an immunodominant DQ2-restricted glutenpeptide was well tolerated and resulted in a dose-depen-dent decrease in T-cell proliferation and development oftolerance in CD4 T lymphocytes without any significantside effect in these animals.116 A gluten vaccine (Nex-vax2) has been developed based on a mixture of the fre-quently recognised gluten peptides and recentlycompleted phase I clinical trial on HLA DQ2 + volun-teers with coeliac disease (NCT00879749). Immunisationwith this method was shown to be well tolerated andfairly safe without any serious adverse events in volun-teers. It also resulted in activation of gluten-specific Tcells in these patients, which is indicative of bioavailabil-ity of the vaccine. This method will be investigated in aphase II clinical trial to evaluate its efficacy. It should benoted that vaccine therapy, despite being attractive formanagement of coeliac disease, could be associated withthe risk of immune system activation and consequentflare of the disease.

MISCELLANEOUS THERAPEUTIC STRATEGIESAlterations of the gut microbiota have been thought tobe associated with coeliac disease.117 In addition, persis-tence of gastrointestinal symptoms after gluten with-drawal in some cases of coeliac disease has beenattributed to the small intestinal bacterial overgrowth(SIBO), especially as antibiotic therapy has been shownto be effective in this subgroup of patients.118

An epithelial mitogen (R-spondin 1) with the abilityof inducing mucosal reconstruction in the intestine hasbeen studied in a mouse model of drug (Dextran Sul-phate Sodium)-induced enteropathy. This agentimproved mucosal architecture of the small intestine andcolon by stimulating crypt cell growth and reducing




the inflammatory infiltration. These findings are thussuggestive of a future pharmacological role of this com-pound for patients with inflammatory bowel diseases orcoeliac disease.119

CONCLUSIONThe increasing number of patients diagnosed with coe-liac disease, as well as recent advances in characterizationof its underlying pathology, has driven development ofadjunctive or even alternative therapeutic approachesthat could effectively manage or even cure this condition.Although several pharmacological agents for coeliac dis-ease are currently under development or has been triedin clinical studies, gluten-free diet is still the only treat-ment option for these patients, which, regardless of thesocial aspect, lacks any significant or potentially lifethreatening side effects. Therefore, in addition to efficacyin terms of preventing both symptoms and histologicaldamage, the ideal alternative therapy to lifelong glutenwithdrawal will need excellent safety and efficacy. For

example, antirejection medication may be effective, butcould be associated with increased long-term adverseconsequences.120

Nonetheless, the potential therapeutic approaches thatcan be applied as either replacement for gluten with-drawal or an adjunctive treatment for coeliac diseasehave raised hopes in management of this condition andits adverse complications.

ACKNOWLEDGEMENTSDeclaration of personal interests: Dr Rashtak has no con-flicts to disclose. Dr Murray has served on the advisoryboards of Alvine Pharmaceutcials, Inc. and Nexpept, andhas been a consultant to Ironwood Inc., Flamentera, Ac-togenix, Ferring Research Institute, Inc., Bayer Health-care Pharmaceuticals, Vysera Biomedical, 2G Pharma,Inc., Shire US Inc., and ImmunosanT, Inc. Declarationof funding interests: This work supported in part bygrants from the National Institute of Health, DK071003and DK57892 (JAM).

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Celiac Disease New Approaches to Therapy : A Review

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