Experimental therapeutics for celiac disease and refractory celiac disease.
The only currently available management option for Celiac disease is a life-long strict adherence to a gluten-free diet. Unfortunately, compliance with a gluten-free diet is very difficult in practice due to the widespread presence of gluten in Western diets.
For this reason, more than one half of celiac subjects following a gluten-free diet continue to suffer from clinically relevant disease activity (intestinal mucosal atrophy, symptoms and/or autoantibodies) despite following a gluten-free diet. A rare (~0.5%) but potentially fatal complication of celiac disease is the development of an intestinal T-cell lymphoma termed Refractory Celiac Disease.
It is therefore important for our industry, in conjunction with the clinical community, to explore new therapies to increase the management options for celiac disease patients and the treatment of refractory celiac disease. Several experimental therapies are currently in active development for celiac disease (food products and nutraceuticals are not covered in this review). In order of the most advanced stage of clinical development at the time of this review, these experimental therapies include:
Larazotide acetate, a tight-junction modulator, has reportedly completed Phase IIb trials and reduces the para-cellular passage of gluten to the lamina propria.
The endopeptidase ALV003, reportedly in final stages of Phase IIb development, breaks down gluten to produce less or non-toxic peptide fragments.
The therapeutic vaccine, NexVax2, is reportedly slated to start a Phase IIa study having completed Phase Ib testing in celiac patients, and is being developed with the aim of inducing gluten tolerance via regulatory T-cells.
The anti-IL-15 monoclonal antibody AMG 714, which blocks IL-15, a key mediator of the pathophysiology of celiac disease, is slated to commence Phase IIa studies in refractory celiac disease and diet non-responsive celiac disease.
The gluten-binding polymer BL-7010, which sequesters gluten in the intestinal lumen to reduce exposure to the immune system, has reportedly completed Phase IIb testing and is slated to start Phase IIA studies.
The transglutaminase inhibitor ZED1227, which blocks a key enzyme in the pathophysiology of celiac disease, is reportedly being studied in a Phase I clinical trial.
Celiac disease is one of the most prevalent genetically- determined clinical conditions1,2. It is characterised by an excessive immunological reaction against dietary gluten that starts in the small intestine. This reaction triggers an autoimmune response against several auto-antigens, most prominently the ubiquitous enzyme tissue transglutaminase (tTG), and results in the development of intestinal and extra-intestinal manifestations3-6. Several epidemiological studies have estimated a prevalence of one case per 130-400 individuals in the general population3,6, with lower prevalence in Asian countries.
Celiac disease may start in the first years of life and remain undiagnosed until adulthood (the average diagnostic delay in the USA is 5-11 years). In other cases, the true onset takes place in adult life7. The most frequent clinical presentation nowadays is with concomitant intestinal and extra-intestinal manifestations, up to 15 times more common than the presence of intestinal symptoms in isolation3. Celiac disease is heavily under-diagnosed, as for every patient diagnosed there are 5-10 patients who are not8-10. The discovery and introduction in clinical practice of sensitive and specific serological tests (anti-tTG antibodies and anti-deamidated gluten peptide antibodies, DGP)6 have increased the diagnosis rates. It is crucial to diagnose this condition early on, since death associated with celiac disease is 2-4 times greater than in the general population, mainly associated with an increase in T- and B-cell lymphomas and, to a lesser extent, other digestive tumours3-4.
Ethiology of celiac disease
Celiac disease has a multi-factorial pathophysiology. Genetic, immunological and environmental factors (gluten, intestinal infections) are involved3,6. Celiac disease presents one of the closest associations described with the HLA region. In most populations, >90% of patients express the HLADQ2 heterodimer encoded by alleles DQA1*0501 and DQB1*02. The remainder express the HLADQ8 heterodimer encoded by alleles DQA1*03 and DQB1*03023,6. The predominant role of HLA DQ2 is explained by the fact that the gluten peptides modified by the tissue transglutaminase enzyme have an increased affinity for the DQ2 molecules of the antigen-presenting cells2-6.
Gluten is a complex mixture of polypeptides present in cereals such as wheat, barley, rye and, to a lesser extent, oats. It consists of two fractions: an alcohol-soluble fraction called gliadin, hordein, secalin or avenin depending on the cereal of origin (wheat, barley, rye and oats, respectively) and an insoluble fraction called glutenin3,6,11. Given the high content of proline and glutamine residues in gluten proteins, they are highly resistant to digestion by gastrointestinal enzymes since they lack major cleavage points for such proteases3,6. When these incompletely-processed peptides reach the lamina propria, they become an adequate substrate for the tTG enzyme, which deamidates and transforms glutamine residues into glutamic acid, producing negatively-charged peptides that are presented by HLA Class II DQ2 and DQ8 molecules11- 13. One of these peptides, known as 33-mer, has a highly immunogenic sequence that is recognised by T-cells of the intestinal mucosa, and in all there are more than 200 immunogenic peptides in gluten13. They trigger the activation of CD4 T helper cells in the lamina propria, leading to intestinal inflammation and ultimately hyperplasia of the crypts and atrophy of the intestinal villi14.
It is not fully understood how gluten peptides reach the lamina propria of the gut. There is some initial evidence that this can occur by epithelial trans-cytosis15 and by the para-cellular route through disassembled epithelial tight junctions16. Following antigen presentation of such immunogenic peptides to lamina propria CD4-positive Tcells (presumably in the lymph nodes), responding T-cells are primed towards a Th1 cytokine profile mainly mediated by secretion of IFN-17, although other Th1/Th17 related cytokines have been related as well (IL-1518, IL-21, IL-23 and IL-1719). The final result is intestinal damage with villous atrophy and hyperplasia of the crypts, with a reduced intestinal absorptive surface.
The experimental therapeutic approaches under investigation have complementary targets6. In the future this will possibly mean that celiac disease may be treated by a combination of two or more drugs.
Current management of celiac disease: the gluten-free diet and its limitations
A gluten-free diet is a diet that excludes all products containing gluten. In other words, all products made from flours of wheat, barley, rye and (due to frequent cross-contamination) oats in many countries20- 22. The main challenge to a total adherence to a gluten-free diet is that cereal flours are widely used in the food industry and are present in numerous food products. In addition, labelling of food products is deficient in many countries. For these reasons, celiac sufferers are regularly exposed to gluten contamination in the food and beverages they consume. One of the main anticipated advances is the expected commercialisation of a new test to measure gluten consumption by detecting gluten immunogenic peptides (GIP, present in the immunogenic 33-mer) in stools25, given the otherwise current inability of celiac patients to accurately assess gluten exposure. This exposure and its consequences results in a limitation of social activities and/or a reduction in the variety of foods consumed. Moreover, specifically manufactured gluten-free products may be difficult to find, tend to be less flavourful and are more expensive than regular gluten containing products.
In addition, food labelled ‘gluten-free’ may nevertheless contain gluten. In northern European countries, amounts of up to 100 parts per million (ppm) are permitted in gluten-free products designated apt for celiac sufferers26. A more conservative limit of 20ppm is established in the United States and Southern Europe22. In a double-blind, placebo-controlled prospective study, Catassi et al demonstrated that an intake of 50mg of gluten per day for three months was sufficient to cause a significant decrease in the gut mucosa villous height/crypt depth ratio23. As a result of gluten contamination, it has been estimated that more than 50% of celiac sufferers are not able to strictly follow a gluten-free diet for prolonged periods and have objectively demonstrated active disease at any given time, with mucosal atrophy and recurrent symptoms and signs20,23,24. Alternative treatment options that can be administered independently or in combination with a gluten-free diet are required in order to improve the quality of life of celiac patients.
Therapeutic clinical trials in celiac disease
Tight junction modulation: Larazotide acetate (AT-1001)
The permeability of the intestinal epithelium is partly regulated by the tight junctions, dynamic intercellular points of contact between the enterocytes (intestinal epithelial cells), closely linked to the underlying cellular cytoskeleton16. In celiac disease and other immune intestinal diseases, inflammatory cytokines trigger the opening of tight junctions and increase paracellular permeability16, potentially allowing the entry of harmful gluten peptides into the lamina propria. Larazotide acetate (AT-1001, being developed by Alba Therapeutics27) is an octapeptide derived from a cholera toxin characterised by Fasano and colleagues, ZOT28-29, that inhibits the opening of intestinal epithelial tight junctions by acting on the cytoskeleton33 and is reported to reduce the paracellular transport of gluten to the lamina propria. Seven clinical trials have been completed with larazotide acetate. Three of them were Phase I trials and four were Phase II studies. In a Phase IIa trial with 86 celiac patients in remission with no symptoms or detectable autoantibodies, the patients took a gluten challenge after administration of larazotide acetate or placebo, three times a day for two weeks (approximately 2.5g of gluten per day). Larazotide acetate was well-tolerated and, while the primary endpoint of intestinal paracellular permeability was not met, the symptoms triggered by the two-week gluten challenge were significantly ameliorated27.
In the first Phase IIb study, three doses of larazotide (1, 4 and 8mg) were compared against placebo. The study enrolled 184 celiac patients in remission to be subjected to a six-week gluten challenge of 900mg administered three times a day. While larazotide acetate could not demonstrate statistically significant efficacy in the reduction in intestinal permeability, a favourable trend was observed30. Larazotide acetate resulted in a reduction in anti-tTG IgA and symptoms with a satisfactory safety profile30. A second Phase IIb study in celiac patients with active disease assigned to a strict gluten-free diet at the beginning of the study has not been published as of the date of this review. The most recent Phase IIb trial was a study of 320 gluten-free diet non-responsive celiac patients with symptoms and measureable autoantibodies. Larazotide acetate 0.5, 1 or 2mg, or placebo, was administered three times daily for 12 weeks. All doses were well tolerated. The primary endpoint of improved average on-treatment CeD-GSRS score was met at the 0.5mg dose, while higher doses (1 and 2mg) reportedly showed no effect34.
Glutenase enzyme therapy: ALV003
When gluten polypeptides are hydrolysed they lose their capacity to stimulate the intestinal immune system and damage the intestine, as extensively studied by Khosla, Sollid and collaborators. ALV003 (being developed by Alvine Pharmaceuticals) is a combination of two different gluten-targeting proteases (‘glutenases’) with complementary substrates: a cysteine-endoprotease derived from germinated barley seeds and a prolyl-endopeptidase from Sphingomonas capsulatum31. A Phase I clinical trial was conducted with 20 celiac patients in remission who were randomised to receive a diet containing gluten (16g a day for three days) pre-treated with ALV003 versus a diet containing gluten pre-treated with placebo. The group given ALV003-treated gluten presented a reduction in markers of immunological activation (IFN-g production measured with the ELISpot technique)31. A subsequent Phase IIb study showed that ALV003 is effective in breaking down foods with a high gluten content in the stomach32. Finally, a sixweek Phase IIb/IIa study of ALV003 administered to celiac subjects exposed to a gluten challenge has recently been published35. This study was a randomised, placebo-controlled, double-blind trial in 41 well-controlled celiac patients, negative for symptoms and autoantibodies, instructed to take 2g a day of gluten. ALV003 900 mg or placebo was administered once daily. ALV003 was well tolerated. Biopsies from the placebo groups showed mucosal injury while biopsies from the ALV003 group reportedly did not show significant mucosal deterioration35. A Phase IIb study to evaluate safety and efficacy of ALV003 in the treatment of symptoms in patients on a glutenfree diet was being conducted as of the date of this review.
Therapeutic vaccine: NexVax2
NexVax2 is a desensitising or therapeutic vaccine under development by ImmuSanT after extensive research by Anderson and colleagues identified the most immunogenic peptides in celiac disease36. NexVax2 uses three gluten peptides with the goal of inducing a ‘tolerogenic’ response in celiac patients with HLA DQ2. The rationale of the reported method has been recently reviewed37. NexVax2 has showed efficacy in mice transgenic for HLA DQ2 and with gluten-sensitive T-cells38. A recently-completed Phase I study, consisted of weekly subcutaneous injections of increasing doses of Nexvax2 in patients with well-controlled celiac disease. The results have not been published as of the date of this review, but they have been communicated in abstract form. Dose escalation could apparently be completed safely and the vaccine reportedly displayed biological activity39. The intention to proceed with Phase IIa studies has been announced.
Anti-IL-15 monoclonal antibody: AMG 714
Interleukin 15 (IL-15) is considered to be a central regulator of celiac disease immunopathology4,6,40 and a non-redundant driver of lymphomagenesis in refractory celiac disease, the intestinal T-cell lymphoma complication of celiac disease40,41. IL-15 is an essential, non-redundant growth and activation factor for the intra epithelial lymphocytes (IELs), which destroy the gut mucosa41, and the expression of IL-15 in the intestinal epithelium is necessary for villous atrophy41. IL-15 renders activated CD4 T-cells resistant to inhibition by regulatory T-cells and has been proven to be a key factor in the loss of tolerance to oral antigens18. Inhibition of IL-15 in celiac disease has been proposed by Cerf- Bensussan, Meresse, Jabri and colleagues, and has been shown effective in mouse models of celiac disease42 and in the destruction by apoptosis of the malignant lymphocytes found in the intestine of patients with refractory celiac disease43.
AMG 714 is a fully human immunoglobulin (IgG1) monoclonal antibody that binds to bioactive IL-15 (soluble IL-15 and IL-15 associated with the IL-15R chain). AMG 714 has been studied in four clinical trials in healthy volunteers and patients with rheumatoid arthritis and psoriasis. The results of the Phase IIb study in rheumatoid arthritis have been published and AMG 714 appeared efficacious and well-tolerated44. AMG 714 reportedly does not result in NK cell depletion unlike non-human primate IL-15 inhibition45. Forthcoming Phase IIa studies in refractory celiac disease and diet non-responsive celiac disease have been announced by AMG 714 licensee Celimmune.
Gluten binding polymer: BL-7010
Gluten-binding polymers have been reported by Pinier, Verdu and colleagues to be beneficial in animal models of celiac disease, by sequestering gluten in the intestinal lumen, thereby reducing gluten exposure to the immune system46,47. The gluten-binding polymer BL-7010 has shown efficacy in an animal model of celiac disease48 and is currently in Phase I testing in healthy volunteers and celiac patients sponsored by BioLineRx. At the time of this review, Phase I results have not been published.
Transglutaminase inhibitor: ZED1227
The transglutaminase inhibitor ZED1227 is a direct acting inhibitor of the enzyme tTG, a key enzyme in the pathophysiology of celiac disease4,6,49. After a substantial body of work by Schuppan and colleagues, the first Phase I clinical trial was reportedly recently initiated, sponsored by Zedira and Dr Falk Pharma. No results are available as of the date of this review.
Celiac disease is a highly prevalent autoimmune disease triggered by dietary gluten, with no approved medication. Celiac disease leads to morbidity and increased mortality. Gluten is ‘everywhere’ and is very hard to eliminate from the diet. While a strict gluten-free diet reduces most of the risk for complications of celiac disease, at any given time approximately 50% of subjects on a gluten-free diet have active disease, mostly due to gluten contamination. While substantial progress has been made in the last few years in the development of experimental medications for celiac disease, these therapies remain in early- or mid-phases of clinical research, and additional effort is required to provide alternative management options to patients with celiac disease. The six experimental therapeutic approaches currently reported as being under clinical investigation have complementary targets, opening up the possibility for future effective combination therapies.
Prior to Celimmune, Dr Francisco Leon was Vice- President and Head of Translational Medicine at Johnson & Johnson’s Janssen Pharmaceuticals and Chief Medical Officer at Alba Therapeutics. Dr Leon received his MD and PhD from Autónoma University in Madrid, Spain, and has authored more than 70 peer-reviewed articles and publications.
Beth Llewellyn provides pharmaceutical consulting in the areas of Clinical Operations Management at 2L Pharma, LLC. Prior to founding the company, she served as a Clinical Operations Management Consultant at Alba Therapeutics.
1 Di Sabatino, A, Corazza, GR. Celiac disease. Lancet 2009;373:1480-1493.
2 Farrel, RF, Nelly, CP. Celiac sprue. N Engl J Med 2002; 346:180-188.
3 Green, PH, Cellier, C. Celiac disease. N Engl J Med 2007; 357:1731-1743.
4 Mulder, C, Cellier, C. Celiac disease. Best Pract Res Clin Gastroenterol 2005; 19:313-321.
5 Green, PH, Jabri, B. Celiac disease. Lancet 2003; 362:383-391.
6 Schuppan, D, Junker, Y, Barisani, D. Celiac Disease: From pathogenesis to novel therapies. Gastroenterology 2009;137:1912-1933.
7 Fernández-Bañares, F, Esteve- Comas, M, Rosinach, M. Screening of celiac disease in high risk groups. Gastroenterol Hepatol 2005; 28:561-566.
8 Fasano, A, Berti, I, Gerarduzzi, T, Not, T, Colleti, RB, Drago, S et al. Prevalence of celiac disease in at risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;63:286-292.
9 Maki, M, Mustalahti, K, Kokkonen, J, Kulmala, P, Haapalahti, M, Karttunen, T et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348:2517- 2524.
10 Riestra, S, Fernández, E, Rodrigo, L. Prevalence of celiac disease in the general population of Northern Spain. Strategies of serologic screening. Scand J Gastroenterol 2000; 35:398-402.
11 Fleckenstein, B, Molberg, O, Qiao, SW, Schmid, DG, von der Mülbe, F et al. Gliadin T cell epitope selection by tissue transglutaminase in celiac disease. Role of enzyme specificity and pH influence on the influence on the transamidation versus deamidation process. J Biol Chem 2002; 277:34109-34116.
12 Molberg, O, Mcadam, SN, Körner, R, Quarsten, H, Kristiansen, C, Madsen, L et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognised by gutderived T cells in celiac disease. Nat Med 1998; 4:713-717.
13 Shan, L, Molberg, O, Parrot, I, Hausch, F, Filiz, F, Gray, GM et al . Structural basis for gluten intolerance in celiac disease. Science 2002; 297:2275-2279.
14 Van de Wal, Y, Kooy, Y, Van Veelen, P, Peña, S, Mearin, L, Papadopoulos, G et al. Selective deamination by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 1998; 161:1585-1588.
15 Matysiak-Budnik, T, Candalh, C, Dugave, C, Namane, A, Cellier, C, Cerf-Bensussan, N et al. Alterations of the intestinal transport and processing of gliadin peptides in celiac disease. Gastroenterology 2003; 125:696-707.
16 Schulzke, JD, Bentzel, CJ, Schulzke, I, Riecken, EO, Fromm, M. Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatr Res 1998; 43:435-41.
17 Mauri, L, Ciacci, C, Ricciardelli, I, Vacca, L, Raia, V, Auricchio, S et al. Association between innate response to gliadin and activation of pathogenic T cells in celiac disease. Lancet 2003; 362:30-37
18 DePaolo, RW, Abadie, V, Tang, F, Fehlner-Peach, H, Hall, JA, Wang, W et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 2011; 471:220-224.
19 Castellanos-Rubio, A, Santin, I, Irastorza, I, Castaño, L, Carlos Vitoria, J, Ramon Bilbao, J. Th17 (and Th1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity 2009; 42:69-73.
20 Lee, SK, Lo, W, Memeo, L, Rotterdam, H, Green, PH. Duodenal histology in patients with celiac disease after treatment with a gluten-free diet. Gastrointest Endosc 2003; 57:187-91.
21 Holm, K, Maki, M, Vuolteenaho, K, Mustalahti, K, Ashorn, M, Ruuska, T et al. Oats in the treatment of childhood celiac disease: a 2 year controlled trial and a long term follow up study. Aliment Pharmacol Ther 2006; 23:1463-1472.
22 Kupper, C. Dietary guidelines and implementation for celiac disease. Gastroenterology 2005; 128:S124-127.
23 Catassi, C; Fabiani, E; Iacono, G, D’Agate, C, Francavilla, R, Biagi, F et al. A prospective, double blind, placebo controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr 2007; 85:160-166.
24 Lanzini, A, Lanzarotto, F, Villanacci, V, Mora, A, Bertolazzi, S, Turini, D et al. Complete recovery of intestinal mucosa occurs very rarely in adult celiac patients despite adherence to gluten-free diet. Aliment Pharmacol Ther 2009, 29:1299-308.
25 Comino, I, Real, A, Vivas, S et al. Monitoring of gluten-free diet compliance in celiac patients by assessment of gliadin 33-mer equivalent epitopes in feces. Am J Clin Nutr. 2012;95:670-7.
26 Gibert, A, Espadaler, M, Canela, A, Sánchez, A, Vaqué, C, Rafecas, M et al. Consumption of gluten-free products: should the threshold value for trace amounts of gluten be 20, 100 or 200 ppm? Eur J Gastroenterol Hepatol 2006; 18:1187-1195.
27 Paterson, BM, Lammers, KM, Arrieta, MC, Fasano, A, Meddings, JB. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in celiac disease subjects: a proof of concept study. Aliment Pharmacol Ther 2007; 26:757-766.
28 Fasano, A, Uzzau, S, Fiore, C, Margaretten, K. The enterotoxic effect on zonula occludens toxin on rabbit small intestine involves the paracellular pathway. Gastroenterology 1997; 112:839-846.
29 Marinaro, M, Fasano, A, De Magistris, MT. Zonula occludens toxin acts as an adjuvant through different mucosal routes and induces protective immune responses. Infect Immun 2003; 71:1897-1902.
30 Kelly, CP, Green, PHR, Murray, JA, Di Marino, A, Colatrella, A, Leffler, DA et al. Larazotide acetate in patients with celiac disease undergoing a gluten challenge: a randomized placebo-controlled study. Aliment Pharmacol Ther 2013; 37:252-62.
31 Pyle, GG, Paaso, B, Anderson, BE, Allen, DD, Marti, T, Li, Q et al. Effect of pretreatment of food gluten with prolyl endopeptidase on gluten-induced malabsorption in celiac sprue. Clin Gastroenterol Hepatol 2005; 3:687-94.
32 Tye-Din, JA, Anderson, RP, Ffrench, RA, Brown, GJ, Hodsman, P, Siegel, M et al. The effects of ALV003 pre-digestion of gluten on immune and symptoms in celiac disease in vivo. Clinical Immunol 2010; 134:289-295.
33 Gopalakrishnan, S, Tripathi, A, Tamiz, AP, Alkan, SS, Pandey, NB. Larazotide acetate promotes tight junction assembly in epithelial cells. Peptides. 2012;35:95-101.
34 Leffler, DA, Kelly, CP, Green, PH, Fedorak, RN, DiMarino, A, Perrow, W et al. Larazotide Acetate for Persistent Symptoms of Celiac Disease Despite a Gluten-Free Diet: A Randomized Controlled Trial. Gastroenterology. 2015 Feb 12 [Epub ahead of print].
35 Lähdeaho, ML, Kaukinen, K, Laurila, K et al. Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology. 2014;146:1649-58.
36 Anderson, RP, Degano, P, Godkin, AJ, Jewell, DP, Hill, AV. In vivo antigen challenge in celiac disease identifies a single transglutaminasemodified peptide as the dominant A-gliadin T-cell epitope. Nat Med. 2000; 6:337-42.
37 Anderson, RP, Jabri, B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr Opin Immunol. 2013;25:410-7.
38 de Kauwe, AL, Chen, Z, Anderson, RP, Keech, CL, Price, JD, Wijburg, O et al. Resistance to celiac disease in humanized HLA-DR3-DQ2- transgenic mice expressing specific anti-gliadin CD4+ T cells. J Immunol, 2009; 182:7440-50.
39 Brown, GJ, Daveson, J, Marjason, JK, Ffrench, RA, Smith, D, Sullivan, M et al. A Phase I Study to Determine Safety, Tolerability and Bioactivity of Nexvax2® in HLA DQ2+ Volunteers with Celiac Disease Following a Long-Term, Strict Gluten-Free Diet. Gastroenterology 2011;140:S-437-438.
40 Meresse, B, Malamut, G, Cerf-Bensussan, N. Celiac disease: an immunological jigsaw. Immunity. 2012;36:907-19.
41 Abadie, V, Jabri, B. IL-15: a central regulator of celiac disease immunopathology. Immunol Rev. 2014 Jul;260:221-34.
42 Yokoyama, S, Takada, K, Hirasawa, M, Perera, LP, Hiroi, T. Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease. J Clin Immunol. 2011;31(6):1038-44.
43 Malamut, G, El Machhour, R, Montcuquet, N, Martin-Lannerée, S, Dusanter-Fourt, I, Verkarre, V et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest. 2010;120:2131-43.
44 Baslund, B, Tvede, N, Danneskiold-Samsoe, B et al. Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum. 2005;52:2686-92.
45 Lebrec, H, Horner, MJ, Gorski, KS et al. Homeostasis of human NK cells is not IL-15 dependent. J Immunol. 2013;191:5551-8.
46 Pinier, M, Verdu, EF, Nasser-Eddine, M, David, CS, Vézina, A, Rivard, N et al. Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology. 2009;136:288-98.
47 Pinier, M, Fuhrmann, G, Galipeau, HJ, Rivard, N, Murray, JA, David, CS et al. The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues. Gastroenterology. 2012;142:316-25.
48 McCarville, JL, Nisemblat, Y, Galipeau, HJ, Jury, J, Tabakman, R, Cohen, A et al. BL-7010 demonstrates specific binding to gliadin and reduces gluten-associated pathology in a chronic mouse model of gliadin sensitivity. PLoS One. 2014;9:e109972.
49 Elli, L, Bergamini, CM, Bardella, MT, Schuppan, D. Transglutaminases in inflammation and fibrosis of the gastrointestinal tract and the liver. Dig Liver Dis. 2009;41:541-50.