Downloaded from http://gut.bmj.com/ on April 18, 2015 - Published by group.bmj.com
Gut Online First, published on March 24, 2015 as 10.1136/gutjnl-2015-309464 Commentary
Failure of interleukin 13 blockade in ulcerative colitis Herbert Tilg,1 Arthur Kaser2 Contrary to a decade ago, clinical development in ulcerative colitis (UC) has become highly active with multiple promising innovative assets currently in early and late phase clinical studies. The antiintegrin α4β7 monoclonal antibody vedolizumab has been leading this wave, and has received marketing authorisation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) based on an excellent efficacy and safety record. One of the targets that had raised high hopes several years ago was interleukin 13 (IL-13), together with IL-4 and IL-5 the signature cytokine of a T helper 2 (Th2) immune response. As such, its blockade was hypothesised as a brilliant therapeutic strategy in diseases such as allergic asthma and UC. However, in this issue of Gut, results from a trial with anrukinzumab in active UC are reported,1 which, together with results of a trial with tralokinumab reported in the January issue,2 crush enthusiasm for anti-IL-13 blockade as a therapeutic strategy in UC. Anrukinzumab is a humanised IgG1 antibody, which binds IL-13 and inhibits IL-13’s binding to the IL-4Rα chain, part of the IL-13 receptor complex, while it does not block binding of IL-13 to IL-13Rα1 or α2 chains. In a randomised, double-blind, phase IIa study conducted in 38 centres in 10 countries, a total of 84 patients (out of 152 screened) were randomised to three doses (200 mg, 400 mg and 600 mg) anrukinzumab or placebo, with five doses of study medication administered over a 14-week treatment period.1 As a first in a UC trial, fold-change from baseline faecal calprotectin at week 14 was chosen as the primary end point—which turned out not to be significantly different for the three
1
Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria; 2Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK Correspondence to Professor Herbert Tilg, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck 6020, Austria; [email protected]; Professor Arthur Kaser, Div of Gastroenterology and Hepatology, Dept of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; [email protected]
treatment groups compared with placebo. Indeed, while the 200 mg dose resulted in a higher fold-decrease in faecal calprotectin than placebo, the 600 mg dose even yielded a 24% increase (ie, deterioration) from baseline. The study was not powered to assess more conventional clinical outcome parameters, but exploratory and post hoc analyses did not provide any indication of a beneficial effect with regards to clinical response and remission. However, biologically relevant serum levels of anrukinzumab were achieved as reflected by pharmacokinetic studies; the dose-dependent decrease in serum IgE levels; and decreased IL-13-induced STAT6 phosphorylation in HT29 intestinal epithelial cells incubated with patient serum. The second trial was with tralokinumab, a human anti-IL-13 IgG4 monoclonal antibody that binds and neutralises IL-13. Based on its pharmacological profile in a phase 2 trial in asthma,3 a single dose of 300 mg tralokinumab was chosen. Hundred and eleven patients (out of 147 screened) recruited at 30 sites in six countries were randomised 1:1 to receive six doses of tralokinumab or placebo over a 12-week treatment period.2 Clinical response at week 8 was chosen as the primary end point, which was achieved in 38% in the tralokinumab group and 33% in the placebo group, a difference that was statistically not significant—and which would barely be conceived as clinically meaningful anyway. Nonetheless, the proportion of patients who achieved clinical remission was higher (18%) in the tralokinumab group compared with the placebo (6%) group, which was statistically significant, and mucosal ‘healing’ rates trended higher as well.2 Similar to the anrukinzumab trial, relevant serum levels of tralokinumab were achieved according to results from the pharmacokinetic analysis. Reminiscent of observations made in the asthma trial, eosinophil counts trended higher in the tralokinumab group compared with the placebo group. Altogether, these data are pretty convincing—in that IL-13 blockade in ‘allcomer’ patients with active UC is clearly not effective. There are several points worth discussing. First, descriptive evidence for the presence of an atypical ‘Th2’ immune response dates back to studies initially conducted Tilg H, et al. Gut Month 2015 Vol 0 No 0
two decades ago, which revealed that in vitro stimulated lamina propria T cells from UC, but not Crohn’s disease or healthy individuals, secrete high amounts of IL-5 (although no IL-4, the ‘posterchild’ Th2 cytokine).4 Such cells were later shown to also characteristically secrete high levels of IL-13.5 Indeed evidence indicated that this IL-13 might predominantly arise from T cell receptor α chain non-invariant natural killer T (NKT) cells.5 6 CD1d-restricted NKT cells are an intriguing cell population that respond to lipid antigens presented on the non-polymorphic major histocompatibility complex MHC class I-homologue CD1d, a mechanism that also serves major homoeostatic functions.7 In an experimental murine model of mucosal hypersensitivity that is exogenously induced by the rectal instillation of the hapten oxazolone under barrierbreaching (via rectal alcohol) conditions, and which leads to a short-lived form of colonic inflammation, a critical role of IL-13, presumably derived from T cell receptor α-invariant (which is distinct from the ‘non-invariant’) CD1d-restricted NKT cells,8 as well as of IL-4,8 could be demonstrated. Some other, also meticulously conducted studies analysing IL-13 expression in colonic tissue contested its increased expression in UC, which included measurements of IL-13 protein and mRNA in colonic tissue lysates,9 colonic biopsy cultures10 11 and stimulated lamina propria mononuclear cells.11 It is worth mentioning that transcriptomic analysis conducted as part of the anrukinzumab trial did report 20-fold increased expression of Il13 mRNA in inflamed tissue compared with noninflamed tissue.1 IL-13 does have multiple functions in the mucosa, ranging from impairing intestinal barrier function,12 13 upregulating epithelial antimicrobial function,14 15 to protective roles in the Il10–/– model of murine colitis.16 This pleiotropy could be relevant in interpreting the hints towards a possible inverse dose-effect relationship observed in the anrukinzumab trial —if the latter is real (see discussion on end points below). Second, could there nonetheless be a substratum of patients with UC where IL-13 blockade could be beneficial? This indeed relates to the point in the previous paragraph that increased IL-13 expression may not be a general feature of UC as previously thought, but indeed be more heterogenous and perhaps confined to a subset of patients. While the clarity of lack of clinical efficacy in these two anti-IL-13 trials in UC can hardly be contested,1 2 there is precedent from studies in asthma with biomarkers that identify the presence 1
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from http://gut.bmj.com/ on April 18, 2015 - Published by group.bmj.com
Commentary of a strong Th2 response17 (serum periostin and sputum IL-13) and which predict therapeutic efficacy of IL-13 blockade.3 18 In the most remarkable example, an asthma trial with the anti-IL-13 antibody lebrikizumab, the prespecified highperiostin subgroup had a fivefold stronger percentage improvement in forced expiratory volume in 1 s compared with the lowperiostin group.18 Third, what is the ideal outcome parameter to gain confidence on efficacy of a novel asset in early phase clinical development? The anrukinzumab trial took the bold step of using a fold-change in faecal calprotectin compared with baseline as the primary end point.1 Is this a step forward? In their online supplement, the authors report quite a minimal (r=0.3), though nominally statistically significant, correlation between total Mayo score and the fold-change from baseline of the logarithm of faecal calprotectin.1 Similarly, error bars of faecal calprotectin in the much larger phase 3 trial of vedolizumab in UC might not be too encouraging,19 but it remains to be established through a ‘successful’ asset whether faecal calprotectin is a useful biomarker for early drug development in UC. Anyway, this is all on the background that we lack a validated, truly robust, precisely quantitative and prognostically relevant gold standard of ‘disease activity’. Fourth, a trend over recent years has been that even relatively small phase 2a trials require a vast number of centres in multiple countries to meet their target recruitment numbers. As an example, the 38 sites in the anrukinzumab trial randomised a total of 84 patients, meaning 2.2 patients per site—over a 2-year period.1 How representative is this cohort of patients then, after all? The situation is not much better for phase 3 trials either, and there is no easy and obvious solution to this problem.
2
In summary, the two trials leave little hope that IL-13 blockade will ever become a blockbuster strategy in active UC. On the positive side, the robust, well-thought-out design including carefully chosen ( partly novel!) primary end points, the secondary pharmacokinetic, pharmacodynamic and biomarker analyses, which clearly demonstrate target engagement, have yielded an unambiguous, though negative result—and hence at least a crystal-clear outcome. To state the obvious, no matter how sophisticated we become in predicting and preclinically validating novel targets, ultimately it requires pharmacological intervention in patients to prove, or disprove, a mechanism of disease. Competing interests None.
5
6
7
8
9
10
Provenance and peer review Not commissioned; internally peer reviewed. To cite Tilg H, Kaser A. Gut Published Online First: [please include Day Month Year] doi:10.1136/gutjnl2015-309464
11
12
Received 26 February 2015 Accepted 7 March 2015 13
▸ http://dx.doi.org/10.1136/gutjnl-2014-308337
14
Gut 2015;0:1–2. doi:10.1136/gutjnl-2015-309464 15
REFERENCES 1
2
3
4
Reinisch W, Panes J, Khurana S, et al. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study. Gut Published Online First: 7 Jan 2015 Doi: 10.1136/ gutjnl-2014-308337. Danese S, Rudzinski J, Brandt W, et al. Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study. Gut 2015;64:243–9. Piper E, Brightling C, Niven R, et al. A phase II placebocontrolled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 2013;41:330–8. Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4 + lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn’s disease LP
16
17
18
19
cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 1996;157:1261–70. Fuss IJ, Heller F, Boirivant M, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 2004;113:1490–7. Fuss IJ, Joshi B, Yang Z, et al. IL-13Ralpha2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis. Gut 2014;63:1728–36. Olszak T, Neves JF, Dowds CM, et al. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 2014;509:497–502. Heller F, Fuss IJ, Nieuwenhuis EE, et al. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 2002;17:629–38. Vainer B, Nielsen OH, Hendel J, et al. Colonic expression and synthesis of interleukin 13 and interleukin 15 in inflammatory bowel disease. Cytokine 2000;12:1531–6. Kadivar K, Ruchelli ED, Markowitz JE, et al. Intestinal interleukin-13 in pediatric inflammatory bowel disease patients. Inflamm Bowel Dis 2004;10:593–8. Biancheri P, Di Sabatino A, Ammoscato F, et al. Absence of a role for interleukin-13 in inflammatory bowel disease. Eur J Immunol 2014;44:370–85. Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 2005;129:550–64. Kawashima R, Kawamura YI, Oshio T, et al. Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis. Gastroenterology 2011;141:2119–29 e8. Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/ FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci USA 2004;101:13596–600. Herbert DR, Yang JQ, Hogan SP, et al. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med 2009;206:2947–57. Wilson MS, Ramalingam TR, Rivollier A, et al. Colitis and intestinal inflammation in IL10-/- mice results from IL-13Ralpha2-mediated attenuation of IL-13 activity. Gastroenterology 2011;140:254–64. Saha SK, Berry MA, Parker D, et al. Increased sputum and bronchial biopsy IL-13 expression in severe asthma. J Allergy Clin Immunol 2008;121:685–91. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011;365:1088–98. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699–710.
Tilg H, et al. Gut Month 2015 Vol 0 No 0
Downloaded from http://gut.bmj.com/ on April 18, 2015 - Published by group.bmj.com
Failure of interleukin 13 blockade in ulcerative colitis Herbert Tilg and Arthur Kaser Gut published online March 24, 2015
Updated information and services can be found at: http://gut.bmj.com/content/early/2015/03/24/gutjnl-2015-309464
These include:
References
This article cites 18 articles, 6 of which you can access for free at: http://gut.bmj.com/content/early/2015/03/24/gutjnl-2015-309464#BIBL
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Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Gut Online First, published on March 24, 2015 as 10.1136/gutjnl-2015-309464 Commentary
Failure of interleukin 13 blockade in ulcerative colitis Herbert Tilg,1 Arthur Kaser2 Contrary to a decade ago, clinical development in ulcerative colitis (UC) has become highly active with multiple promising innovative assets currently in early and late phase clinical studies. The antiintegrin α4β7 monoclonal antibody vedolizumab has been leading this wave, and has received marketing authorisation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) based on an excellent efficacy and safety record. One of the targets that had raised high hopes several years ago was interleukin 13 (IL-13), together with IL-4 and IL-5 the signature cytokine of a T helper 2 (Th2) immune response. As such, its blockade was hypothesised as a brilliant therapeutic strategy in diseases such as allergic asthma and UC. However, in this issue of Gut, results from a trial with anrukinzumab in active UC are reported,1 which, together with results of a trial with tralokinumab reported in the January issue,2 crush enthusiasm for anti-IL-13 blockade as a therapeutic strategy in UC. Anrukinzumab is a humanised IgG1 antibody, which binds IL-13 and inhibits IL-13’s binding to the IL-4Rα chain, part of the IL-13 receptor complex, while it does not block binding of IL-13 to IL-13Rα1 or α2 chains. In a randomised, double-blind, phase IIa study conducted in 38 centres in 10 countries, a total of 84 patients (out of 152 screened) were randomised to three doses (200 mg, 400 mg and 600 mg) anrukinzumab or placebo, with five doses of study medication administered over a 14-week treatment period.1 As a first in a UC trial, fold-change from baseline faecal calprotectin at week 14 was chosen as the primary end point—which turned out not to be significantly different for the three
1
Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria; 2Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK Correspondence to Professor Herbert Tilg, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck 6020, Austria; [email protected]; Professor Arthur Kaser, Div of Gastroenterology and Hepatology, Dept of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; [email protected]
treatment groups compared with placebo. Indeed, while the 200 mg dose resulted in a higher fold-decrease in faecal calprotectin than placebo, the 600 mg dose even yielded a 24% increase (ie, deterioration) from baseline. The study was not powered to assess more conventional clinical outcome parameters, but exploratory and post hoc analyses did not provide any indication of a beneficial effect with regards to clinical response and remission. However, biologically relevant serum levels of anrukinzumab were achieved as reflected by pharmacokinetic studies; the dose-dependent decrease in serum IgE levels; and decreased IL-13-induced STAT6 phosphorylation in HT29 intestinal epithelial cells incubated with patient serum. The second trial was with tralokinumab, a human anti-IL-13 IgG4 monoclonal antibody that binds and neutralises IL-13. Based on its pharmacological profile in a phase 2 trial in asthma,3 a single dose of 300 mg tralokinumab was chosen. Hundred and eleven patients (out of 147 screened) recruited at 30 sites in six countries were randomised 1:1 to receive six doses of tralokinumab or placebo over a 12-week treatment period.2 Clinical response at week 8 was chosen as the primary end point, which was achieved in 38% in the tralokinumab group and 33% in the placebo group, a difference that was statistically not significant—and which would barely be conceived as clinically meaningful anyway. Nonetheless, the proportion of patients who achieved clinical remission was higher (18%) in the tralokinumab group compared with the placebo (6%) group, which was statistically significant, and mucosal ‘healing’ rates trended higher as well.2 Similar to the anrukinzumab trial, relevant serum levels of tralokinumab were achieved according to results from the pharmacokinetic analysis. Reminiscent of observations made in the asthma trial, eosinophil counts trended higher in the tralokinumab group compared with the placebo group. Altogether, these data are pretty convincing—in that IL-13 blockade in ‘allcomer’ patients with active UC is clearly not effective. There are several points worth discussing. First, descriptive evidence for the presence of an atypical ‘Th2’ immune response dates back to studies initially conducted Tilg H, et al. Gut Month 2015 Vol 0 No 0
two decades ago, which revealed that in vitro stimulated lamina propria T cells from UC, but not Crohn’s disease or healthy individuals, secrete high amounts of IL-5 (although no IL-4, the ‘posterchild’ Th2 cytokine).4 Such cells were later shown to also characteristically secrete high levels of IL-13.5 Indeed evidence indicated that this IL-13 might predominantly arise from T cell receptor α chain non-invariant natural killer T (NKT) cells.5 6 CD1d-restricted NKT cells are an intriguing cell population that respond to lipid antigens presented on the non-polymorphic major histocompatibility complex MHC class I-homologue CD1d, a mechanism that also serves major homoeostatic functions.7 In an experimental murine model of mucosal hypersensitivity that is exogenously induced by the rectal instillation of the hapten oxazolone under barrierbreaching (via rectal alcohol) conditions, and which leads to a short-lived form of colonic inflammation, a critical role of IL-13, presumably derived from T cell receptor α-invariant (which is distinct from the ‘non-invariant’) CD1d-restricted NKT cells,8 as well as of IL-4,8 could be demonstrated. Some other, also meticulously conducted studies analysing IL-13 expression in colonic tissue contested its increased expression in UC, which included measurements of IL-13 protein and mRNA in colonic tissue lysates,9 colonic biopsy cultures10 11 and stimulated lamina propria mononuclear cells.11 It is worth mentioning that transcriptomic analysis conducted as part of the anrukinzumab trial did report 20-fold increased expression of Il13 mRNA in inflamed tissue compared with noninflamed tissue.1 IL-13 does have multiple functions in the mucosa, ranging from impairing intestinal barrier function,12 13 upregulating epithelial antimicrobial function,14 15 to protective roles in the Il10–/– model of murine colitis.16 This pleiotropy could be relevant in interpreting the hints towards a possible inverse dose-effect relationship observed in the anrukinzumab trial —if the latter is real (see discussion on end points below). Second, could there nonetheless be a substratum of patients with UC where IL-13 blockade could be beneficial? This indeed relates to the point in the previous paragraph that increased IL-13 expression may not be a general feature of UC as previously thought, but indeed be more heterogenous and perhaps confined to a subset of patients. While the clarity of lack of clinical efficacy in these two anti-IL-13 trials in UC can hardly be contested,1 2 there is precedent from studies in asthma with biomarkers that identify the presence 1
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from http://gut.bmj.com/ on April 18, 2015 - Published by group.bmj.com
Commentary of a strong Th2 response17 (serum periostin and sputum IL-13) and which predict therapeutic efficacy of IL-13 blockade.3 18 In the most remarkable example, an asthma trial with the anti-IL-13 antibody lebrikizumab, the prespecified highperiostin subgroup had a fivefold stronger percentage improvement in forced expiratory volume in 1 s compared with the lowperiostin group.18 Third, what is the ideal outcome parameter to gain confidence on efficacy of a novel asset in early phase clinical development? The anrukinzumab trial took the bold step of using a fold-change in faecal calprotectin compared with baseline as the primary end point.1 Is this a step forward? In their online supplement, the authors report quite a minimal (r=0.3), though nominally statistically significant, correlation between total Mayo score and the fold-change from baseline of the logarithm of faecal calprotectin.1 Similarly, error bars of faecal calprotectin in the much larger phase 3 trial of vedolizumab in UC might not be too encouraging,19 but it remains to be established through a ‘successful’ asset whether faecal calprotectin is a useful biomarker for early drug development in UC. Anyway, this is all on the background that we lack a validated, truly robust, precisely quantitative and prognostically relevant gold standard of ‘disease activity’. Fourth, a trend over recent years has been that even relatively small phase 2a trials require a vast number of centres in multiple countries to meet their target recruitment numbers. As an example, the 38 sites in the anrukinzumab trial randomised a total of 84 patients, meaning 2.2 patients per site—over a 2-year period.1 How representative is this cohort of patients then, after all? The situation is not much better for phase 3 trials either, and there is no easy and obvious solution to this problem.
2
In summary, the two trials leave little hope that IL-13 blockade will ever become a blockbuster strategy in active UC. On the positive side, the robust, well-thought-out design including carefully chosen ( partly novel!) primary end points, the secondary pharmacokinetic, pharmacodynamic and biomarker analyses, which clearly demonstrate target engagement, have yielded an unambiguous, though negative result—and hence at least a crystal-clear outcome. To state the obvious, no matter how sophisticated we become in predicting and preclinically validating novel targets, ultimately it requires pharmacological intervention in patients to prove, or disprove, a mechanism of disease. Competing interests None.
5
6
7
8
9
10
Provenance and peer review Not commissioned; internally peer reviewed. To cite Tilg H, Kaser A. Gut Published Online First: [please include Day Month Year] doi:10.1136/gutjnl2015-309464
11
12
Received 26 February 2015 Accepted 7 March 2015 13
▸ http://dx.doi.org/10.1136/gutjnl-2014-308337
14
Gut 2015;0:1–2. doi:10.1136/gutjnl-2015-309464 15
REFERENCES 1
2
3
4
Reinisch W, Panes J, Khurana S, et al. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study. Gut Published Online First: 7 Jan 2015 Doi: 10.1136/ gutjnl-2014-308337. Danese S, Rudzinski J, Brandt W, et al. Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study. Gut 2015;64:243–9. Piper E, Brightling C, Niven R, et al. A phase II placebocontrolled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 2013;41:330–8. Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4 + lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn’s disease LP
16
17
18
19
cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 1996;157:1261–70. Fuss IJ, Heller F, Boirivant M, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 2004;113:1490–7. Fuss IJ, Joshi B, Yang Z, et al. IL-13Ralpha2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis. Gut 2014;63:1728–36. Olszak T, Neves JF, Dowds CM, et al. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 2014;509:497–502. Heller F, Fuss IJ, Nieuwenhuis EE, et al. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 2002;17:629–38. Vainer B, Nielsen OH, Hendel J, et al. Colonic expression and synthesis of interleukin 13 and interleukin 15 in inflammatory bowel disease. Cytokine 2000;12:1531–6. Kadivar K, Ruchelli ED, Markowitz JE, et al. Intestinal interleukin-13 in pediatric inflammatory bowel disease patients. Inflamm Bowel Dis 2004;10:593–8. Biancheri P, Di Sabatino A, Ammoscato F, et al. Absence of a role for interleukin-13 in inflammatory bowel disease. Eur J Immunol 2014;44:370–85. Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 2005;129:550–64. Kawashima R, Kawamura YI, Oshio T, et al. Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis. Gastroenterology 2011;141:2119–29 e8. Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/ FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci USA 2004;101:13596–600. Herbert DR, Yang JQ, Hogan SP, et al. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med 2009;206:2947–57. Wilson MS, Ramalingam TR, Rivollier A, et al. Colitis and intestinal inflammation in IL10-/- mice results from IL-13Ralpha2-mediated attenuation of IL-13 activity. Gastroenterology 2011;140:254–64. Saha SK, Berry MA, Parker D, et al. Increased sputum and bronchial biopsy IL-13 expression in severe asthma. J Allergy Clin Immunol 2008;121:685–91. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011;365:1088–98. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699–710.
Tilg H, et al. Gut Month 2015 Vol 0 No 0
Downloaded from http://gut.bmj.com/ on April 18, 2015 - Published by group.bmj.com
Failure of interleukin 13 blockade in ulcerative colitis Herbert Tilg and Arthur Kaser Gut published online March 24, 2015
Updated information and services can be found at: http://gut.bmj.com/content/early/2015/03/24/gutjnl-2015-309464
These include:
References
This article cites 18 articles, 6 of which you can access for free at: http://gut.bmj.com/content/early/2015/03/24/gutjnl-2015-309464#BIBL
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
