Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

Gastroenterology

Volumn 152, Issue 2, 2017, Pages 374-388.e4

  Abraham, Clara ^a   Dulai, Parambir S ^b   Vermeire, Séverine ^c   Sandborn, William J ^b  

^a YALE UNIVERSITY   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY HOSPITALS LEUVEN   (Belgium)

Author keywords

Crohn's Disease; Intestine; Therapy; Ulcerative Colitis

Indexed keywords

IMMUNOLOGIC AGENT; INTERLEUKIN 17; INTERLEUKIN 23; JANUS KINASE; SMAD7 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; BI 655066; BRIAKINUMAB; CYTOKINE; FONTOLIZUMAB; LYSOPHOSPHOLIPID; MONGERSEN; MONOCLONAL ANTIBODY; OLIGONUCLEOTIDE; PIPERIDINE DERIVATIVE; PROTEIN KINASE INHIBITOR; PYRIMIDINE DERIVATIVE; PYRROLE DERIVATIVE; SECUKINUMAB; SPHINGOSINE; SPHINGOSINE 1-PHOSPHATE; TOFACITINIB; USTEKINUMAB;

ANTIINFLAMMATORY ACTIVITY; ARTICLE; CLINICAL FEATURE; DRUG TARGETING; HUMAN; IMMUNE SYSTEM; INFLAMMATORY BOWEL DISEASE; INTRACELLULAR SIGNALING; NONHUMAN; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; TH17 CELL; ANALOGS AND DERIVATIVES; IMMUNOLOGY; INFLAMMATORY BOWEL DISEASES; MOLECULARLY TARGETED THERAPY; SIGNAL TRANSDUCTION;

ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; CYTOKINES; HUMANS; INFLAMMATORY BOWEL DISEASES; INTERLEUKIN-23; JANUS KINASES; LYSOPHOSPHOLIPIDS; MOLECULAR TARGETED THERAPY; OLIGONUCLEOTIDES; PIPERIDINES; PROTEIN KINASE INHIBITORS; PYRIMIDINES; PYRROLES; SIGNAL TRANSDUCTION; SMAD7 PROTEIN; SPHINGOSINE; TH17 CELLS; TRANSFORMING GROWTH FACTOR BETA; USTEKINUMAB;

EID: 85007417721     PISSN: 00165085     EISSN: 15280012     Source Type: Journal    
DOI: 10.1053/j.gastro.2016.10.018     Document Type: Article

References (145)

1. 1 Dulai, P.S., Siegel, C.A., The risk of malignancy associated with the use of biological agents in patients with inflammatory bowel disease. Gastroenterol Clin North Am 43 (2014), 525–541.
2. 2 Dulai, P.S., Thompson, K.D., Blunt, H.B., et al. Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease: a systematic review. Clin Gastroenterol Hepatol 12 (2014), 1443–1451.
3. 3 Ding, N.S., Hart, A., De Cruz, P., Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease - algorithm for practical management. Aliment Pharmacol Ther 43 (2016), 30–51.
4. 4 Abraham, C., Cho, J.H., Inflammatory bowel disease. N Engl J Med 361 (2009), 2066–2078.
5. 5 Dambacher, J., Beigel, F., Zitzmann, K., et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut 58 (2009), 1207–1217.
6. 6 Meller, S., Di Domizio, J., Voo, K.S., et al. T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat Immunol 16 (2015), 970–979.
7. 7 Gerlach, K., Hwang, Y., Nikolaev, A., et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 15 (2014), 676–686.
8. 8 Gaffen, S.L., Jain, R., Garg, A.V., et al. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14 (2014), 585–600.
9. 9 Patel, D.D., Kuchroo, V.K., Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity 43 (2015), 1040–1051.
10. 10 Donaldson, D.S., Bradford, B.M., Artis, D., et al. Reciprocal regulation of lymphoid tissue development in the large intestine by IL-25 and IL-23. Mucosal Immunol 8 (2015), 582–595.
11. 11 Abraham, C., Cho, J., Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis 15 (2009), 1090–1100.
12. 12 Shih, V.F., Cox, J., Kljavin, N.M., et al. Homeostatic IL-23 receptor signaling limits Th17 response through IL-22-mediated containment of commensal microbiota. Proc Natl Acad Sci U S A 111 (2014), 13942–13947.
13. 13 Macho-Fernandez, E., Koroleva, E.P., Spencer, C.M., et al. Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells. Mucosal Immunol 8 (2015), 403–413.
14. 14 Kvedaraite, E., Lourda, M., Idestrom, M., et al. Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD. Gut 65 (2016), 1632–1641.
15. 15 Friedrich, M., Diegelmann, J., Schauber, J., et al. Intestinal neuroendocrine cells and goblet cells are mediators of IL-17A-amplified epithelial IL-17C production in human inflammatory bowel disease. Mucosal Immunol 8 (2015), 943–958.
16. 16 Yang, Y., Torchinsky, M.B., Gobert, M., et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510 (2014), 152–156.
17. 17 Kleinewietfeld, M., Manzel, A., Titze, J., et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496 (2013), 518–522.
18. 18 Wu, C., Yosef, N., Thalhamer, T., et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496 (2013), 513–517.
19. 19 Qiu, J., Heller, J.J., Guo, X., et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36 (2012), 92–104.
20. 20 Veldhoen, M., Hirota, K., Westendorf, A.M., et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453 (2008), 106–109.
21. 21 Atarashi, K., Tanoue, T., Ando, M., et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163 (2015), 367–380.
22. 22 Wiekowski, M.T., Leach, M.W., Evans, E.W., et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J Immunol 166 (2001), 7563–7570.
23. 23 Elson, C.O., Cong, Y., Weaver, C.T., et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132 (2007), 2359–2370.
24. 24 Yen, D., Cheung, J., Scheerens, H., et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116 (2006), 1310–1316.
25. 25 Kullberg, M.C., Jankovic, D., Feng, C.G., et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 203 (2006), 2485–2494.
26. 26 Izcue, A., Hue, S., Buonocore, S., et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28 (2008), 559–570.
27. 27 Uhlig, H.H., McKenzie, B.S., Hue, S., et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25 (2006), 309–318.
28. 28 O'Connor, W. Jr., Kamanaka, M., Booth, C.J., et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 10 (2009), 603–609.
29. 29 Sugimoto, K., Ogawa, A., Mizoguchi, E., et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118 (2008), 534–544.
30. 30 Zenewicz, L.A., Yancopoulos, G.D., Valenzuela, D.M., et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29 (2008), 947–957.
31. 31 Huber, S., Gagliani, N., Zenewicz, L.A., et al. The IL-22—IL-22BP axis is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491 (2012), 259–263.
32. 32 Eken, A., Singh, A.K., Treuting, P.M., et al. IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol 7 (2014), 143–154.
33. 33 Cox, J.H., Kljavin, N.M., Ota, N., et al. Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice. Mucosal Immunol 5 (2012), 99–109.
34. 34 Geremia, A., Arancibia-Carcamo, C.V., Fleming, M.P., et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med 208 (2011), 1127–1133.
35. 35 Kleinschek, M.A., Boniface, K., Sadekova, S., et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med 206 (2009), 525–534.
36. 36 Barrett, J.C., Hansoul, S., Nicolae, D.L., et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40 (2008), 955–962.
37. 37 Jostins, L., Ripke, S., Weersma, R.K., et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491 (2012), 119–124.
38. 38 Duerr, R.H., Taylor, K.D., Brant, S.R., et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314 (2006), 1461–1463.
39. 39 Sarin, R., Wu, X., Abraham, C., Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci U S A 108 (2011), 9560–9565.
40. 40 Pidasheva, S., Trifari, S., Phillips, A., et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS One, 6, 2011, e25038.
41. 41 Di Meglio, P., Di Cesare, A., Laggner, U., et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS One, 6, 2011, e17160.
42. 42 Ahern, P.P., Schiering, C., Buonocore, S., et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33 (2010), 279–288.
43. 43 Papp, K.A., Menter, A., Sofen, H., et al. Efficacy and safety of different dose regimens of a selective IL-23p19 inhibitor (BI 655066) compared with ustekinumab in patients with moderate-to-severe plaque psoriasis with and without psoriatic arthritis (abstr 2144). Arthritis Rheumatol, 67(Suppl 10), 2015.
44. 44 Mannon, P.J., Fuss, I.J., Mayer, L., et al. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med 351 (2004), 2069–2079.
45. 45 Sandborn, W.J., Feagan, B.G., Fedorak, R.N., et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 135 (2008), 1130–1141.
46. 46 Sandborn, W.J., Gasink, C., Gao, L.L., et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med 367 (2012), 1519–1528.
47. 47 Feagan, B.G., Sandborn, W.J., Gasink, C., et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 375 (2016), 1946–1960.
48. 48 Panaccione, R., Sandborn, W.J., Gordon, G.L., et al. Briakinumab for treatment of Crohn's disease: results of a randomized trial. Inflamm Bowel Dis 21 (2015), 1329–1340.
49. 49 Fuss, I.J., Neurath, M., Boirivant, M., et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 157 (1996), 1261–1270.
50. 50 Fais, S., Capobianchi, M.R., Silvestri, M., et al. Interferon expression in Crohn's disease patients: increased interferon-gamma and -alpha mRNA in the intestinal lamina propria mononuclear cells. J Interferon Res 14 (1994), 235–238.
51. 51 Hommes, D.W., Mikhajlova, T.L., Stoinov, S., et al. Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease. Gut 55 (2006), 1131–1137.
52. 52 Reinisch, W., Hommes, D.W., Van Assche, G., et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease. Gut 55 (2006), 1138–1144.
53. 53 Reinisch, W., de Villiers, W., Bene, L., et al. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 16 (2010), 233–242.
54. 54 Sheikh, S.Z., Matsuoka, K., Kobayashi, T., et al. Cutting edge: IFN-gamma is a negative regulator of IL-23 in murine macrophages and experimental colitis. J Immunol 184 (2010), 4069–4073.
55. 55 Feagan, B.G., Sandborn, W., Panés, J., et al. Efficacy and safety of induction therapy with the selective IL-23 inhibitor BI 655066, in patients with moderate-to-severe Crohn's disease: results of a randomized, double-blind, placebo-controlled phase II study. Gastroenterology, 150, 2016, S1266.
56. 56 Sands, B.E., Chen, J., Penney, M., et al. Initial evaluation of MEDI2070 (specific anti-IL-23 antibody) in patients with active Crohn's disease who have failed anti-TNF antibody therapy: a randomized, double-blind placebo-controlled phase 2A induction study. Gastroenterology 148 (2015), S163–S164.
57. 57 Hueber, W., Sands, B.E., Lewitzky, S., et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61 (2012), 1693–1700.
58. 58 Mozaffari, S., Nikfar, S., Abdollahi, M., Inflammatory bowel disease therapies discontinued between 2009 and 2014. Expert Opin Investig Drugs 24 (2015), 949–956.
59. 59 Ogawa, A., Andoh, A., Araki, Y., et al. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol 110 (2004), 55–62.
60. 60 Zhang, Z., Zheng, M., Bindas, J., et al. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 12 (2006), 382–388.
61. 61 Maxwell, J.R., Zhang, Y., Brown, W.A., et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity 43 (2015), 739–750.
62. 62 Lee, J.S., Tato, C.M., Joyce-Shaikh, B., et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43 (2015), 727–738.
63. 63 McInnes, I.B., Mease, P.J., Kirkham, B., et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386 (2015), 1137–1146.
64. 64 Sherlock, J.P., Joyce-Shaikh, B., Turner, S.P., et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med 18 (2012), 1069–1076.
65. 65 Ota, N., Wong, K., Valdez, P.A., et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nat Immunol 12 (2011), 941–948.
66. 66 Tumanov, A.V., Koroleva, E.P., Guo, X., et al. Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe 10 (2011), 44–53.
67. 67 Wang, Y., Koroleva, E.P., Kruglov, A.A., et al. Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32 (2010), 403–413.
68. 68 Mizuno, S., Mikami, Y., Kamada, N., et al. Cross-talk between RORgammat+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease. Inflamm Bowel Dis 20 (2014), 1426–1434.
69. 69 Pearson, C., Thornton, E.E., McKenzie, B., et al. ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation. Elife, 5, 2016, e10066.
70. 70 Buonocore, S., Ahern, P.P., Uhlig, H.H., et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464 (2010), 1371–1375.
71. 71 Mukasa, R., Balasubramani, A., Lee, Y.K., et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32 (2010), 616–627.
72. 72 Lee, Y.K., Turner, H., Maynard, C.L., et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30 (2009), 92–107.
73. 73 Esplugues, E., Huber, S., Gagliani, N., et al. Control of TH17 cells occurs in the small intestine. Nature 475 (2011), 514–518.
74. 74 Gagliani, N., Amezcua Vesely, M.C., Iseppon, A., et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523 (2015), 221–225.
75. 75 Harbour, S.N., Maynard, C.L., Zindl, C.L., et al. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 112 (2015), 7061–7066.
76. 76 McGeachy, M.J., Bak-Jensen, K.S., Chen, Y., et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8 (2007), 1390–1397.
77. 77 Cohen, C.J., Crome, S.Q., MacDonald, K.G., et al. Human Th1 and Th17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. J Immunol 187 (2011), 5615–5626.
78. 78 Nistala, K., Adams, S., Cambrook, H., et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A 107 (2010), 14751–14756.
79. 79 Hirota, K., Duarte, J.H., Veldhoen, M., et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12 (2011), 255–263.
80. 80 Ghoreschi, K., Laurence, A., Yang, X.P., et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467 (2010), 967–971.
81. 81 Lee, Y., Awasthi, A., Yosef, N., et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13 (2012), 991–999.
82. 82 Codarri, L., Gyulveszi, G., Tosevski, V., et al. RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12 (2011), 560–567.
83. 83 Ramesh, R., Kozhaya, L., McKevitt, K., et al. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med 211 (2014), 89–104.
84. 84 Griseri, T., Arnold, I.C., Pearson, C., et al. Granulocyte macrophage colony-stimulating factor-activated eosinophils promote interleukin-23 driven chronic colitis. Immunity 43 (2015), 187–199.
85. 85 Yosef, N., Shalek, A.K., Gaublomme, J.T., et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 496 (2013), 461–468.
86. 86 Gaublomme, J.T., Yosef, N., Lee, Y., et al. Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell 163 (2015), 1400–1412.
87. 87 Ciofani, M., Madar, A., Galan, C., et al. A validated regulatory network for Th17 cell specification. Cell 151 (2012), 289–303.
88. 88 Huang, W., Thomas, B., Flynn, R.A., et al. DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature 528 (2015), 517–522.
89. 89 Krausgruber, T., Schiering, C., Adelmann, K., et al. T-bet is a key modulator of IL-23-driven pathogenic CD4(+) T cell responses in the intestine. Nat Commun, 7, 2016, 11627.
90. 90 Wang, C., Yosef, N., Gaublomme, J., et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163 (2015), 1413–1427.
91. 91 Jain, R., Chen, Y., Kanno, Y., et al. Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells. Immunity 44 (2016), 131–142.
92. 92 Wang, Y., Godec, J., Ben-Aissa, K., et al. The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-gamma-producing T helper 17 cells. Immunity 40 (2014), 355–366.
93. 93 Withers, D.R., Hepworth, M.R., Wang, X., et al. Transient inhibition of ROR-gammat therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat Med 22 (2016), 319–323.
94. 94 Leppkes, M., Becker, C., Ivanov, I.I., et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136 (2009), 257–267.
95. 95 Inoue, S., Matsumoto, T., Iida, M., et al. Characterization of cytokine expression in the rectal mucosa of ulcerative colitis: correlation with disease activity. Am J Gastroenterol 94 (1999), 2441–2446.
96. 96 Mannon, P., Reinisch, W., Interleukin 13 and its role in gut defence and inflammation. Gut 61 (2012), 1765–1773.
97. 97 Biancheri, P., Di Sabatino, A., Ammoscato, F., et al. Absence of a role for interleukin-13 in inflammatory bowel disease. Eur J Immunol 44 (2014), 370–385.
98. 98 Fuss, I.J., 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 113 (2004), 1490–1497.
99. 99 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 129 (2005), 550–564.
100. 100 Fichtner-Feigl, S., Fuss, I.J., Young, C.A., et al. Induction of IL-13 triggers TGF-beta1-dependent tissue fibrosis in chronic 2,4,6-trinitrobenzene sulfonic acid colitis. J Immunol 178 (2007), 5859–5870.
101. 101 Heller, F., Fuss, I.J., Nieuwenhuis, E.E., et al. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17 (2002), 629–638.
102. 102 Danese, S., Rudzinski, J., Brandt, W., et al. Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study. Gut 64 (2015), 243–249.
103. 103 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 64 (2015), 894–900.
104. 104 Waldner, M.J., Neurath, M.F., Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development. Semin Immunol 26 (2014), 75–79.
105. 105 Ito, H., Takazoe, M., Fukuda, Y., et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 126 (2004), 989–996.
106. 106 Danese, S., Vermeire, S., Hellstern, P., et al. Results of andante, a randomized clinical study with an anti-IL6 antibody (PF-04236921) in subjects with Crohn's disease who are anti-TNF inadequate responders. Gastroenterology, 150, 2016, S155.
107. 107 Smolen, J.S., Schoels, M.M., Nishimoto, N., et al. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis 72 (2013), 482–492.
108. 108 Kuhn, K.A., Manieri, N.A., Liu, T.C., et al. IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS One, 9, 2014, e114195.
109. 109 O'Shea, J.J., Schwartz, D.M., Villarino, A.V., et al. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66 (2015), 311–328.
110. 110 Sandborn, W.J., Ghosh, S., Panes, J., et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 367 (2012), 616–624.
111. 111 Sandborn, W., Sands, B.E., D'Haens, G.R., et al. Efficacy and safety of oral tofacitinib as induction therapy in patients with moderate to severe ulcerative colitis: results from two phase 3 randomized controlled trials. Gastroenterology, 150, 2016, S157.
112. 112 Sandborn, W.J., Ghosh, S., Panes, J., et al. A phase 2 study of tofacitinib, an oral janus kinase inhibitor, in patients with Crohn's disease. Clin Gastroenterol Hepatol 12 (2014), 1485–1493.
113. 113 Panés, J., Sandborn, W., Schreiber, S., et al. Efficacy and safety of tofacitinib for oral induction therapy in patients with moderate to severe Crohn's disease: results of a phase 2B randomized placebo-controlled trial. Gastroenterology 150 (2016), S182–S183.
114. 114 Vermeire, S., Schreiber, S., Petryka, R., et al. Filgotinib (GLPG0634), an oral JAK1 selective inhibitor, induces clinical remission in patients with moderate-to-severe Crohn's disease: results from the phase 2 FITZROY study interim analysis. Gastroenterology, 150, 2016, S1267.
115. 115 Kumar, N., Mishra, J., Narang, V.S., et al. Janus kinase 3 regulates interleukin 2-induced mucosal wound repair through tyrosine phosphorylation of villin. J Biol Chem 282 (2007), 30341–30345.
116. 116 Mishra, J., Verma, R.K., Alpini, G., et al. Role of Janus kinase 3 in mucosal differentiation and predisposition to colitis. J Biol Chem 288 (2013), 31795–31806.
117. 117 Hainzl, E., Stockinger, S., Rauch, I., et al. Intestinal epithelial cell tyrosine kinase 2 transduces IL-22 signals to protect from acute colitis. J Immunol 195 (2015), 5011–5024.
118. 118 Koon, H.W., Zhao, D., Zhan, Y., et al. Substance P stimulates cyclooxygenase-2 and prostaglandin E2 expression through JAK-STAT activation in human colonic epithelial cells. J Immunol 176 (2006), 5050–5059.
119. 119 Yamaoka, T., Yan, F., Cao, H., et al. Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis. Proc Natl Acad Sci U S A 105 (2008), 11772–11777.
120. 120 Kim, H.J., Hart, J., Knatz, N., et al. Janus kinase 3 down-regulates lipopolysaccharide-induced IL-1 beta-converting enzyme activation by autocrine IL-10. J Immunol 172 (2004), 4948–4955.
121. 121 Pattison, M.J., Mackenzie, K.F., Arthur, J.S., Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking IL-10-mediated feedback. J Immunol 189 (2012), 2784–2792.
122. 122 Wang, H., Brown, J., Gao, S., et al. The role of JAK-3 in regulating TLR-mediated inflammatory cytokine production in innate immune cells. J Immunol 191 (2013), 1164–1174.
123. 123 Hedl, M., Proctor, D.D., Abraham, C., JAK2 disease-risk variants are gain of function and JAK signaling threshold determines innate receptor-induced proinflammatory cytokine secretion in macrophages. J Immunol 197 (2016), 3695–3704.
124. 124 Yarilina, A., Xu, K., Chan, C., et al. Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum 64 (2012), 3856–3866.
125. 125 Ley, K., Rivera-Nieves, J., Sandborn, W.J., et al. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 15 (2016), 173–183.
126. 126 Rivera-Nieves, J., Strategies that target leukocyte traffic in inflammatory bowel diseases: recent developments. Curr Opin Gastroenterol 31 (2015), 441–448.
127. 127 Baeyens, A., Fang, V., Chen, C., et al. Exit strategies: S1P signaling and T cell migration. Trends Immunol 36 (2015), 778–787.
128. 128 Sandborn, W.J., Feagan, B.G., Wolf, D.C., et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med 374 (2016), 1754–1762.
129. 129 Travis, M.A., Sheppard, D., TGF-beta activation and function in immunity. Annu Rev Immunol 32 (2014), 51–82.
130. 130 Konkel, J.E., Maruyama, T., Carpenter, A.C., et al. Control of the development of CD8alphaalpha+ intestinal intraepithelial lymphocytes by TGF-beta. Nat Immunol 12 (2011), 312–319.
131. 131 Cortez, V.S., Cervantes-Barragan, L., Robinette, M.L., et al. Transforming growth factor-beta signaling guides the differentiation of innate lymphoid cells in salivary glands. Immunity 44 (2016), 1127–1139.
132. 132 Reis, B.S., Rogoz, A., Costa-Pinto, F.A., et al. Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4(+) T cell immunity. Nat Immunol 14 (2013), 271–280.
133. 133 Shull, M.M., Ormsby, I., Kier, A.B., et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359 (1992), 693–699.
134. 134 Kulkarni, A.B., Huh, C.-G., Becker, D., et al. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 90 (1993), 770–774.
135. 135 Li, M.O., Sanjabi, S., Flavell, R.A., Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25 (2006), 455–471.
136. 136 Monteleone, G., Kumberova, A., Croft, N.M., et al. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest 108 (2001), 601–609.
137. 137 Boirivant, M., Pallone, F., Di Giacinto, C., et al. Inhibition of Smad7 with a specific antisense oligonucleotide facilitates TGF-beta1-mediated suppression of colitis. Gastroenterology 131 (2006), 1786–1798.
138. 138 Babyatsky, M.W., Rossiter, G., Podolsky, D.K., Expression of transforming growth factors alpha and beta in colonic mucosa in inflammatory bowel disease. Gastroenterology 110 (1996), 975–984.
139. 139 Fantini, M.C., Rizzo, A., Fina, D., et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology 136 (2009), 1308–1316 e3.
140. 140 Monteleone, G., Neurath, M.F., Ardizzone, S., et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N Engl J Med 372 (2015), 1104–1113.
141. 141 Peyrin-Biroulet, L., Reinisch, W., Colombel, J.F., et al. Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial. Gut 63 (2014), 88–95.
142. 142 Li, C., Kuemmerle, J.F., Mechanisms that mediate the development of fibrosis in patients with Crohn's disease. Inflamm Bowel Dis 20 (2014), 1250–1258.
143. 143 Di Sabatino, A., Jackson, C.L., Pickard, K.M., et al. Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures. Gut 58 (2009), 777–789.
144. 144 Feagins, L.A., Role of transforming growth factor-beta in inflammatory bowel disease and colitis-associated colon cancer. Inflamm Bowel Dis 16 (2010), 1963–1968.
145. 145 Dudakov, J.A., Hanash, A.M., van den Brink, M.R., Interleukin-22: immunobiology and pathology. Annu Rev Immunol 33 (2015), 747–785.