Immunological pathogenesis of inflammatory bowel disease

Intestinal Research

Volumn 16, Issue 1, 2018, Pages 26-42

  Lee, Seung Hoon ^a   Kwon, Jeong eun ^a   Cho, Mi La ^a  

^a The Catholic University of Korea   (South Korea)

Author keywords

Inflammatory bowel disease; Innate lymphoid cells; Th17 cells

Indexed keywords

EID: 85040658303     PISSN: 15989100     EISSN: 22881956     Source Type: Journal    
DOI: 10.5217/ir.2018.16.1.26     Document Type: Review

References (184)

1. Bernstein CN, Fried M, Krabshuis JH, et al. Inflammatory bowel disease: a global perspective. Global guidelines. Milwaukee: World Gatroenterology Organization, 2009
2. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007;369:1641-1657
3. Leppkes M, Becker C, Ivanov II, et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 2009;136:257-267
4. Lee SY, Lee SH, Yang EJ, et al. Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS One 2015;10:e0135858. doi: 10.1371/journal. pone.0135858
5. Dinarello CA. Interleukin-1beta and the autoinflammatory diseases. N Engl J Med 2009;360:2467-2470
6. McAlindon ME, Hawkey CJ, Mahida YR. Expression of interleukin 1 beta and interleukin 1 beta converting enzyme by intestinal macrophages in health and inflammatory bowel disease. Gut 1998;42:214-219
7. Pizarro TT, Michie MH, Bentz M, et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. J Immunol 1999;162:6829-6835
8. Dinarello CA. IL-18: a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol 1999;103:11-24
9. Kanai T, Watanabe M, Okazawa A, et al. Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. Gastroenterology 2001;121:875-888
10. Maerten P, Shen C, Colpaert S, et al. Involvement of interleukin 18 in Crohn's disease: evidence from in vitro analysis of human gut inflammatory cells and from experimental colitis models. Clin Exp Immunol 2004;135:310-317
11. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005;23:479-490
12. Beltran CJ, Nunez LE, Diaz-Jimenez D, et al. Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease. Inflamm Bowel Dis 2010;16:1097-1107
13. Kobori A, Yagi Y, Imaeda H, et al. Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J Gastroenterol 2010;45:999-1007
14. Mitsuyama K, Toyonaga A, Sasaki E, et al. Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6. Gut 1995;36:45-49
15. Reinisch W, Gasché C, Tillinger W, et al. Clinical relevance of serum interleukin-6 in Crohn's disease: single point measurements, therapy monitoring, and prediction of clinical relapse. Am J Gastroenterol 1999;94:2156-2164
16. Li Y, de Haar C, Chen M, et al. Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut 2010;59:227-235
17. Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut 1993;34:1705-1709
18. Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in inflammatory bowel disease. World J Gastroenterol 2008;14:4280-4288
19. Li MC, He SH. IL-10 and its related cytokines for treatment of inflammatory bowel disease. World J Gastroenterol 2004;10:620-625
20. Schreiber S, Heinig T, Thiele HG, Raedler A. Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease. Gastroenterology 1995;108:1434-1444
21. Melgar S, Yeung MM, Bas A, et al. Over-expression of interleukin 10 in mucosal T cells of patients with active ulcerative colitis. Clin Exp Immunol 2003;134:127-137
22. Wang AH, Lam WJ, Han DY, et al. The effect of IL-10 genetic variation and interleukin 10 serum levels on Crohn's disease susceptibility in a New Zealand population. Hum Immunol 2011;72:431-435
23. Nielsen OH, Køppen T, Rüdiger N, Horn T, Eriksen J, Kirman I. Involvement of interleukin-4 and-10 in inflammatory bowel disease. Dig Dis Sci 1996;41:1786-1793
24. Mitsuyama K, Tomiyasu N, Takaki K, et al. Interleukin-10 in the pathophysiology of inflammatory bowel disease: increased serum concentrations during the recovery phase. Mediators Inflamm 2006;2006:26875
25. Ljuca F, Gegic A, Salkic NN, Pavlovic-Calic N. Circulating cytokines reflect mucosal inflammatory status in patients with Crohn's disease. Dig Dis Sci 2010;55:2316-2326
26. Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell 2008;134:392-404
27. Del Zotto B, Mumolo G, Pronio AM, Montesani C, Tersigni R, Boirivant M. TGF-beta1 production in inflammatory bowel disease: differing production patterns in Crohn's disease and ulcerative colitis. Clin Exp Immunol 2003;134:120-126
28. Rani R, Smulian AG, Greaves DR, Hogan SP, Herbert DR. TGF-beta limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function. Eur J Immunol 2011;41:2000-2009
29. Gu FM, Li QL, Gao Q, et al. IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer 2011;10:150
30. Wruck CJ, Fragoulis A, Gurzynski A, et al. Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 2011;70:844-850
31. Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003;52:65-70
32. Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001;15:985-995
33. O'Connor W Jr, Kamanaka M, Booth CJ, et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 2009;10:603-609
34. Kinugasa T, Sakaguchi T, Gu X, Reinecker HC. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 2000;118:1001-1011
35. Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T. Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn's disease. Gastroenterology 2009;137:1736-1745
36. Kleinschek MA, Boniface K, Sadekova S, et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med 2009;206:525-534
37. Strober W, Zhang F, Kitani A, Fuss I, Fichtner-Feigl S. Proinflammatory cytokines underlying the inflammation of Crohn's disease. Curr Opin Gastroenterol 2010;26:310-317
38. Mahida YR, Ceska M, Effenberger F, Kurlak L, Lindley I, Hawkey CJ. Enhanced synthesis of neutrophil-activating peptide-1/interleukin-8 in active ulcerative colitis. Clin Sci (Lond) 1992;82:273-275
39. Grimm MC, Doe WF. Chemokines in inflammatory bowel disease mucosa: expression of RANTES, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and gamma-interferon-inducible protein-10 by macrophages, lymphocytes, endothelial cells, and granulomas. Inflamm Bowel Dis 1996;2:88-96
40. Uguccioni M, Gionchetti P, Robbiani DF, et al. Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitis. Am J Pathol 1999;155:331-336
41. Kaser A, Ludwiczek O, Holzmann S, et al. Increased expression of CCL20 in human inflammatory bowel disease. J Clin Immunol 2004;24:74-85
42. Mitsuyama K, Toyonaga A, Sasaki E, et al. IL-8 as an important chemoattractant for neutrophils in ulcerative colitis and Crohn's disease. Clin Exp Immunol 1994;96:432-436
43. Zenewicz LA, Antov A, Flavell RA. CD4 T-cell differentiation and inflammatory bowel disease. Trends Mol Med 2009;15:199-207
44. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007;8:942-949
45. Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007;8:967-974
46. Gálvez J. Role of Th17 cells in the pathogenesis of human IBD. ISRN Inflamm 2014;2014:928461
47. Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 2007;282:9358-9363
48. Lathrop SK, Bloom SM, Rao SM, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011;478:250-254
49. Venema K. Role of gut microbiota in the control of energy and carbohydrate metabolism. Curr Opin Clin Nutr Metab Care 2010;13:432-438
50. Asquith M, Powrie F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J Exp Med 2010;207:1573-1577
51. Manichanh C, Rigottier-Gois L, Bonnaud E, et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 2006;55:205-211
52. Lepage P, Häsler R, Spehlmann ME, et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 2011;141:227-236
53. Guarner F, Bourdet-Sicard R, Brandtzaeg P, et al. Mechanisms of disease: the hygiene hypothesis revisited. Nat Clin Pract Gastroenterol Hepatol 2006;3:275-284
54. Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009;139:485-498
55. Wu S, Rhee KJ, Albesiano E, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 2009;15:1016-1022
56. Ivanov II, Frutos Rde L, Manel N, et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 2008;4:337-349
57. Atarashi K, Nishimura J, Shima T, et al. ATP drives lamina propria T(H)17 cell differentiation. Nature 2008;455:808-812
58. Kamada N, Núñez G. Role of the gut microbiota in the development and function of lymphoid cells. J Immunol 2013; 190:1389-1395
59. Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol 2010;11:674-680
60. Seiderer J, Elben I, Diegelmann J, et al. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis 2008;14:437-445
61. Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut 2008;57:1682-1689
62. Raza A, Shata MT. Letter: pathogenicity of Th17 cells may differ in ulcerative colitis compared with Crohn's disease. Aliment Pharmacol Ther 2012;36:204
63. Thompson AI, Lees CW. Genetics of ulcerative colitis. Inflamm Bowel Dis 2011;17:831-848
64. Biancheri P, Powell N, Monteleone G, Lord G, MacDonald TT. The challenges of stratifying patients for trials in inflammatory bowel disease. Trends Immunol 2013;34:564-571
65. Ogawa A, Andoh A, Araki Y, Bamba T, Fujiyama Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol 2004;110:55-62
66. Garrido-Mesa N, Utrilla P, Comalada M, et al. The association of minocycline and the probiotic Escherichia coli Nissle 1917 results in an additive beneficial effect in a DSS model of reactivated colitis in mice. Biochem Pharmacol 2011;82:1891-1900
67. Yang XO, Chang SH, Park H, et al. Regulation of inflammatory responses by IL-17F. J Exp Med 2008;205:1063-1075
68. Wedebye Schmidt EG, Larsen HL, Kristensen NN, et al. TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis. Inflamm Bowel Dis 2013;19:1567-1576
69. Omenetti S, Pizarro TT. The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome. Front Immunol 2015;6:639
70. Brand S. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut 2009;58:1152-1167
71. Boden EK, Snapper SB. Regulatory T cells in inflammatory bowel disease. Curr Opin Gastroenterol 2008;24:733-741
72. Wirtz S, Neurath MF. Mouse models of inflammatory bowel disease. Adv Drug Deliv Rev 2007;59:1073-1083
73. Chaudhry A, Samstein RM, Treuting P, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011;34:566-578
74. Geem D, Harusato A, Flannigan K, Denning TL. Harnessing regulatory T cells for the treatment of inflammatory bowel disease. Inflamm Bowel Dis 2015;21:1409-1418
75. Boehm F, Martin M, Kesselring R, et al. Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation. BMC Gastroenterol 2012;12:97
76. Huber S, Schramm C, Lehr HA, et al. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol 2004;173:6526-6531
77. Rubtsov YP, Rasmussen JP, Chi EY, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008;28:546-558
78. Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med 2003;197:111-119
79. Uhlig HH, Coombes J, Mottet C, et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol 2006;177:5852-5860
80. Collins CB, Aherne CM, McNamee EN, et al. Flt3 ligand expands CD103+ dendritic cells and FoxP3+ T regulatory cells, and attenuates Crohn's-like murine ileitis. Gut 2012;61:1154-1162
81. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-238
82. Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce CD4+CD25-Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 2007;178:6725-6729
83. de Beaucoudrey L, Puel A, Filipe-Santos O, et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med 2008;205:1543-1550
84. Ogino H, Nakamura K, Ihara E, Akiho H, Takayanagi R. CD4+CD25+ regulatory T cells suppress Th17-responses in an experimental colitis model. Dig Dis Sci 2011;56:376-386
85. Becker C, Dornhoff H, Neufert C, et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol 2006;177:2760-2764
86. 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 2006;116:1310-1316
87. Stolfi C, Rizzo A, Franzè E, et al. Involvement of interleukin-21 in the regulation of colitis-associated colon cancer. J Exp Med 2011;208:2279-2290
88. Fitzpatrick LR, Small JS, Doblhofer R, Ammendola A. Vidofludimus inhibits colonic interleukin-17 and improves hapten-induced colitis in rats by a unique dual mode of action. J Pharmacol Exp Ther 2012;342:850-860
89. Herrlinger KR, Diculescu M, Fellermann K, et al. Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study. J Crohns Colitis 2013;7:636-643
90. Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 2006;12:382-388
91. Hueber W, Sands BE, 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 2012;61:1693-1700
92. McLean LP, Cross RK, Shea-Donohue T. Combined blockade of IL-17A and IL-17F may prevent the development of experimental colitis. Immunotherapy 2013;5:923-925
93. Fitzpatrick LR. Inhibition of IL-17 as a pharmacological approach for IBD. Int Rev Immunol 2013;32:544-555
94. Klotz L, Burgdorf S, Dani I, et al. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med 2009;206:2079-2089
95. Hontecillas R, Horne WT, Climent M, et al. Immunoregulatory mechanisms of macrophage PPAR-gamma in mice with experimental inflammatory bowel disease. Mucosal Immunol 2011;4:304-313
96. Kim JK, Lee SH, Lee SY, et al. Grim19 attenuates DSS induced colitis in an animal model. PLoS One 2016;11:e0155853. doi: 10.1371/journal.pone.0155853
97. Spits H, Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol 2012;30:647-675
98. Klose CS, Flach M, Möhle L, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 2014;157:340-356
99. Fallon PG, Ballantyne SJ, Mangan NE, et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med 2006;203:1105-1116
100. Reynders A, Yessaad N, Vu Manh TP, et al. Identity, regulation and in vivo function of gut NKp46+RORgammat+ and NKp46+RORgammat-lymphoid cells. EMBO J 2011;30:2934-2947
101. Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 2008;29:958-970
102. Gladiator A, Wangler N, Trautwein-Weidner K, LeibundGut-Landmann S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J Immunol 2013;190:521-525
103. Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, Artis D. CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 2011;34:122-134
104. Takatori H, Kanno Y, Watford WT, et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 2009;206:35-41
105. Sanos SL, Bui VL, Mortha A, et al. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol 2009;10:83-91
106. Buonocore S, Ahern PP, Uhlig HH, et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 2010;464:1371-1375
107. Powell N, Walker AW, Stolarczyk E, et al. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 2012;37:674-684
108. Garrett WS, Lord GM, Punit S, et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 2007;131:33-45
109. Garrett WS, Punit S, Gallini CA, et al. Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell 2009;16:208-219
110. Geremia A, Arancibia-Cárcamo CV, Fleming MP, et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med 2011;208:1127-1133
111. Bernink JH, Peters CP, Munneke M, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol 2013;14:221-229
112. Fuchs A, Vermi W, Lee JS, et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12-and IL-15-responsive IFN-gamma-producing cells. Immunity 2013;38:769-781
113. Vonarbourg C, Mortha A, Bui VL, et al. Regulated expression of nuclear receptor RORgmamat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity 2010;33:736-751
114. Bailey JR, Bland PW, Tarlton JF, et al. IL-13 promotes collagen accumulation in Crohn's disease fibrosis by down-regulation of fibroblast MMP synthesis: a role for innate lymphoid cells? PLoS One 2012;7:e52332. doi: 10.1371/journal.pone.0052332
115. Ermann J, Staton T, Glickman JN, de Waal Malefyt R, Glimcher LH. Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet-/-.Rag2-/-(TRUC) mice. Proc Natl Acad Sci U S A 2014;111:E2559-E2566
116. Longman RS, Diehl GE, Victorio DA, et al. CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med 2014;211:1571-1583
117. Kamada N, Hisamatsu T, Okamoto S, et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest 2008;118:2269-2280
118. Ogino T, Nishimura J, Barman S, et al. Increased Th17-inducing activity of CD14+ CD163 low myeloid cells in intestinal lamina propria of patients with Crohn's disease. Gastroenterology 2013;145:1380-1391.e1
119. 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 2014;20:1426-1434
120. Mortha A, Chudnovskiy A, Hashimoto D, et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 2014;343:1249288
121. Neill DR, Wong SH, Bellosi A, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 2010;464:1367-1370
122. Hepworth MR, Monticelli LA, Fung TC, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 2013;498:113-117
123. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol 2011;12:383-390
124. Goto Y, Panea C, Nakato G, et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014;40:594-607
125. Magri G, Miyajima M, Bascones S, et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol 2014;15:354-364
126. Cella M, Fuchs A, Vermi W, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 2009;457:722-725
127. Goto Y, Obata T, Kunisawa J, et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 2014;345:1254009
128. Pham TA, Clare S, Goulding D, et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 2014;16:504-516
129. Desreumaux P, Romano O. 5-Aminosalicylates and colorectal cancer: preventive role in chronic inflammatory bowel disease? Gastroenterol Clin Biol 2004;28:509
130. Rousseaux C, Lefebvre B, Dubuquoy L, et al. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med 2005;201:1205-1215
131. Allgayer H. Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther 2003;18 Suppl 2:10-14
132. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 2005;100:1345-1353
133. Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of remission or response in Crohn's disease. Cochrane Database Syst Rev 2016;7:CD008870. doi: 10.1002/14651858.CD008870
134. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med 2011;365:1713-1725
135. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol 2013;132:1033-1044
136. Rezaie A, Kuenzig ME, Benchimol EI, et al. Budesonide for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2015;(6):CD000296. doi: 10.1002/14651858. CD000296.pub4
137. Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003;111:1133-1145
138. D'Haens G, Geboes K, Ponette E, Penninckx F, Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease. Gastroenterology 1997;112:1475-1481
139. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362:1383-1395
140. Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. N Engl J Med 2000;342:1627-1632
141. Feuerstein JD, Akbari M, Tapper EB, Cheifetz AS. Systematic review and meta-analysis of third-line salvage therapy with infliximab or cyclosporine in severe ulcerative colitis. Ann Gastroenterol 2016;29:341-347
142. Steiner S, Daniel C, Fischer A, et al. Cyclosporine A regulates pro-inflammatory cytokine production in ulcerative colitis. Arch Immunol Ther Exp (Warsz) 2015;63:53-63
143. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology 2000;47:119-125
144. Nielsen CH, Albertsen L, Bendtzen K, Baslund B. Methotrexate induces poly(ADP-ribose) polymerase-dependent, caspase 3-independent apoptosis in subsets of proliferating CD4+ T cells. Clin Exp Immunol 2007;148:288-295
145. Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2008;47:249-255
146. Glatzer T, Killig M, Meisig J, et al. RORgammat+ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. Immunity 2013; 38:1223-1235
147. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-1549
148. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014;146:392-400.e3
149. Biancheri P, Brezski RJ, Di Sabatino A, et al. Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease. Gastroenterology 2015;149:1564-1574.e3
150. Van den Brande JM, Koehler TC, Zelinkova Z, et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease. Gut 2007;56:509-517
151. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's disease. N Engl J Med 2003;348:24-32
152. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 2005;353:1912-1925
153. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE trial. Gastroenterology 2007;132:1672-1683
154. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-368
155. Warnke C, Menge T, Hartung HP, et al. Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided? Arch Neurol 2010;67:923-930
156. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870-1880
157. Munneke JM, Bjorklund AT, Mjosberg JM, et al. Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood 2014;124:812-821
158. Fischer A, Zundler S, Atreya R, et al. Differential effects of alpha4beta7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut 2016;65:1642-1664
159. 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
160. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013;369:711-721
161. Wyant T, Leach T, Sankoh S, et al. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut 2015;64:77-83
162. Lam MC, Bressler B. Vedolizumab for ulcerative colitis and Crohn's disease: results and implications of GEMINI studies. Immunotherapy 2014;6:963-971
163. Stallmach A, Langbein C, Atreya R, et al. Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease: a prospective multicenter observational study. Aliment Pharmacol Ther 2016;44:1199-1212
164. Zundler S, Schillinger D, Fischer A, et al. Blockade of alpha-Ebeta7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo. Gut 2017;66:1936-1948
165. Vermeire S, O'Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014;384:309-318
166. Rutgeerts PJ, Fedorak RN, Hommes DW, et al. Randomised phase I study of etrolizumab (rhuMAb beta7) in moderate to severe ulcerative colitis. Gut 2013;62:1122-1130
167. Gonzalez-Cabrera PJ, Brown S, Studer SM, Rosen H. S1P signaling: new therapies and opportunities. F1000Prime Rep 2014;6:109
168. Deguchi Y, Andoh A, Yagi Y, et al. The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice. Oncol Rep 2006;16:699-703
169. Degagné E, Saba JD. S1pping fire: sphingosine-1-phosphate signaling as an emerging target in inflammatory bowel disease and colitis-associated cancer. Clin Exp Gastroenterol 2014;7:205-214
170. Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med 2016;374:1754-1762
171. Gilead terminates phase 2/3 study of GS-5745 in patients with ulcerative colitis. Gilead Science, Inc. Web site. http://www. gilead.com/news/press-releases/2016/9/gilead-terminates-phase-23-study-of-gs5745-in-patients-with-ulcerative-colitis. Accessed July 12, 2017
172. Suzuki K, Yokoyama J, Kawauchi Y, et al. Phase 1 clinical study of siRNA targeting carbohydrate sulphotransferase 15 in Crohn's disease patients with active mucosal lesions. J Crohns Colitis 2017;11:221-228
173. Reinisch W, Hommes DW, 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 2006;55:1138-1144
174. Maxwell JR, Zhang Y, Brown WA, et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity 2015;43:739-750
175. Atreya R, Mudter J, Finotto S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat Med 2000;6:583-588
176. 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 2004;126:989-996
177. Fuss IJ, Becker C, Yang Z, et al. Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis 2006;12:9-15
178. Monteleone G, Biancone L, Marasco R, et al. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 1997;112:1169-1178
179. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 2008;135:1130-1141
180. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med 2012;367:1519-1528
181. Kock K, Pan WJ, Gow JM, et al. Preclinical development of AMG 139, a human antibody specifically targeting IL-23. Br J Pharmacol 2015;172:159-172
182. Sandborn WJ, 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 2014;12:1485-1493.e2
183. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012;367:616-624
184. Mazur M, Karczewski J, Lodyga M, Zaba R, Adamski Z. Inhibitors of phosphodiesterase 4 (PDE 4): a new therapeutic option in the treatment of psoriasis vulgaris and psoriatic arthritis. J Dermatolog Treat 2015;26:326-328