Inflammatory bowel disease-From mechanisms to treatment strategies

Autoimmunity

Volumn 43, Issue 7, 2010, Pages 463-477

  Melgar, Silvia ^a,b   Shanahan, Fergus ^a  

^a UNIVERSITY COLLEGE CORK   (Ireland)

^b GLAXOSMITHKLINE   (United Kingdom)

Author keywords

autophagy; IBD; microbiota; miRNA; Th17 cells

Indexed keywords

ANTIINFLAMMATORY AGENT; CHEMOKINE RECEPTOR CCR9; CHEMOKINE RECEPTOR CXCR2 ANTAGONIST; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 23; MICRORNA; NATALIZUMAB; PROBIOTIC AGENT; RESPIRATORY TRACT AGENT; UNCLASSIFIED DRUG; VALATEGRAST; VEDOLIZUMAB;

ASTHMA; CELL MIGRATION; CLINICAL TRIAL; CROHN DISEASE; DISEASE COURSE; ENTERITIS; ENVIRONMENTAL FACTOR; GENETIC HETEROGENEITY; GENETIC RISK; HUMAN; IMMUNITY; INTESTINE FLORA; LEUKOENCEPHALOPATHY; LIFESTYLE; MULTIPLE SCLEROSIS; NONHUMAN; PHAGOCYTE; REVIEW; TH17 CELL; TISSUE INJURY; TREATMENT PLANNING; ULCERATIVE COLITIS; VIRUS INFECTION;

ANIMALS; DRUG DESIGN; GENETIC PREDISPOSITION TO DISEASE; HUMANS; IMMUNOLOGIC FACTORS; INFLAMMATORY BOWEL DISEASES; RISK FACTORS;

EID: 77957993829     PISSN: 08916934     EISSN: 1607842X     Source Type: Journal    
DOI: 10.3109/08916931003674709     Document Type: Review

References (135)

1. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: Clinical aspects and established and evolving therapies. Lancet 2007;369:1641.
2. Brain O, Travis SPL. Therapy of ulcerative colitis: State of the art. Curr Opin Gastroenterol 2008;24:469-474, doi: 410.1097/MOG. 1090b1013e3282ff1090dd1095.
3. Waldner MJ, Neurath MF. Novel cytokine-targeted therapies and intestinal inflammation. Curr Opin Pharmacol 2009;9: 702.
4. Hugot J-P, Chamaillard M, Zouali H, Lesage S, Cezard J-P, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001;411: 599-603.
5. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001;411:603-606.
6. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, SteinhartAH, AbrahamC,RegueiroM, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314:1461-1463.
7. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW, Shugart YY, Griffiths AM, Targan SR, Ippoliti AF, Bernard EJ, Mei L, Nicolae DL, Regueiro M, Schumm LP, Steinhart AH, Rotter JI, Duerr RH, Cho JH, Daly MJ, Brant SR. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596-604.
8. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, Günther S, Prescott NJ, Onnie CM, Häsler R, Sipos B, Fölsch UR, Lengauer T, Platzer M, Mathew CG, Krawczak M, Schreiber S. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 2007; 39:207-211. (Pubitemid 46184351)
9. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988;29: 990-996.
10. Bernstein CN, Shanahan F. Disorders of a modern lifestyle: Reconciling the epidemiology of inflammatory bowel diseases. Gut 2008;57:1185-1191.
11. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005;122:107.
12. Bouskra D, Brézillon C, Bérard M, Werts C, Varona R, Boneca IG, Eberl G. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 2008;456:507-510.
13. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology 2008;134:577.
14. Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M, Lochs H. Mucosal flora in inflammatory bowel disease. Gastroenterology 2002;122:44.
15. Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser A-L, Barnich N, Bringer MA, Swidsinski A, Beaugerie L, Colombel JF. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology 2004;127:412-421.
16. Abubakar I, Myhill D, Aliyu SH, Hunter PR. Detection of Mycobacterium avium subspecies paratuberculosis from patients with Crohn's disease using nucleic acid-based techniques: A systematic review and meta-analysis. Inflamm Bowel Dis 2008;14:401-410.
17. Ananthakrishnan AN, Issa M, Binion DG. Clostridium difficile and inflammatory bowel disease. Gastroenterol Clin N Amer 2009;38:711.
18. Clayton EM, Rea MC, Shanahan F, Quigley EMM, Kiely B, Hill C, Ross RP. The vexed relationship between Clostridium difficile and inflammatory bowel disease: An assessment of carriage in an outpatient setting among patients in remission. Am J Gastroenterol 2009;104:1162-1169.
19. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA 2007;104:13780-13785.
20. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez- Humarán LG, Gratadoux J-J, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottière HM, Doré J, Marteau P, Seksik P, Langella P. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 2008;105:16731-16736.
21. Ryu JH, Kim SH, Lee HY, Bai JY, Nam YD, Bae JW, Lee DG, Shin SC, Ha EM, Lee WJ. Innate immune homeostasisby the homeobox gene caudal and commensal-gut mutualism in Drosophila. Science 2008;319:777-782.
22. Suzuki K, Meek B, Doi Y, Muramatsu M, Chiba T, Honjo T, Fagarasan S. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc Natl Acad Sci USA 2004; 101:1981-1986.
23. Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, Glickman JN, Glimcher LH. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 2007;131:33-45.
24. Knight P, Campbell BJ, Rhodes JM. Host-bacteria interaction in inflammatory bowel disease. Br Med Bull 2008;88:95-113.
25. Smith AM, Rahman FZ, Hayee BH, Graham SJ, Marks DJB, Sewell GW, Palmer CD, Wilde J, Foxwell BM, Gloger IS, Sweeting T, Marsh M, Walker AP, Bloom SL, Segal AW. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J Exp Med 2009;206:1883-1897.
26. Marks D, Rahman F, Sewell G, Segal A. Crohn's disease: An immune deficiency state. Clin Rev Allergy Immunol 2010; 38(1):20-31.
27. Sewell GW, Marks DJB, Segal AW. The immunopathogenesis of Crohn's disease: A three-stage model. Curr Opin Immunol 2009;21:506-513.
28. Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, Schuldt D, Nikolaus S, Rosenstiel P, Krawczak M, Schreiber S. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet 2008;40:713-715.
29. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ; Belgian-French IBD Consortium; Wellcome Trust Case Control Consortium. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008;40:955-962.
30. Stoll M, Corneliussen B, Costello CM, Waetzig GH, Mellgard B, Koch WA, Rosenstiel P, Albrecht M, Croucher PJ, Seegert D, Nikolaus S, Hampe J, Lengauer T, Pierrou S, Foelsch UR, Mathew CG, Lagerstrom-Fermer M, Schreiber S. Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet 2004;36:476-480. (Pubitemid 38620031)
31. Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A, Wesley E, Parnell K, Zhang H, Drummond H, Nimmo ER, Massey D, Blaszczyk K, Elliott T, Cotterill L, Dallal H, Lobo AJ, Mowat C, Sanderson JD, Jewell DP, Newman WG, Edwards C, Ahmad T, Mansfield JC, Satsangi J, Parkes M, Mathew CG, Donnelly P, Peltonen L, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Craddock N, Deloukas P, Duncanson A, Jankowski J, Markus HS, Mathew CG, McCarthy MI, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Samani N, Trembath RC, Viswanathan AC, Wood N, Spencer CC, Barrett JC, Bellenguez C, Davison D, Freeman C, Strange A, Donnelly P, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Perez ML, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, Deloukas P, Peltonen L, Mathew CG, Blackwell JM, Brown MA, Corvin A, McCarthy MI, Spencer CC, Attwood AP, Stephens J, Sambrook J, Ouwehand WH, McArdle WL, Ring SM, Strachan DP; Wellcome Trust Case Control Consortium 2. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 2009;41:1330-1334.
32. KaserA, Lee A-H, Franke A, Glickman JN, ZeissigS,Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS. XBP1 links ER Stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008;134:743-756.
33. McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P, Zody MC, Hall JL, Brant SR, Cho JH, Duerr RH, Silverberg MS, Taylor KD, Rioux JD, Altshuler D, Daly MJ, Xavier RJ. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet 2008;40:1107-1112.
34. Cuthbert AP, Fisher SA, Mirza MM, King K, Hampe J, Roucher PJ, Mascheretti S, Sanderson J, Forbes A, Mansfield J, Schreiber S, Lewis CM, Mathew CG. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 2002;122:867-874.
35. Gutierrez O, Pipaon C, Inohara N, Fontalba A, Ogura Y, Prosper F, Nunez G, Fernandez-Luna JL. Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kB activation. J Biol Chem 2002;277:41701-41705.
36. Hisamatsu T, Suzuki M, Reinecker H-C, Nadeau WJ, McCormick BA, Podolsky DK. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 2003;124:993.
37. Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, Ogunbiyi O, Nuñez G, Keshav S. Crohn's disease and the NOD2 gene: A role for paneth cells. Gastroenterology 2003; 125:47-57.
38. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nuñez G. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem 2003; 278:5509-5512.
39. Bonen DK, Cho JH. The genetics of inflammatory bowel disease. Gastroenterology 2003;124:521.
40. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307:731-734.
41. Maeda S, Hsu L-C, Liu H, Bankston LA, Iimura M, Kagnoff MF, Eckmann L, Karin M. Nod2 mutation in Crohn's disease potentiates NF-{kappa}B activity and IL-1{beta} processing. Science 2005;307:734-738.
42. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M, Herrlinger KR, Stallmach A, Noack F, Fritz P, Schröder JM, Bevins CL, Fellermann K, Stange EF. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal {alpha}-defensin expression. Gut 2004;53:1658-1664.
43. ZuzanaZ, van Beelen AJ,de Kort F, Moerland PD, Ver Loren van Themaat E, te Velde AA, van Deventer SJ, de Jong EC, Hommes DW. Muramyl dipeptide-induced differential gene expression in NOD2 mutant and wild-type Crohn's disease patient-derived dendritic cells. Inflam Bowel Dis 2008;14: 186-194.
44. Mizushima N. Autophagy: Process and function. Genes Dev 2007;21:2861-2873.
45. Schmid D, Münz C. Innate and adaptive immunity through autophagy. Immunity 2007;27:11.
46. Kuballa P, Huett A, Rioux JD, Daly MJ, Xavier RJ. Impaired Autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant. PLoS One 2008;3: e3391.
47. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S, Stone CD, Brunt EM, Xavier RJ, Sleckman BP, Li E, Mizushima N, Stappenbeck TS, Virgin HW, IV. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 2008;456:259-263.
48. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 2008;456:264-268.
49. Singh SB, Davis AS, Taylor GA, Deretic V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 2006;313:1438-1441.
50. Collazo CM, Yap GS, Sempowski GD, Lusby KC, Tessarollo L, Woude GF, Sher A, Taylor GA. Inactivation of Lrg-47 and Irg-47 reveals a family of interferon {gamma}-Inducible Genes with essential, pathogen-specific roles in resistance to infection. J Exp Med 2001;194:181-188.
51. Inoue N, Tamura K, Kinouchi Y, Fukuda Y, Takahashi S, Ogura Y, Inohara N, Núñez G, Kishi Y, Koike Y, Shimosegawa T, Shimoyama T, Hibi T. Lack of common NOD2 variants in Japanese patients with Crohn's disease. Gastroenterology 2002;123:86-91.
52. Yamazaki K, Onouchi Y, Takazoe M, Kubo M, Nakamura Y, Hata A. Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients. J Human Genet 2007;52:575.
53. Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P,Mathew CG, Parkes M, Satsangi J; Wellcome Trust Case Control Consortium. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet 2008;40:710-712.
54. Festen EAM, Goyette P, Scott R, Annese V, Zhernakova A, Lian J, Lefèbvre C, Brant SR, Cho JH, Silverberg MS, Taylor KD, de Jong DJ, Stokkers PC, Mcgovern D, Palmieri O, Achkar JP, Xavier RJ, Daly MJ, Duerr RH, Wijmenga C, Weersma RK, Rioux JD. Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 2009;58:799-804.
55. Silverberg MS, Cho JH, Rioux JD, McGovern DPB, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, SteinhartAH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 2009;41: 216-220.
56. Ahn SH, Shah YM, Inoue J, Morimura K, Kim I, Yim S, LambertG, KurotaniR,NagashimaK,Gonzalez FJ, Inoue Y. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflamm Bowel Dis 2008;14:908-920.
57. Hermiston ML, Gordon JI. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 1995;270:1203-1207.
58. Pabst O, Forster R, Lipp M, Engel H, Arnold H-H. NKX2.3 is required for MAdCAM-1 expression and homing of lymphocytes in spleen and mucosa-associated lymphoid tissue. EMBO J 2000;19:2015.
59. Tarlinton D, Light A, Metcalf D, Harvey RP, Robb L. Architectural defects in the spleens of Nkx2-3-deficient mice are intrinsic and associated with defects in both B cell maturation and T cell-dependent immune responses. J Immunol 2003;170:4002-4010.
60. Shanahan F. Therapeutic implications of manipulating and mining the microbiota. J Physiol 2009;587:4175-4179.
61. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008;453:620.
62. Baumgart DC, Carding SR. Inflammatory bowel disease: Cause and immunobiology. Lancet 2007;369:1627.
63. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 2004;113: 1490-1497.
64. Melgar S, Yeung MW, Bas A, Forsberg G, Suhr O, Oberg A, Hammarstrom S, Danielsson A, Hammarstrom ML. Over-expression of interleukin 10 in mucosal T cells of patients with active ulcerative colitis. Clin Exp Immunol 2003;134: 127-137.
65. Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 2006;203:2473-2483.
66. Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, Cua DJ, Powrie F, Cheever AW, Maloy KJ, Sher A. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 2006;203: 2485-2494.
67. Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R, Robinson N, Buonocore S, Tlaskalova-Hogenova H, Cua DJ, Powrie F. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 2006;25:309-318.
68. Fuss IJ, Becker C, Yang Z, Groden C, Hornung RL, Heller F, Neurath MF, Strober W, Mannon PJ. 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. Inflam Bowel Dis 2006;12:9-15.
69. Becker C, Dornhoff H, Neufert C, Fantini MC, Wirtz S, Huebner S, Nikolaev A, Lehr HA, Murphy AJ, Valenzuela DM, Yancopoulos GD, Galle PR, Karow M, Neurath MF. Cutting edge: IL-23 Cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol 2006;177:2760-2764.
70. Izcue A, Hue S, Buonocore S, Arancibia-Cárcamo CV, Ahern PP, Iwakura Y, Maloy KJ, Powrie F. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 2008;28:559-570.
71. Pene J, Chevalier S, Preisser L, Venereau E, Guilleux M-H, Ghannam S, Molès JP, Danger Y, Ravon E, Lesaux S, Yssel H, Gascan H. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol 2008;180:7423-7430.
72. Dambacher J, Beigel F, Zitzmann K, de Toni E, Goke B, Diepolder HM, Auernhammer CJ, Brand S. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut 2008;58(9):1207-1217.
73. Kleinschek MA, Boniface K, Sadekova S, Grein J, Murphy EE, Turner SP, Raskin L, Desai B, Faubion WA, de Waal MalefytR,Pierce RH, McClanahanT,Kastelein RA. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med 2009;206:525-534.
74. McGeachy MJ, Cua D. Th17 cell differentiation: The long and winding road. Immunity 2008;28:445.
75. Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R, Kitazume MT, Nakazawa A, Sugita A, Koganei K, Isobe K, Hibi T. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut 2008;57:1682-1689.
76. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133-1141.
77. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fil̀ L, Ferri S, Frosali F, Giudici F, RomagnaniP, Parronchi P, Tonelli F, Maggi E, Romagnani S. Phenotypic and functional features of human Th17 cells. J Exp Med 2007;204:1849-1861.
78. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 2007;8:639-646.
79. Divangahi M, Mostowy S, Coulombe F, Kozak R, Guillot L, Veyrier F, Kobayashi KS, Flavell RA, Gros P, Behr MA. NOD2-deficient mice have impaired resistance to Mycobac-terium tuberculosis infection through defective innate and adaptive immunity. J Immunol 2008;181:7157-7165.
80. Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, Bamba T, Fujiyama Y. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003;52:65-70. (Pubitemid 36020767)
81. Ke X-S, Liu C-M, Liu D-P, Liang C-C. MicroRNAs: Key participants in gene regulatory networks. Curr Opin Chem Biol 2003;7:516.
82. Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004;116:281.
83. Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell 2009;136:215.
84. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science 2004;303:83-86.
85. Li Q-J, Chau J, Ebert PJR, Sylvester G, Min H, Liu G, Braich R, Manoharan M, Soutschek J, Skare P, Klein LO, Davis MM, Chen CZ. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 2007;129:147-161.
86. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4:499.
87. Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 2006;103:12481-12486.
88. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M, Bradley A. Requirement of bic/microRNA-155 for normal immune function. Science 2007;316:608-611.
89. Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E. Cutting edge: The Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol 2009;182:2578-2582.
90. Cobb BS, Hertweck A, Smith J, O'Connor E, Graf D, Cook T, Smale ST, Sakaguchi S, Livesey FJ, Fisher AG, Merkenschlager M. A role for Dicer in immune regulation. J Exp Med 2006;203:2519-2527.
91. Chong MM, Rasmussen JP, Rudensky AY, Littman DR. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med 2008;205:2005.
92. Mattes J, Collison A, Plank M, Phipps S, Foster PS. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc Natl Acad Sci USA 2009;106: 18704-18709.
93. Moschos S, Williams A, Perry M, Birrell M, Belvisi M, Lindsay M. Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysacchar-ide-induced inflammation but not in the anti-inflammatory action of glucocorticoids. BMC Genom 2007;8:240.
94. Worm J, Stenvang J, Petri A, Frederiksen KS, Obad S, Elmen J, Hedtjärn M, Straarup EM, Hansen JB, Kauppinen S. Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ ebp beta and down-regulation of G-CSF. Nucl Acids Res 2009;37:5784-5792.
95. Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, Li Z, Wu Z, Pei G. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 2009;10(12):1252-1259.
96. Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, Brant SR, Chakravarti S, Kwon JH. Micro-RNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2[alpha]. Gastroenterology 2008;135:1624-1635.
97. Ceppi M, Pereira PM, Dunand-Sauthier I, Barras EI, Reith W, Santos MA, Pierre P. MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci USA 2009;106:2735-2740.
98. Souza HS, Elia CCS, Spencer J, MacDonald TT. Expression of lymphocyte-endothelial receptor-ligand pairs, alpha 4beta 7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut 1999;45:856-863.
99. Jesús R-N, Gezahegn G, Klaus L. Leukocyte adhesion molecules in animal models of inflammatory bowel disease. Inflamm Bowel Dis 2008;14:1715-1735.
100. Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GPA, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O'Connor PW. A controlled trial of natalizu-mab for relapsing multiple sclerosis. N Engl J Med 2003;348: 15-23.
101. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S, van Deventer S, Goldblum R, Despain D, Hogge GS, Rutgeerts P. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 2005;353:1912-1925. (Pubitemid 41565956)
102. Carson KR, Focosi D, Major EO, Petrini M, Richey EA, West DP, Bennett CL. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: A review from the Research on Adverse Drug Events and Reports (RADAR) project. Lancet Oncol 2009;10:816-824.
103. Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JWD, Cohen A, Bitton A, Baker J, Dubé R, Landau SB, Vandervoort MK, Parikh A. Treatment of active Crohn's disease with MLN0002, a humanized antibody to the [alpha]4[beta]7 integrin. Clin Gastroenterol Hepatol 2008;6:1370-1377.
104. Feagan BG, Greenberg GR, Wild G, Fedorak RN, Pare P, McDonald JWD, Dubé R, Cohen A, Steinhart AH, Landau S, Aguzzi RA, Fox IH, Vandervoort MK. Treatment of ulcerative colitis with a humanized antibody to the {alpha}4{beta}7 integrin. N Engl J Med 2005;352: 2499-2507.
105. Cortijo J, Sanz MJ, Iranzo A, Montesinos JL, Nabah YN, Alfón J, Gómez LA, Merlos M, Morcillo EJ. A small molecule, orally active, alpha4beta1/alpha4beta7 dual antagonist reduces leukocyte infiltration and airway hyper-responsiveness in an experimental model of allergic asthma in Brown Norway rats. Br J Pharmacol 2006;147:661-670.
106. Okigami H, Takeshita K, Tajimi M, Komura H, Albers M, Lehmann TE, Rölle T, Bacon KB. Inhibition of eosinophilia in vivo by a small molecule inhibitor of very late antigen (VLA)-4. Euro J Pharmacol 2007;559:202-209.
107. Glasner J, Blum H, Wehner V, Stilz HU, Humphries JD, Curley GP, Mould AP, Humphries MJ, Hallmann R, Röllinghoff M, Gessner A. A small molecule {alpha}4{beta}1 antagonist prevents development of murine lyme arthritis without affecting protective immunity. J Immunol 2005;175: 4724-4734.
108. HijaziY, Welker H,Dorr AE, Tang J-P, BlainR,Renzetti LM, Abbas R. Pharmacokinetics, safety, and tolerability of R411, a dual {alpha}4{beta}1- {alpha}4{beta}7 integrin antagonist after oral administration at single and multiple once-daily ascending doses in healthy volunteers. J Clin Pharmacol 2004;44:1368-1378.
109. Farooq SM, Stillie R, Svensson M, Svanborg C, Strieter RM, Stadnyk AW. Therapeutic effect of blocking CXCR2 on neutrophil recruitment and dextran sodium sulfate-induced colitis. J Pharmacol Exper Therap 2009;329:123-129.
110. Bento AF, Leite DFP, Claudino RF, Hara DB, Leal PC, Calixto JB. The selective nonpeptide CXCR2 antagonist SB225002 ameliorates acute experimental colitis in mice. J Leukoc Biol 2008;84:1213-1221.
111. Rivera-Nieves J, Ho J, Bamias G, Ivashkina N, Ley K, Oppermann M, Cominelli F. Antibody blockade of CCL25/ CCR9 ameliorates early but not late chronic murine ileitis. Gastroenterology 2006;131:1518-1529.
112. Fortun PJ, Hawkey CJ. The role of stem cell transplantation in inflammatory bowel disease. Autoimmunity 2008;41: 654-659.
113. Oyama Y, Craig RM, Traynor AE, Quigley K, Statkute L, Halverson A, Brush M, Verda L, Kowalska B, Krosnjar N, Kletzel M, Whitington PF, Burt RK. Autologous hemato-poietic stem cell transplantation in patients with refractory Crohn's disease. Gastroenterology 2005;128:552-563.
114. Cassinotti A, Annaloro C, Ardizzone S, Onida F, Volpe AD, Clerici M, Usardi P, Greco S, Maconi G, Porro GB, Deliliers GL. Autologous haematopoietic stem cell transplantation without CD34 \+ cell selection in refractory Crohn's disease. Gut 2008;57:211-217.
115. Glocker E-O, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hätscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009;361:2033-2045.
116. Caplan AI. Why are MSCs therapeutic? New data: New insight. J Pathol 2009;217:318-324.
117. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008;8:726.
118. Brittan M, Chance V, Elia G, Poulsom R, Alison MR, MacDonald TT, Wright NA. A regenerative role for bone marrow following experimental colitis: Contribution to neovasculogenesis and myofibroblasts. Gastroenterology 2005;128:1984-1995.
119. Bamba S, Lee CY, Brittan M, Preston SL, Direkze NC, Poulsom R, Alison MR, Wright NA, Otto WR. Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice. J Pathol 2006;209:265-273.
120. Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, Yamashita K, Yamamoto H, Adachi Y, Sasaki Y, Isobe M, Fujimiya M, Imai K, Shinomura Y. Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol 2009;218:350-359.
121. González MA, Gonzalez-Rey E, Rico L, Büscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 2009;136: 978.
122. Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009;58:929-939.
123. Garća-Olmo D, Garća-Arranz M, Herreros D, Pascual I, Peiro C, Rodŕguez-Montes JA. A phase I clinical trial of the treatment of Crohn's Fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005, 48. 1416.
124. O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep 2006;7:688-693.
125. Molly P, Robert B. Use of antibiotics in the treatment of inflammatory bowel disease. Inflam Bowel Dis 2006;12: 651-664.
126. Deshpande G, Rao S, Patole S. Probiotics for prevention of necrotising enterocolitis in preterm neonates with very low birthweight: A systematic review of randomised controlled trials. Lancet 2007;369:1614.
127. Whorwell PJ, Altringer L, Morel J, Bond Y, Charbonneau D, O'Mahony L, Kiely B, Shanahan F, Quigley EM. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 2006;101:1581.
128. Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS. The utility of probiotics in the treatment of irritable bowel syndrome: A systematic review. Am J Gastroenterol 2009; 104:1033.
129. Hedin C, Whelan K, Lindsay JO. Evidence for the use of probiotics and prebiotics in inflammatory bowel disease: A review of clinical trials. Proc Nutr Soc 2007;66: 307-315.
130. Corr SC,LiY,Riedel CU, O'Toole PW, HillC,Gahan CGM. Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118. Proc Natl Acad Sci USA 2007;104:7617-7621.
131. Sonnenburg JL, Chen CTL, Gordon JI. Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLoS Biol 2006;4:e413.
132. Mahowald MA, Rey FE, Seedorf H, Turnbaugh PJ, Fulton RS, Wollam A, Shah N, Wang C, Magrini V, Wilson RK, Cantarel BL, Coutinho PM, Henrissat B, Crock LW, Russell A, Verberkmoes NC, Hettich RL, Gordon JI. Characterizing a model
133. Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, Fiers W, Remaut E. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000;289: 1352-1355.
134. Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clin Gastroenterol Hepatol 2006;4:754-759.
135. Vandenbroucke K, de Haard H, Beirnaert E, Dreier T, Lauwereys M, Huyck L, Van Huysse J, Demetter P, Steidler L, Remaut E, Cuvelier C, Rottiers P. Orally administered L. lactis secreting an anti-TNF Nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol 2009;3(1):49-56.