Immunotherapy in inflammatory bowel disease: Novel and emerging treatments

References

• Abraham C, Cho JH. Inflammatory Bowel Disease. N Engl J Med. 2009;361:2066–78. doi:10.1056/NEJMra0804647. PMID:19923578.
   PubMed Web of Science ®Google Scholar
• Ordas I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcerative colitis. Lancet. 2012;380:1606–19. doi:10.1016/S0140-6736(12)60150-0. PMID:22914296.
   PubMed Web of Science ®Google Scholar
• Baumgart DC, Sandborn WJ. Crohn's disease. Lancet. 2012;380:1590–605. doi:10.1016/S0140-6736(12)60026-9. PMID:22914295.
   PubMed Web of Science ®Google Scholar
• Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54.e42. doi:10.1053/j.gastro.2011.10.001. PMID:22001864.
   PubMed Web of Science ®Google Scholar
• Rocchi A, Benchimol EI, Bernstein CN, Bitton A, Feagan B, Panaccione R. Inflammatory bowel disease: a Canadian burden of illness review. Can J Gastroenterol. 2012;26(11):811–817. doi:10.1155/2012/984575. PMID:23166905.
   PubMed Web of Science ®Google Scholar
• Burisch J, Jess T, Martinato M, Lakatos PL. The burden of inflammatory bowel disease in Europe. Journal of Crohn's and colitis. 2013;7:322. doi:10.1016/j.crohns.2013.01.010.
   PubMed Web of Science ®Google Scholar
• de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol. 2016;13:13–27. doi:10.1038/nrgastro.2015.186. PMID:26627550.
   PubMed Web of Science ®Google Scholar
• de Souza HSP, Fiocchi C, Iliopoulos D. The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol. 2017;14:739–49. doi:10.1038/nrgastro.2017.110. PMID:28831186.
   PubMed Web of Science ®Google Scholar
• Hugot J-P, Chamaillard M, Zouali H, Lesage S, Cezard J-P, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411:599–603. doi:10.1038/35079107. PMID:11385576.
   PubMed Web of Science ®Google Scholar
• Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–11. doi:10.1038/ng1954. PMID:17200669.
   PubMed Web of Science ®Google Scholar
• Zeissig S, Burgel N, Gunzel D, Richter J, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease. Gut. 2007;56:61–72. doi:10.1136/gut.2006.094375. PMID:16822808.
   PubMed Web of Science ®Google Scholar
• Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A, Wesley E, Parnell K, Zhang H, Drummond H, et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 2009;41:1330–4. doi:10.1038/ng.483. PMID:19915572.
   PubMed Web of Science ®Google Scholar
• Buisine MP, Desreumaux P, Debailleul V, Gambiez L, Geboes K, Ectors N, Delescaut MP, Degand P, Aubert JP, Colombel JF, et al. Abnormalities in mucin gene expression in Crohn's disease. Inflamm Bowel Dis 1999;5:24–32. doi:10.1097/00054725-199902000-00004. PMID:10028446.
   PubMed Web of Science ®Google Scholar
• Braun A, Treede I, Gotthardt D, Tietje A, Zahn A, Ruhwald R, Schoenfeld U, Welsch T, Kienle P, Erben G, et al. Alterations of phospholipid concentration and species composition of the intestinal mucus barrier in ulcerative colitis: a clue to pathogenesis. Inflamm Bowel Dis. 2009;15:1705–20. doi:10.1002/ibd.20993. PMID:19504612.
   PubMed Web of Science ®Google Scholar
• Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R, et al. Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A. 2005;102:18129–34. doi:10.1073/pnas.0505256102. PMID:16330776.
   PubMed Web of Science ®Google Scholar
• Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134:743–56. doi:10.1016/j.cell.2008.07.021. PMID:18775308.
   PubMed Web of Science ®Google Scholar
• Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14:329–42. doi:10.1038/nri3661. PMID:24751956.
   PubMed Web of Science ®Google Scholar
• Mayne CG, Williams CB. Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:1772–88. doi:10.1097/MIB.0b013e318281f5a3. PMID:23656897.
   PubMed Web of Science ®Google Scholar
• Peters CP, Mjosberg JM, Bernink JH, Spits H. Innate lymphoid cells in inflammatory bowel diseases. Immunology letters. 2016;172:124–31. doi:10.1016/j.imlet.2015.10.004. PMID:26470815.
   PubMed Web of Science ®Google Scholar
• Catalan-Serra I, Sandvik AK, Bruland T, Andreu-Ballester JC. Gammadelta T Cells in Crohn's Disease: A New Player in the Disease Pathogenesis? Journal of Crohn's & colitis. 2017;11:1135–45.
   PubMed Web of Science ®Google Scholar
• Danese S, Panes J. Development of drugs to target interactions between leukocytes and endothelial cells and treatment algorithms for inflammatory bowel diseases. Gastroenterology. 2014;147:981–9. doi:10.1053/j.gastro.2014.08.044. PMID:25220794.
   PubMed Web of Science ®Google Scholar
• Gomollon F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO, Peyrin-Biroulet L, Cullen GJ, Daperno M, Kucharzik T, et al. 3rd european evidence-based consensus on the diagnosis and management of crohn's disease 2016: part 1: diagnosis and medical management. Journal of Crohn's & colitis. 2017;11:3–25. doi:10.1093/ecco-jcc/jjw168.
   PubMed Web of Science ®Google Scholar
• Harbord M, Eliakim R, Bettenworth D, Karmiris K, Katsanos K, Kopylov U, Kucharzik T, Molnar T, Raine T, Sebastian S, et al. third european evidence-based consensus on diagnosis and management of ulcerative colitis. part 2: Current management. Journal of Crohn's & colitis. 2017;11:769–84. doi:10.1093/ecco-jcc/jjx009..
   PubMed Web of Science ®Google Scholar
• Cohen BL, Sachar DB. Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease. BMJ (Clinical research ed). 2017;357:j2505. doi:10.1136/bmj.j2505. PMID:28630047.
   PubMed Web of Science ®Google Scholar
• Ding NS, 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. 2016;43:30–51. doi:10.1111/apt.13445. PMID:26515897.
   PubMed Web of Science ®Google Scholar
• Dulai PS, Thompson KD, Blunt HB, Dubinsky MC, Siegel CA. Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease: a systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12:1443–51; quiz e88-9. doi:10.1016/j.cgh.2014.01.021. PMID:24462626.
   PubMed Web of Science ®Google Scholar
• Dulai PS, Siegel CA. The risk of malignancy associated with the use of biological agents in patients with inflammatory bowel disease. Gastroenterol Clin North Am. 2014;43:525–41. doi:10.1016/j.gtc.2014.05.010. PMID:25110257.
   PubMed Web of Science ®Google Scholar
• Frolkis AD, Dykeman J, Negrón ME, deBruyn J, Jette N, Fiest KM, Frolkis T, Barkema HW, Rioux KP, Panaccione R, et al. Risk of Surgery for Inflammatory Bowel Diseases Has Decreased Over Time: A Systematic Review and Meta-analysis of Population-Based Studies. Gastroenterology. 2013;145:996–1006. doi:10.1053/j.gastro.2013.07.041. PMID:23896172.
   PubMed Web of Science ®Google Scholar
• Gionchetti P, Dignass A, Danese S, Magro Dias FJ, Rogler G, Lakatos PL, Adamina M, Ardizzone S, Buskens CJ, Sebastian S, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 2: Surgical Management and Special Situations. Journal of Crohn's & colitis. 2017;11:135–49. doi:10.1093/ecco-jcc/jjw169..
   PubMed Web of Science ®Google Scholar
• Trinchieri G, Pflanz S, Kastelein RA. The IL-12 Family of Heterodimeric Cytokines: New Players in the Regulation of T Cell Responses. Immunity. 2003;19:641–4. doi:10.1016/S1074-7613(03)00296-6. PMID:14614851.
   PubMed Web of Science ®Google Scholar
• McGovern D, Powrie F. The IL23 axis plays a key role in the pathogenesis of IBD. Gut. 2007;56:1333–6. doi:10.1136/gut.2006.115402. PMID:17872562.
   PubMed Web of Science ®Google Scholar
• Abraham C, Dulai PS, Vermeire S, Sandborn WJ. Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases. Gastroenterology. 2017;152:374–88.e4. doi:10.1053/j.gastro.2016.10.018. PMID:27780712.
   PubMed Web of Science ®Google Scholar
• Vignali DAA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012;13:722. doi:10.1038/ni.2366. PMID:22814351.
   PubMed Web of Science ®Google Scholar
• Yadav V, Varum F, Bravo R, Furrer E, Bojic D, Basit AW. Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Translational research : the journal of laboratory and clinical medicine. 2016;176:38–68. doi:10.1016/j.trsl.2016.04.009. PMID:27220087.
   PubMed Web of Science ®Google Scholar
• Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, et al. A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene. Science. 2006;314:1461–3. doi:10.1126/science.1135245. PMID:17068223.
   PubMed Web of Science ®Google Scholar
• Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009;41:216–20. doi:10.1038/ng.275. PMID:19122664.
   PubMed Web of Science ®Google Scholar
• Pidasheva S, Trifari S, Phillips A, Hackney JA, Ma Y, Smith A, Sohn SJ, Spits H, Little RD, Behrens TW, et al. Functional Studies on the IBD Susceptibility Gene IL23R Implicate Reduced Receptor Function in the Protective Genetic Variant R381Q. PLOS ONE. 2011;6:e25038. doi:10.1371/journal.pone.0025038. PMID:22022372.
   PubMed Web of Science ®Google Scholar
• Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, Wehkamp J, Feagan BG, Yao MD, Karczewski M, 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;61:1693–700. doi:10.1136/gutjnl-2011-301668. PMID:22595313.
   PubMed Web of Science ®Google Scholar
• Targan SR, Feagan B, Vermeire S, Panaccione R, Melmed GY, Landers C, Li D, Russell C, Newmark R, Zhang N, et al. A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn's Disease. Am J Gastroenterol. 2016;111:1599–607. doi:10.1038/ajg.2016.298. PMID:27481309.
   PubMed Web of Science ®Google Scholar
• Lee Jacob S, Tato Cristina M, Joyce-Shaikh B, Gulen Muhammet F, Cayatte C, Chen Y, Blumenschein Wendy M, Judo M, Ayanoglu G, McClanahan Terrill K, et al. Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. Immunity. 2015;43:727–38. doi:10.1016/j.immuni.2015.09.003. PMID:26431948.
   PubMed Web of Science ®Google Scholar
• Maloy KJ, Kullberg MC. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 2008;1:339. doi:10.1038/mi.2008.28. PMID:19079198.
   PubMed Web of Science ®Google Scholar
• Aden K, Rehman A, Falk-Paulsen M, Secher T, Kuiper J, Tran F, Pfeuffer S, Sheibani-Tezerji R, Breuer A, Luzius A, et al. Epithelial IL-23R Signaling Licenses Protective IL-22 Responses in Intestinal Inflammation. Cell Rep. 2016;16:2208–18. doi:10.1016/j.celrep.2016.07.054. PMID:27524624.
   PubMed Web of Science ®Google Scholar
• Macho-Fernandez E, Koroleva EP, Spencer CM, Tighe M, Torrado E, Cooper AM, Fu YX, Tumanov AV. Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells. Mucosal Immunol. 2015;8:403–13. doi:10.1038/mi.2014.78. PMID:25183367.
   PubMed Web of Science ®Google Scholar
• Cox JH, Kljavin NM, Ota N, Leonard J, Roose-Girma M, Diehl L, Ouyang W, Ghilardi N. Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice. Mucosal Immunol. 2012;5:99–109. doi:10.1038/mi.2011.54. PMID:22089030.
   PubMed Web of Science ®Google Scholar
• Eken A, Singh AK, Treuting PM, Oukka M. IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol. 2014;7:143–54. doi:10.1038/mi.2013.33. PMID:23715173.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Gasink C, Gao L-L, Blank MA, Johanns J, Guzzo C, Sands BE, Hanauer SB, Targan S, Rutgeerts P, et al. Ustekinumab Induction and Maintenance Therapy in Refractory Crohn's Disease. N Engl J Med. 2012;367:1519–28. doi:10.1056/NEJMoa1203572. PMID:23075178.
   PubMed Web of Science ®Google Scholar
• Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, Dolin B, Goodman N, Groden C, Hornung RL, et al. Anti–Interleukin-12 Antibody for Active Crohn's Disease. N Engl J Med. 2004;351:2069–79. doi:10.1056/NEJMoa033402. PMID:15537905.
   PubMed Web of Science ®Google Scholar
• Panaccione R, Sandborn WJ, Gordon GL, Lee SD, Safdi A, Sedghi S, Feagan BG, Hanauer S, Reinisch W, Valentine JF, et al. Briakinumab for treatment of Crohn's disease: results of a randomized trial. Inflamm Bowel Dis. 2015;21:1329–40. PMID:25989338.
   PubMed Web of Science ®Google Scholar
• MacDonald JK, Nguyen TM, Khanna R, Timmer A. Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2016;11:Cd007572. PMID:27885650.
   PubMedGoogle Scholar
• Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Ann Rheum Dis. 2018;77:175–87. doi:10.1136/annrheumdis-2017-211555. PMID:28765121.
   PubMed Web of Science ®Google Scholar
• Ryan C, Leonardi CL, Krueger JG, Kimball AB, Strober BE, Gordon KB, Langley RG, de Lemos JA, Daoud Y, Blankenship D, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. Jama. 2011;306:864–71. PMID:21862748.
   PubMed Web of Science ®Google Scholar
• Tzellos T, Kyrgidis A, Trigoni A, Zouboulis CC. Association of ustekinumab and briakinumab with major adverse cardiovascular events: An appraisal of meta-analyses and industry sponsored pooled analyses to date. Dermato-endocrinology. 2012;4:320–3. doi:10.4161/derm.23100. PMID:23467502.
   PubMedGoogle Scholar
• Sands BE, Chen J, Feagan BG, Penney M, Rees WA, Danese S, Higgins PDR, Newbold P, Faggioni R, Patra K, et al. Efficacy and Safety of MEDI2070, an Antibody Against Interleukin 23, in Patients With Moderate to Severe Crohn's Disease: A Phase 2a Study. Gastroenterology. 2017;153:77–86.e6. doi:10.1053/j.gastro.2017.03.049. PMID:28390867.
   PubMed Web of Science ®Google Scholar
• Feagan BG, Sandborn W, Panés J, Ferrante M, Louis E, D'Haens GR, Franchimont D, Kaser A, Dewit O, Seidler U, et al. 812a 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. 2016;150:S1266. doi:10.1016/S0016-5085(16)34278-0..
   Google Scholar
• Coskun M, Vermeire S, Nielsen OH. Novel Targeted Therapies for Inflammatory Bowel Disease. Trends in pharmacological sciences. 2017;38:127–42. doi:10.1016/j.tips.2016.10.014. PMID:27916280.
   PubMed Web of Science ®Google Scholar
• Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57. doi:10.1038/ni.3153. PMID:25898198.
   PubMed Web of Science ®Google Scholar
• Tanaka T, Narazaki M, Ogata A, Kishimoto T. A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy. Semin Immunol. 2014;26:88–96. doi:10.1016/j.smim.2014.01.009. PMID:24594001.
   PubMed Web of Science ®Google Scholar
• Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265:621–36. doi:10.1042/bj2650621. PMID:1689567.
   PubMed Web of Science ®Google Scholar
• Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10:720. doi:10.1038/nrrheum.2014.127. PMID:25136784.
   PubMed Web of Science ®Google Scholar
• Gross V, Andus T, Caesar I, Roth M, Scholmerich J. Evidence for continuous stimulation of interleukin-6 production in Crohn's disease. Gastroenterology 1992;102:514–9. doi:10.1016/0016-5085(92)90098-J. PMID:1370661.
   PubMed Web of Science ®Google Scholar
• Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517. doi:10.1146/annurev.immunol.021908.132710. PMID:19132915.
   PubMed Web of Science ®Google Scholar
• Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8. doi:10.1038/nature04753. PMID:16648838.
   PubMed Web of Science ®Google Scholar
• Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40:1830–5. doi:10.1002/eji.201040391. PMID:20583029.
   PubMed Web of Science ®Google Scholar
• Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70:11–20. doi:10.1016/j.cyto.2014.05.024. PMID:24986424.
   PubMed Web of Science ®Google Scholar
• Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. IL-6 is required for the development of Th1 cell-mediated murine colitis. Journal of immunology (Baltimore, Md : 1950). 2000;164:4878–82. doi:10.4049/jimmunol.164.9.4878. PMID:10779797.
   PubMed Web of Science ®Google Scholar
• Hosokawa T, Kusugami K, Ina K, Ando T, Shinoda M, Imada A, Ohsuga M, Sakai T, Matsuura T, Ito K, et al. Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease. J Gastroenterol Hepatol. 1999;14:987–96. doi:10.1046/j.1440-1746.1999.01989.x. PMID:10530495.
   PubMed Web of Science ®Google Scholar
• Louis E, Belaiche J, van Kemseke C, Franchimont D, de Groote D, Gueenen V, Mary JY. A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn's disease. Eur J Gastroenterol Hepatol. 1997;9:939–44. doi:10.1097/00042737-199710000-00004..
   PubMed Web of Science ®Google Scholar
• Ito H, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A, Matsumoto T, Yamamura T, Azuma J, Nishimoto N, et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology. 2004;126:989–96; discussion 47. doi:10.1053/j.gastro.2004.01.012. PMID:15057738.
   PubMed Web of Science ®Google Scholar
• Danese S, Vermeire S, Hellstern P, Panaccione R, Rogler G, Fraser G, Kohn A, Desreumaux P, Leong RW, Comer GM, et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II). Gut. 2017;1–9. doi:10.1136/gutjnl-2017-314562.
   Web of Science ®Google Scholar
• Kuhn KA, Manieri NA, Liu T-C, Stappenbeck TS. IL-6 Stimulates Intestinal Epithelial Proliferation and Repair after Injury. PLOS ONE. 2014;9:e114195. doi:10.1371/journal.pone.0114195. PMID:25478789.
   PubMed Web of Science ®Google Scholar
• Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, Gruben D, Wallenstein GV, Zwillich SH, Kanik KS. Placebo-Controlled Trial of Tofacitinib Monotherapy in Rheumatoid Arthritis. N Engl J Med. 2012;367:495–507. doi:10.1056/NEJMoa1109071. PMID:22873530.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, Estrov Z, Fridman JS, Bradley EC, Erickson-Viitanen S, et al. Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis. N Engl J Med. 2010;363:1117–27. doi:10.1056/NEJMoa1002028. PMID:20843246.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, Niezychowski W. Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis. N Engl J Med. 2012;367:616–24. doi:10.1056/NEJMoa1112168. PMID:22894574.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S, Danese S, Feagan BG, Reinisch W, Niezychowski W, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2017;376:1723–36. doi:10.1056/NEJMoa1606910. PMID:28467869.
   PubMed Web of Science ®Google Scholar
• Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 2013;76:1–8. doi:10.1016/j.phrs.2013.06.007. PMID:23827161.
   PubMed Web of Science ®Google Scholar
• Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228:273–87. doi:10.1111/j.1600-065X.2008.00754.x. PMID:19290934.
   PubMed Web of Science ®Google Scholar
• O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36:542–50. doi:10.1016/j.immuni.2012.03.014. PMID:22520847.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Ghosh S, Panes J, Vranic I, Wang W, Niezychowski W. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12:1485–93.e2. doi:10.1016/j.cgh.2014.01.029. PMID:24480677.
   PubMed Web of Science ®Google Scholar
• Panés J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D'Haens G, Panaccione R, Higgins PDR, Colombel J-F, Feagan BG, et al. Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials. Gut. 2017;66(6):1049–1059. doi:10.1136/gutjnl-2016-312735.
   Google Scholar
• Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, Klopocka M, Goldis A, Wisniewska-Jarosinska M, Baranovsky A, et al. Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet. 2017;389:266–75. doi:10.1016/S0140-6736(16)32537-5. PMID:27988142.
   PubMed Web of Science ®Google Scholar
• Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, Filippi M. Placebo-Controlled Trial of Oral Laquinimod for Multiple Sclerosis. N Engl J Med. 2012;366:1000–9. doi:10.1056/NEJMoa1104318. PMID:22417253.
   PubMed Web of Science ®Google Scholar
• Vollmer TL, Sorensen PS, Selmaj K, Zipp F, Havrdova E, Cohen JA, Sasson N, Gilgun-Sherki Y, Arnold DL. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014;261:773–83. doi:10.1007/s00415-014-7264-4. PMID:24535134.
   PubMed Web of Science ®Google Scholar
• Jayne D, Appel G, Chan TM, Barkay H, Weiss R, Wofsy D. LB0003 A Randomized Controlled Study of Laquinimod in Active Lupus Nephritis Patients in Combination with Standard of Care. Ann Rheum Dis. 2013;72:A164–A. doi:10.1136/annrheumdis-2013-eular.528..
   Google Scholar
• Bruck W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011;306:173–9. doi:10.1016/j.jns.2011.02.019. PMID:21429524.
   PubMed Web of Science ®Google Scholar
• Thöne J, Linker RA. Laquinimod in the treatment of multiple sclerosis: a review of the data so far. Drug Design, Development and Therapy. 2016;10:1111–8. doi:10.2147/DDDT.S55308. PMID:27042003.
   PubMed Web of Science ®Google Scholar
• D'Haens G, Sandborn WJ, Colombel JF, Rutgeerts P, Brown K, Barkay H, Sakov A, Haviv A, Feagan BG. Laquinimod for Crohn's Disease I. A phase II study of laquinimod in Crohn's disease. Gut. 2015;64:1227–35. doi:10.1136/gutjnl-2014-307118. PMID:25281416.
   PubMed Web of Science ®Google Scholar
• Gorelik L, Flavell RA. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol. 2002;2:46–53. doi:10.1038/nri704. PMID:11905837.
   PubMed Web of Science ®Google Scholar
• Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol. 1998;16:137–61. doi:10.1146/annurev.immunol.16.1.137. PMID:9597127.
   PubMed Web of Science ®Google Scholar
• Sedda S, Marafini I, Dinallo V, Di Fusco D, Monteleone G. The TGF-beta/Smad System in IBD Pathogenesis. Inflamm Bowel Dis. 2015;21:2921–5. doi:10.1097/MIB.0000000000000542. PMID:26230862.
   PubMed Web of Science ®Google Scholar
• Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465–71. doi:10.1038/37284. PMID:9393997.
   PubMed Web of Science ®Google Scholar
• Derynck R, Zhang Y, Feng XH. Smads: transcriptional activators of TGF-beta responses. Cell 1998;95:737–40. doi:10.1016/S0092-8674(00)81696-7. PMID:9865691.
   PubMed Web of Science ®Google Scholar
• Monteleone G, Del Vecchio Blanco G, Monteleone I, Fina D, Caruso R, Gioia V, Ballerini S, Federici G, Bernardini S, Pallone F, et al. Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease. Gastroenterology. 2005;129:1420–9. doi:10.1053/j.gastro.2005.09.005. PMID:16285943.
   PubMed Web of Science ®Google Scholar
• Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest. 2001;108:601–9. doi:10.1172/JCI12821. PMID:11518734.
   PubMed Web of Science ®Google Scholar
• Monteleone G, Neurath MF, Ardizzone S, Di Sabatino A, Fantini MC, Castiglione F, Scribano ML, Armuzzi A, Caprioli F, Sturniolo GC, et al. Mongersen, an Oral SMAD7 Antisense Oligonucleotide, and Crohn's Disease. N Engl J Med. 2015;372:1104–13. doi:10.1056/NEJMoa1407250. PMID:25785968.
   PubMed Web of Science ®Google Scholar
• Monteleone G, Fantini MC, Onali S, Zorzi F, Sancesario G, Bernardini S, Calabrese E, Viti F, Monteleone I, Biancone L, et al. Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn's disease. Molecular therapy : the journal of the American Society of Gene Therapy. 2012;20:870–6. doi:10.1038/mt.2011.290. PMID:22252452.
   PubMed Web of Science ®Google Scholar
• Feagan B, Sands B, Rossiter G, Li X, Usiskin K, Zhan X, Colombel JF. PD-008 A Study of Oral Mongersen (GED-0301) on Endoscopy and Clinical Activity (Stool Frequency and Abdominal Pain) in Crohn's Disease. Inflamm Bowel Dis. 2017;23:S8–S.
   Web of Science ®Google Scholar
• Li C, Kuemmerle JF. Mechanisms that mediate the development of fibrosis in patients with Crohn's disease. Inflamm Bowel Dis. 2014;20:1250–8. doi:10.1097/MIB.0000000000000043. PMID:24831560.
   PubMed Web of Science ®Google Scholar
• Zorzi F, Calabrese E, Monteleone I, Fantini M, Onali S, Biancone L, Pallone F, Monteleone G. A phase 1 open-label trial shows that smad7 antisense oligonucleotide (GED0301) does not increase the risk of small bowel strictures in Crohn's disease. Aliment Pharmacol Ther. 2012;36:850–7. doi:10.1111/apt.12051. PMID:22971085.
   PubMed Web of Science ®Google Scholar
• Lobaton T, Vermeire S, Van Assche G, Rutgeerts P. Review article: anti-adhesion therapies for inflammatory bowel disease. Aliment Pharmacol Ther. 2014;39:579–94. doi:10.1111/apt.12639. PMID:24479980.
   PubMed Web of Science ®Google Scholar
• Jones SC, Banks RE, Haidar A, Gearing AJ, Hemingway IK, Ibbotson SH, Dixon MF, Axon AT. Adhesion molecules in inflammatory bowel disease. Gut 1995;36:724–30. doi:10.1136/gut.36.5.724. PMID:7541009.
   PubMed Web of Science ®Google Scholar
• Souza HS, Elia CCS, Spencer J, MacDonald TT. Expression of lymphocyte-endothelial receptor-ligand pairs, α4β7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut. 1999;45:856–63. doi:10.1136/gut.45.6.856. PMID:10562584.
   PubMed Web of Science ®Google Scholar
• Oshima T, Jordan P, Grisham MB, Alexander JS, Jennings M, Sasaki M, Manas K. TNF-alpha induced endothelial MAdCAM-1 expression is regulated by exogenous, not endogenous nitric oxide. BMC Gastroenterol. 2001;1:5. doi:10.1186/1471-230X-1-5. PMID:11481030.
   PubMedGoogle Scholar
• Yacyshyn BR, Chey WY, Goff J, Salzberg B, Baerg R, Buchman AL, Tami J, Yu R, Gibiansky E, Shanahan WR. Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease. Gut. 2002;51:30–6. doi:10.1136/gut.51.1.30. PMID:12077088.
   PubMed Web of Science ®Google Scholar
• Vegter S, Tolley K, Wilson Waterworth T, Jones H, Jones S, Jewell D. Meta-analysis using individual patient data: efficacy and durability of topical alicaforsen for the treatment of active ulcerative colitis. Aliment Pharmacol Ther. 2013;38:284–93. doi:10.1111/apt.12369..
   PubMed Web of Science ®Google Scholar
• Jairath V, Khanna R, Feagan BG. Alicaforsen for the treatment of inflammatory bowel disease. Expert opinion on investigational drugs. 2017;26:991–7. doi:10.1080/13543784.2017.1349753. PMID:28670932.
   PubMed Web of Science ®Google Scholar
• Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, von Andrian UH. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature. 2003;424:88–93. doi:10.1038/nature01726. PMID:12840763.
   PubMed Web of Science ®Google Scholar
• Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, McEvoy LM, Butcher EC, Kassam N, Mackay CR, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 1997;151:97–110. PMID:9212736.
   PubMed Web of Science ®Google Scholar
• Ghosh S, Panaccione R. Anti-adhesion molecule therapy for inflammatory bowel disease. Ther Adv Gastroenterol. 2010;3:239–58. doi:10.1177/1756283X10373176. PMID:21180606.
   PubMedGoogle Scholar
• 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 Natalizumab for Relapsing Multiple Sclerosis. N Engl J Med. 2003;348:15–23. doi:10.1056/NEJMoa020696. PMID:12510038.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S, et al. Natalizumab Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2005;353:1912–25. doi:10.1056/NEJMoa043335. PMID:16267322.
   PubMed Web of Science ®Google Scholar
• Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, Spehlmann ME, Rutgeerts PJ, Tulassay Z, Volfova M, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology. 2007;132:1672–83. doi:10.1053/j.gastro.2007.03.024. PMID:17484865.
   PubMed Web of Science ®Google Scholar
• Pagnini C, Arseneau KO, Cominelli F. Natalizumab in the treatment of Crohn's disease patients. Expert opinion on biological therapy. 2017;17:1433–8. PMID:28832222.
   PubMed Web of Science ®Google Scholar
• Yoshimura N, Watanabe M, Motoya S, Tominaga K, Matsuoka K, Iwakiri R, Watanabe K, Hibi T. Safety and Efficacy of AJM300, an Oral Antagonist of alpha4 Integrin, in Induction Therapy for Patients With Active Ulcerative Colitis. Gastroenterology. 2015;149:1775–83.e2. doi:10.1053/j.gastro.2015.08.044. PMID:26327130.
   PubMed Web of Science ®Google Scholar
• Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel J-F, Sandborn WJ, Van Assche G, Axler J, Kim H-J, Danese S, et al. Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2013;369:699–710. doi:10.1056/NEJMoa1215734. PMID:23964932.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel J-F, Sands BE, Lukas M, Fedorak RN, Lee S, Bressler B, et al. Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2013;369:711–21. doi:10.1056/NEJMoa1215739. PMID:23964933.
   PubMed Web of Science ®Google Scholar
• Stallmach A, Langbein C, Atreya R, Bruns T, Dignass A, Ende K, Hampe J, Hartmann F, Neurath MF, Maul J, 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(11–12):1199–1212. doi:10.1111/apt.13813.
   Web of Science ®Google Scholar
• Loftus EV, Jr., Colombel JF, Feagan BG, Vermeire S, Sandborn WJ, Sands BE, Danese S, D'Haens GR, Kaser A, Panaccione R, et al. Long-term Efficacy of Vedolizumab for Ulcerative Colitis. Journal of Crohn's & colitis. 2017;11:400–11.
   PubMed Web of Science ®Google Scholar
• Vermeire S, Loftus EV, Jr., Colombel JF, Feagan BG, Sandborn WJ, Sands BE, Danese S, D'Haens GR, Kaser A, Panaccione R, et al. Long-term Efficacy of Vedolizumab for Crohn's Disease. Journal of Crohn's & colitis. 2017;11:412–24.
   PubMed Web of Science ®Google Scholar
• Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D'Haens G, Panaccione R, Loftus EV, Jr., Sankoh S, Fox I, et al. The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut. 2016.
   Google Scholar
• Sandborn WJ, Cyrille M, Hansen MB, Feagan BG, Loftus JEV, Rogler G, Vermeire S, Cruz ML, Yang J, Sullivan BA, et al. OP034 Efficacy and safety of abrilumab in subjects with moderate to severe ulcerative colitis: results of a phase 2b, randomised, double-blind, multiple-dose, placebo-controlled study. Journal of Crohn's and Colitis. 2017;11:S21–S2. doi:10.1093/ecco-jcc/jjx002.033..
   Web of Science ®Google Scholar
• Sandborn WJ, Cyrille M, Berner Hansen M, Feagan BG, Loftus JEV, Vermeire S, Cruz ML, Mo M, Sullivan BA, Reinisch W. OP035 Efficacy and safety of abrilumab (AMG 181/MEDI 7183) therapy for moderate to severe Crohn's disease. Journal of Crohn's and Colitis. 2017;11:S22–S3. doi:10.1093/ecco-jcc/jjx002.034..
   Web of Science ®Google Scholar
• Sandborn WJ, Lee SD, Tarabar D, Louis E, Klopocka M, Klaus J, Reinisch W, Hebuterne X, Park DI, Schreiber S, et al. Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study. Gut. 2017;1–12.
   Web of Science ®Google Scholar
• Vermeire S, Sandborn WJ, Danese S, Hebuterne X, Salzberg BA, Klopocka M, Tarabar D, Vanasek T, Gregus M, Hellstern PA, et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:135–44. doi:10.1016/S0140-6736(17)30930-3. PMID:28527704.
   PubMed Web of Science ®Google Scholar
• Vermeire S, O'Byrne S, Keir M, Williams M, Lu TT, Mansfield JC, Lamb CA, Feagan BG, Panes J, Salas A, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet. 2014;384:309–18. doi:10.1016/S0140-6736(14)60661-9..
   PubMed Web of Science ®Google Scholar
• Argollo M, Fiorino G, Hindryckx P, Peyrin-Biroulet L, Danese S. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun. 2017;85:103–16. doi:10.1016/j.jaut.2017.07.004. PMID:28711286.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Feagan BG, Wolf DC, D'Haens G, Vermeire S, Hanauer SB, Ghosh S, Smith H, Cravets M, Frohna PA, et al. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N Engl J Med. 2016;374:1754–62. doi:10.1056/NEJMoa1513248. PMID:27144850.
   PubMed Web of Science ®Google Scholar
• Spiegel S, Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011;11:403–15. doi:10.1038/nri2974. PMID:21546914.
   PubMed Web of Science ®Google Scholar
• Fyrst H, Saba JD. An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol. 2010;6:489–97. doi:10.1038/nchembio.392. PMID:20559316.
   PubMed Web of Science ®Google Scholar
• Nielsen OH, Li Y, Johansson-Lindbom B, Coskun M. Sphingosine-1-Phosphate Signaling in Inflammatory Bowel Disease. Trends Mol Med. 2017;23:362–74. doi:10.1016/j.molmed.2017.02.002. PMID:28283249.
   PubMed Web of Science ®Google Scholar
• Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346–9. doi:10.1126/science.1070238. PMID:11923495.
   PubMed Web of Science ®Google Scholar
• Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science. 2007;316:295–8. doi:10.1126/science.1139221. PMID:17363629.
   PubMed Web of Science ®Google Scholar
• Thangada S, Khanna KM, Blaho VA, Oo ML, Im DS, Guo C, Lefrancois L, Hla T. Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. J Exp Med. 2010;207:1475–83. doi:10.1084/jem.20091343. PMID:20584883.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Arnold DL, Comi G, Bar-Or A, Gujrathi S, Hartung JP, Cravets M, Olson A, Frohna PA, Selmaj KW. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:373–81. doi:10.1016/S1474-4422(16)00018-1. PMID:26879276.
   PubMed Web of Science ®Google Scholar
• Mao F, Tu Q, Wang L, Chu F, Li X, Li HS, Xu W. Mesenchymal stem cells and their therapeutic applications in inflammatory bowel disease. Oncotarget. 2017;8:38008–21. doi:10.18632/oncotarget.16682. PMID:28402942.
   PubMedGoogle Scholar
• Gregoire C, Lechanteur C, Briquet A, Baudoux E, Baron F, Louis E, Beguin Y. Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases. Aliment Pharmacol Ther. 2017;45:205–21. doi:10.1111/apt.13864. PMID:27878827.
   PubMed Web of Science ®Google Scholar
• Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7. doi:10.1080/14653240600855905. PMID:16923606.
   PubMed Web of Science ®Google Scholar
• Li L, Liu S, Xu Y, Zhang A, Jiang J, Tan W, Xing J, Feng G, Liu H, Huo F, et al. Human umbilical cord-derived mesenchymal stem cells downregulate inflammatory responses by shifting the Treg/Th17 profile in experimental colitis. Pharmacology. 2013;92:257–64. doi:10.1159/000354883. PMID:24280970.
   PubMed Web of Science ®Google Scholar
• Choi YS, Jeong JA, Lim DS. Mesenchymal stem cell-mediated immature dendritic cells induce regulatory T cell-based immunosuppressive effect. Immunol Invest. 2012;41:214–29. doi:10.3109/08820139.2011.619022. PMID:22017637.
   PubMed Web of Science ®Google Scholar
• Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136:978–89. doi:10.1053/j.gastro.2008.11.041. PMID:19135996.
   PubMed Web of Science ®Google Scholar
• He XW, He XS, Lian L, Wu XJ, Lan P. Systemic infusion of bone marrow-derived mesenchymal stem cells for treatment of experimental colitis in mice. Dig Dis Sci. 2012;57:3136–44. doi:10.1007/s10620-012-2290-5. PMID:22752635.
   PubMed Web of Science ®Google Scholar
• Liang L, Dong C, Chen X, Fang Z, Xu J, Liu M, Zhang X, Gu DS, Wang D, Du W, et al. Human umbilical cord mesenchymal stem cells ameliorate mice trinitrobenzene sulfonic acid (TNBS)-induced colitis. Cell Transplant. 2011;20:1395–408. doi:10.3727/096368910X557245. PMID:21396175.
   PubMed Web of Science ®Google Scholar
• 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;58:929–39. doi:10.1136/gut.2008.168534. PMID:19136511.
   PubMed Web of Science ®Google Scholar
• Devine SM, Cobbs C, Jennings M, Bartholomew A, Hoffman R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood. 2003;101:2999–3001. doi:10.1182/blood-2002-06-1830. PMID:12480709.
   PubMed Web of Science ®Google Scholar
• Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Iijima H, Nakamura T, Eguchi H, Miyoshi E, Hayashi N, et al. Topical implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther. 2008;326:523–31. doi:10.1124/jpet.108.137083. PMID:18448866.
   PubMed Web of Science ®Google Scholar
• Kachgal S, Putnam AJ. Mesenchymal stem cells from adipose and bone marrow promote angiogenesis via distinct cytokine and protease expression mechanisms. Angiogenesis. 2011;14:47–59. doi:10.1007/s10456-010-9194-9. PMID:21104120.
   PubMed Web of Science ®Google Scholar
• Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, Cai T, Chen W, Sun L, Shi S. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell. 2012;10:544–55. doi:10.1016/j.stem.2012.03.007. PMID:22542159.
   PubMed Web of Science ®Google Scholar
• Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, Yamashita K, Yamamoto H, Adachi Y, Sasaki Y, et al. Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol. 2009;218:350–9. doi:10.1002/path.2535. PMID:19291714.
   PubMed Web of Science ®Google Scholar
• Dave M, Mehta K, Luther J, Baruah A, Dietz AB, Faubion WA, Jr. Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. 2015;21:2696–707. doi:10.1097/MIB.0000000000000543. PMID:26230863.
   PubMed Web of Science ®Google Scholar
• Onken J, Gallup D, Hanson J, Pandak M, Custer L. Successful outpatient treatment of refractory Crohn's disease using adult mesenchymal stem cells. Abstract 121. American College of Gastroenterology Conference. Las Vegas, NV, 2006.
   Google Scholar
• Lazebnik LB, Konopliannikov AG, Kniazev OV, Parfenov AI, Tsaregorodtseva TM, Ruchkina IN, Khomeriki SG, Rogozina VA, Konopliannikova OA. [Use of allogeneic mesenchymal stem cells in the treatment of intestinal inflammatory diseases]. Terapevticheskii arkhiv. 2010;82:38–43. PMID:20387674.
   PubMedGoogle Scholar
• Liang J, Zhang H, Wang D, Feng X, Wang H, Hua B, Liu B, Sun L. Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut. 2012;61:468–9. doi:10.1136/gutjnl-2011-300083. PMID:21617158.
   PubMed Web of Science ®Google Scholar
• Forbes GM, Sturm MJ, Leong RW, Sparrow MP, Segarajasingam D, Cummins AG, Phillips M, Herrmann RP. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn's disease refractory to biologic therapy. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12:64–71. doi:10.1016/j.cgh.2013.06.021. PMID:23872668.
   PubMed Web of Science ®Google Scholar
• Knyazev O, Kagramanova A, Churikova A, Konoplyannikov A, Khomeriki S, Parfenov A, Ruchkina I. P575. The use of mesenchymal stromal cells in order to achieve deep (biological) remission of Ulcerative Colitis. Journal of Crohn's and Colitis. 2015;9:S367–S8. doi:10.1093/ecco-jcc/jju027.693..
   PubMed Web of Science ®Google Scholar
• Knyazev O, Fadeeva N, Kagramanova A, Shcherbakov P, Ruchkina I, Parfenov A, Konoplyannikov A. P485. The combined of mesenchymal stem cells and infliximab reduces the recurrence rate of Crohn's disease. Journal of Crohn's and Colitis. 2016;10:S346–S.
   PubMed Web of Science ®Google Scholar
• Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ. Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): A Systematic Review and Meta-Analysis of Clinical Trials. PLOS ONE. 2012;7:e47559. doi:10.1371/journal.pone.0047559. PMID:23133515.
   PubMed Web of Science ®Google Scholar
• Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, Kooy-Winkelaar EM, Koning F, Zwaginga JJ, Fidder HH, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut. 2010;59:1662–9. doi:10.1136/gut.2010.215152. PMID:20921206.
   PubMed Web of Science ®Google Scholar
• Dhere T, Copland I, Garcia M, Chiang KY, Chinnadurai R, Prasad M, Galipeau J, Kugathasan S. The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn's disease – a phase 1 trial with three doses. Aliment Pharmacol Ther. 2016;44:471–81. doi:10.1111/apt.13717. PMID:27385373.
   PubMed Web of Science ®Google Scholar
• Dave M, Jaiswal P, Cominelli F. Mesenchymal stem/stromal cell therapy for inflammatory bowel disease: an updated review with maintenance of remission. Curr Opin Gastroenterol. 2017;33:59–68. doi:10.1097/MOG.0000000000000327. PMID:28134690.
   PubMed Web of Science ®Google Scholar
• Fantini MC, Monteleone G. Update on the Therapeutic Efficacy of Tregs in IBD: Thumbs up or Thumbs down? Inflamm Bowel Dis. 2017;23:1682–8. doi:10.1097/MIB.0000000000001272. PMID:28906289.
   PubMed Web of Science ®Google Scholar
• Elinav E, Waks T, Eshhar Z. Redirection of regulatory T cells with predetermined specificity for the treatment of experimental colitis in mice. Gastroenterology. 2008;134:2014–24. doi:10.1053/j.gastro.2008.02.060. PMID:18424268.
   PubMed Web of Science ®Google Scholar
• Huber S, Schramm C, Lehr HA, Mann A, Schmitt S, Becker C, Protschka M, Galle PR, Neurath MF, Blessing M. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. Journal of immunology (Baltimore, Md : 1950). 2004;173:6526–31. doi:10.4049/jimmunol.173.11.6526. PMID:15557141.
   PubMed Web of Science ®Google Scholar
• Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, Zeitz M, Duchmann R. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology. 2005;128:1868–78. doi:10.1053/j.gastro.2005.03.043. PMID:15940622.
   PubMed Web of Science ®Google Scholar
• Saruta M, Yu QT, Fleshner PR, Mantel PY, Schmidt-Weber CB, Banham AH, Papadakis KA. Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease. Clinical immunology (Orlando, Fla). 2007;125:281–90. doi:10.1016/j.clim.2007.08.003. PMID:17897887.
   PubMed Web of Science ®Google Scholar
• Takahashi M, Nakamura K, Honda K, Kitamura Y, Mizutani T, Araki Y, Kabemura T, Chijiiwa Y, Harada N, Nawata H. An inverse correlation of human peripheral blood regulatory T cell frequency with the disease activity of ulcerative colitis. Dig Dis Sci. 2006;51:677–86. doi:10.1007/s10620-006-3191-2. PMID:16614988.
   PubMed Web of Science ®Google Scholar
• Fantini MC, Rizzo A, Fina D, Caruso R, Sarra M, Stolfi C, Becker C, Macdonald TT, Pallone F, Neurath MF, et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology. 2009;136:1308–16, e1-3. doi:10.1053/j.gastro.2008.12.053. PMID:19192480.
   PubMed Web of Science ®Google Scholar
• Trzonkowski P, Bieniaszewska M, Juscinska J, Dobyszuk A, Krzystyniak A, Marek N, Mysliwska J, Hellmann A. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clinical immunology (Orlando, Fla). 2009;133:22–6. doi:10.1016/j.clim.2009.06.001. PMID:19559653.
   PubMed Web of Science ®Google Scholar
• Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, Wujtewicz MA, Witkowski P, Mlynarski W, Balcerska A, et al. Administration of CD4+CD25highCD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care. 2012;35:1817–20. doi:10.2337/dc12-0038. PMID:22723342.
   PubMed Web of Science ®Google Scholar
• Desreumaux P, Foussat A, Allez M, Beaugerie L, Hebuterne X, Bouhnik Y, Nachury M, Brun V, Bastian H, Belmonte N, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. Gastroenterology. 2012;143:1207–17.e1-2. doi:10.1053/j.gastro.2012.07.116. PMID:22885333.
   PubMed Web of Science ®Google Scholar
• Canavan JB, Scotta C, Vossenkamper A, Goldberg R, Elder MJ, Shoval I, Marks E, Stolarczyk E, Lo JW, Powell N, et al. Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease. Gut. 2016;65:584–94. doi:10.1136/gutjnl-2014-306919. PMID:25715355.
   PubMed Web of Science ®Google Scholar
• Inagaki-Ohara K, Chinen T, Matsuzaki G, Sasaki A, Sakamoto Y, Hiromatsu K, Nakamura-Uchiyama F, Nawa Y, Yoshimura A. Mucosal T cells bearing TCRgammadelta play a protective role in intestinal inflammation. Journal of immunology (Baltimore, Md : 1950). 2004;173:1390–8. doi:10.4049/jimmunol.173.2.1390. PMID:15240735.
   PubMed Web of Science ®Google Scholar
• Hoffmann JC, Pawlowski NN, Grollich K, Loddenkemper C, Zeitz M, Kuhl AA. Gammadelta T lymphocytes: a new type of regulatory T cells suppressing murine 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. Int J Colorectal Dis. 2008;23:909–20.
   PubMed Web of Science ®Google Scholar
• Fisher JP, Heuijerjans J, Yan M, Gustafsson K, Anderson J. gammadelta T cells for cancer immunotherapy: A systematic review of clinical trials. Oncoimmunology. 2014;3:e27572. doi:10.4161/onci.27572. PMID:24734216.
   PubMed Web of Science ®Google Scholar
• Gallo A, Passaro G, Gasbarrini A, Landolfi R, Montalto M. Modulation of microbiota as treatment for intestinal inflammatory disorders: An uptodate. World J Gastroenterol. 2016;22:7186–202. doi:10.3748/wjg.v22.i32.7186. PMID:27621567.
   PubMed Web of Science ®Google Scholar
• Narula N, Kassam Z, Yuan Y, Colombel JF, Ponsioen C, Reinisch W, Moayyedi P. Systematic Review and Meta-analysis: Fecal Microbiota Transplantation for Treatment of Active Ulcerative Colitis. Inflamm Bowel Dis. 2017;23:1702–9. doi:10.1097/MIB.0000000000001228. PMID:28906291.
   PubMed Web of Science ®Google Scholar
• Arnold GL, Beaves MR, Pryjdun VO, Mook WJ. Preliminary study of ciprofloxacin in active Crohn's disease. Inflamm Bowel Dis. 2002;8:10–5. doi:10.1097/00054725-200201000-00002. PMID:11837933.
   PubMed Web of Science ®Google Scholar
• Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, Summers R, Mekhjian H, Greenberger N, Kelly M, et al. Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut 1991;32:1071–5. doi:10.1136/gut.32.9.1071. PMID:1916494.
   PubMed Web of Science ®Google Scholar
• Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, Luzi C. An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996;91:328–32. PMID:8607501.
   PubMed Web of Science ®Google Scholar
• Prantera C, Lochs H, Grimaldi M, Danese S, Scribano ML, Gionchetti P. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn's disease. Gastroenterology. 2012;142:473–81.e4. doi:10.1053/j.gastro.2011.11.032. PMID:22155172.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Elliott DE, Weinstock J, Summers RW, Landry-Wheeler A, Silver N, Harnett MD, Hanauer SB. Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease. Aliment Pharmacol Ther. 2013;38:255–63. doi:10.1111/apt.12366. PMID:23730956.
   PubMed Web of Science ®Google Scholar
• Weinstock JV. Helminths and mucosal immune modulation. Ann N Y Acad Sci. 2006;1072:356–64. doi:10.1196/annals.1326.033. PMID:17057216.
   PubMed Web of Science ®Google Scholar
• Wong C, Harris PJ, Ferguson LR. Potential Benefits of Dietary Fibre Intervention in Inflammatory Bowel Disease. Int J Mol Sci. 2016;17:919. doi:10.3390/ijms17060919..
   Web of Science ®Google Scholar
• Nie Y, Lin Q, Luo F. Effects of Non-Starch Polysaccharides on Inflammatory Bowel Disease. Int J Mol Sci. 2017;18:1372. doi:10.3390/ijms18071372.
   Web of Science ®Google Scholar
• Mitsuyama K, Saiki T, Kanauchi O, Iwanaga T, Tomiyasu N, Nishiyama T, Tateishi H, Shirachi A, Ide M, Suzuki A, et al. Treatment of ulcerative colitis with germinated barley foodstuff feeding: a pilot study. Aliment Pharmacol Ther. 1998;12:1225–30. doi:10.1046/j.1365-2036.1998.00432.x. PMID:9882030.
   PubMed Web of Science ®Google Scholar
• Karner M, Kocjan A, Stein J, Schreiber S, von Boyen G, Uebel P, Schmidt C, Kupcinskas L, Dina I, Zuelch F, et al. First multicenter study of modified release phosphatidylcholine “LT-02” in ulcerative colitis: a randomized, placebo-controlled trial in mesalazine-refractory courses. Am J Gastroenterol. 2014;109:1041–51. doi:10.1038/ajg.2014.104. PMID:24796768.
   PubMed Web of Science ®Google Scholar
• Langhorst J, Wulfert H, Lauche R, Klose P, Cramer H, Dobos GJ, Korzenik J. Systematic review of complementary and alternative medicine treatments in inflammatory bowel diseases. Journal of Crohn's & colitis. 2015;9:86–106. doi:10.1093/ecco-jcc/jju007.
   PubMed Web of Science ®Google Scholar