Cytokine therapies in Crohn's disease: Where are we now and where should we go?

Inflammation and Allergy - Drug Targets

Volumn 10, Issue 1, 2011, Pages 47-53

  Caprioli, Flavio ^a   Pallone, Francesco ^b   Monteleone, Giovanni ^b  

^a FONDAZIONE IRCCS CA GRANDA OSPEDALE MAGGIORE POLICLINICO   (Italy)

^b UNIVERSITY OF ROME TOR VERGATA   (Italy)

Author keywords

Anti IL 12; Anti IL 6R; Anti TNF; Crohn's disease; Cytokines; IBD

Indexed keywords

ADALIMUMAB; ANTIINFLAMMATORY AGENT; APILIMOD; BRIAKINUMAB; CERTOLIZUMAB PEGOL; CYTOKINE; FONTOLIZUMAB; GAMMA INTERFERON ANTIBODY; INFLIXIMAB; INTERLEUKIN 12; INTERLEUKIN 23; INTERLEUKIN 6; MERCAPTOPURINE; METHOTREXATE; TOCILIZUMAB; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA ANTAGONIST; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; UNCLASSIFIED DRUG; USTEKINUMAB;

ARTICLE; CROHN DISEASE; DRUG MECHANISM; ENTERITIS; ENTEROCUTANEOUS FISTULA; HUMAN; IMMUNOPATHOLOGY; IMMUNOSUPPRESSIVE TREATMENT; INJECTION SITE REACTION; NONHUMAN; RHEUMATOID ARTHRITIS;

EID: 79551619827     PISSN: 18715281     EISSN: None     Source Type: Journal    
DOI: 10.2174/187152811794352051     Document Type: Article

References (75)

1. Travis, S. P.; Stange, E. F.; Lemann, M.; Oresland, T.; Chowers, Y.; Forbes, A.; D'Haens, G.; Kitis, G.; Cortot, A.; Prantera, C.; Marteau, P.; Colombel, J. F.; Gionchetti, P.; Bouhnik, Y.; Tiret, E.; Kroesen, J.; Starlinger, M.; Mortensen, N. J. European evidence based consensus on the diagnosis and management of Crohn's disease: current management, Gut, 2006, 55(Suppl 1), i16-35.
2. Strober, W.; Fuss, I.; Mannon, P. The fundamental basis of inflammatory bowel disease, J. Clin. Invest., 2007, 117, 514-521.
3. 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.
4. Bazzoni, F.; Beutler, B. The tumor necrosis factor ligand and receptor families, N. Engl. J. Med., 1996, 334, 1717-1725.
5. Okuno, T.; Andoh, A.; Bamba, S.; Araki, Y.; Fujiyama, Y.; Fujiyama, M.; Bamba, T. Interleukin-1beta and tumor necrosis factor-alpha induce chemokine and matrix metalloproteinase gene expression in human colonic subepithelial myofibroblasts. Scand. J. Gastroenterol., 2002, 37, 317-324.
6. MacDonald, T. T.; Hutchings, P.; Choy, M. Y.; Murch, S.; Cooke, A. Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin. Exp. Immunol., 1990, 81, 301-305.
7. Rugtveit, J.; Nilsen, E. M.; Bakka, A.; Carlsen, H.; Brandtzaeg, P.; Scott, H. Cytokine profiles differ in newly recruited and resident subsets of mucosal macrophages from inflammatory bowel disease. Gastroenterology, 1997, 112, 1493-1505.
8. Powrie, F.; Leach, M. W.; Mauze, S.; Menon, S.; Caddle, L. B.; Coffman, R. L. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity, 1994, 1, 553-562.
9. Elliott, M. J.; Maini, R. N.; Feldmann, M.; Long-Fox, A.; Charles, P.; Katsikis, P.; Brennan, F. M.; Walker, J.; Bijl, H.; Ghrayeb, J. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum., 1993, 36, 1681-1690.
10. van Dullemen, H. M.; van Deventer, S. J.; Hommes, D. W.; Bijl, H. A.; Jansen, J.; Tytgat, G. N.; Woody, J. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology, 1995, 109, 129-135.
11. Targan, S. R.; Hanauer, S. B.; van Deventer, S. J.; Mayer, L.; Present, D. H.; Braakman, T.; DeWoody, K. L.; Schaible, T. F.; Rutgeerts, P. J. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N. Engl. J. Med., 1997, 337, 1029-1035.
12. Hanauer, S. B.; Feagan, B. G.; Lichtenstein, G. R.; Mayer, L. F.; Schreiber, S.; Colombel, J. F.; Rachmilewitz, D.; Wolf, D. C.; Olson, A.; Bao, W.; Rutgeerts, P. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet, 2002, 359, 1541-1549.
13. Present, D. H.; Rutgeerts, P.; Targan, S.; Hanauer, S. B.; Mayer, L.; van Hogezand, R. A.; Podolsky, D. K.; Sands, B. E.; Braakman, T.; DeWoody, K. L.; Schaible, T. F.; van Deventer, S. J. Infliximab for the treatment of fistulas in patients with Crohn's disease. N. Engl. J. Med., 1999, 340, 1398-1405.
14. Sands, B. E.; Anderson, F. H.; Bernstein, C. N.; Chey, W. Y.; Feagan, B. G.; Fedorak, R. N.; Kamm, M. A.; Korzenik, J. R.; Lashner, B. A.; Onken, J. E.; Rachmilewitz, D.; Rutgeerts, P.; Wild, G.; Wolf, D. C.; Marsters, P. A.; Travers, S. B.; Blank, M. A.; van Deventer, S. J. Infliximab maintenance therapy for fistulizing Crohn's disease. N. Engl. J. Med., 2004, 350, 876-885.
15. Baert, F.; Noman, M.; Vermeire, S.; Van Assche, G.; G, D. H.; Carbonez, A.; Rutgeerts, P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N. Engl. J. Med., 2003, 348, 601-608.
16. Colombel, J. F.; Sandborn, W. J.; Reinisch, W.; Mantzaris, G. J.; Kornbluth, A.; Rachmilewitz, D.; Lichtiger, S.; D'Haens, G.; Diamond, R. H.; Broussard, D. L.; Tang, K. L.; van der Woude, C. J.; Rutgeerts, P. Infliximab, azathioprine, or combination therapy for Crohn's disease. N. Engl. J. Med., 2010, 362, 1383-1395.
17. Sandborn, W. J.; Feagan, B. G.; Fedorak, R. N.; Scherl, E.; Fleisher, M. R.; Katz, S.; Johanns, J.; Blank, M.; Rutgeerts, P. 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.
18. Regueiro, M.; Schraut, W.; Baidoo, L.; Kip, K. E.; Sepulveda, A. R.; Pesci, M.; Harrison, J.; Plevy, S. E. Infliximab prevents Crohn's disease recurrence after ileal resection. Gastroenterology, 2009, 136, 441-450 e1; quiz 716.
19. Blonski, W.; Lichtenstein, G. R. Safety of biologic therapy, Inflamm. Bowel. Dis., 2007, 13, 769-796.
20. Wollina, U.; Hansel, G.; Koch, A.; Schonlebe, J.; Kostler, E.; Haroske, G. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients. Am. J. Clin. Dermatol., 2008, 9, 1-14.
21. Collamer, A. N.; Guerrero, K. T.; Henning, J. S.; Battafarano, D. F. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: a literature review and potential mechanisms of action. Arthritis Rheum., 2008, 59, 996-1001.
22. Nestle, F. O.; Conrad, C.; Tun-Kyi, A.; Homey, B.; Gombert, M.; Boyman, O.; Burg, G.; Liu, Y. J.; Gilliet, M. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J. Exp. Med., 2005, 202, 135-143.
23. Farkas, L.; Beiske, K.; Lund-Johansen, F.; Brandtzaeg, P.; Jahnsen, F. L. Plasmacytoid dendritic cells (natural interferon-alpha/betaproducing cells) accumulate in cutaneous lupus erythematosus lesions. Am. J. Pathol., 2001, 159, 237-243.
24. Palucka, A. K.; Blanck, J. P.; Bennett, L.; Pascual, V.; Banchereau, J. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc. Natl. Acad. Sci. USA., 2005, 102, 3372-3377.
25. Aeberli, D.; Seitz, M.; Juni, P.; Villiger, P. M. Increase of peripheral CXCR3 positive T lymphocytes upon treatment of RA patients with TNF-alpha inhibitors. Rheumatology (Oxford), 2005, 44, 172-175.
26. ten Hove, T.; van Montfrans, C.; Peppelenbosch, M. P.; van Deventer, S. J. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease, Gut, 2002, 50, 206-211.
27. Scallon, B. J.; Moore, M. A.; Trinh, H.; Knight, D. M.; Ghrayeb, J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine, 1995, 7, 251-259.
28. Di Sabatino, A.; Ciccocioppo, R.; Cinque, B.; Millimaggi, D.; Morera, R.; Ricevuti, L.; Cifone, M. G.; Corazza, G. R. Defective mucosal T cell death is sustainably reverted by infliximab in a caspase dependent pathway in Crohn's disease. Gut, 2004, 53, 70-77.
29. Lugering, A.; Schmidt, M.; Lugering, N.; Pauels, H. G.; Domschke, W.; Kucharzik, T. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology, 2001, 121, 1145-1157.
30. Mitoma, H.; Horiuchi, T.; Hatta, N.; Tsukamoto, H.; Harashima, S.; Kikuchi, Y.; Otsuka, J.; Okamura, S.; Fujita, S.; Harada, M. Infliximab induces potent anti-inflammatory responses by outsideto-inside signals through transmembrane TNF-alpha. Gastroenterology, 2005, 128, 376-392.
31. Di Sabatino, A.; Pender, S. L.; Jackson, C. L.; Prothero, J. D.; Gordon, J. N.; Picariello, L.; Rovedatti, L.; Docena, G.; Monteleone, G.; Rampton, D. S.; Tonelli, F.; Corazza, G. R.; MacDonald, T. T. Functional modulation of Crohn's disease myofibroblasts by anti-tumor necrosis factor antibodies. Gastroenterology, 2007, 133, 137-149.
32. Anderson, P. J. Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin. Arthritis Rheum., 2005, 34, 19-22.
33. Colombel, J. F.; Sandborn, W. J.; Rutgeerts, P.; Enns, R.; Hanauer, S. B.; Panaccione, R.; Schreiber, S.; Byczkowski, D.; Li, J.; Kent, J. D.; Pollack, P. F. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology, 2007, 132, 52-65.
34. Sandborn, W. J.; Rutgeerts, P.; Enns, R.; Hanauer, S. B.; Colombel, J. F.; Panaccione, R.; D'Haens, G.; Li, J.; Rosenfeld, M. R.; Kent, J. D.; Pollack, P. F. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann. Intern. Med., 2007, 146, 829-838.
35. Schreiber, S.; Rutgeerts, P.; Fedorak, R. N.; Khaliq-Kareemi, M.; Kamm, M. A.; Boivin, M.; Bernstein, C. N.; Staun, M.; Thomsen, O. O.; Innes, A. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology, 2005, 129, 807-818.
36. Huang, S.; Hendriks, W.; Althage, A.; Hemmi, S.; Bluethmann, H.; Kamijo, R.; Vilcek, J.; Zinkernagel, R. M.; Aguet, M. Immune response in mice that lack the interferon-gamma receptor. Science, 1993, 259, 1742-1745.
37. Harvat, B. L.; Jetten, A. M. Gamma-interferon induces an irreversible growth arrest in mid-G1 in mammary epithelial cells which correlates with a block in hyperphosphorylation of retinoblastoma. Cell Growth Differ., 1996, 7, 289-300.
38. Decker, T.; Stockinger, S.; Karaghiosoff, M.; Muller, M.; Kovarik, P. IFNs and STATs in innate immunity to microorganisms. J. Clin. Invest., 2002, 109, 1271-1277.
39. Mach, B.; Steimle, V.; Martinez-Soria, E.; Reith, W. Regulation of MHC class II genes: lessons from a disease. Annu. Rev. Immunol., 1996, 14, 301-331.
40. Schroder, K.; Hertzog, P. J.; Ravasi, T.; Hume, D. A. Interferongamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol., 2004, 75, 163-189.
41. Lighvani, A. A.; Frucht, D. M.; Jankovic, D.; Yamane, H.; Aliberti, J.; Hissong, B. D.; Nguyen, B. V.; Gadina, M.; Sher, A.; Paul, W. E.; O'Shea, J. J. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc. Natl. Acad. Sci. USA., 2001, 98, 15137-15142.
42. Fuss, I. J.; Neurath, M.; Boirivant, M.; Klein, J. S.; de la Motte, C.; Strong, S. A.; Fiocchi, C.; Strober, W. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol., 1996, 157, 1261-1270.
43. Ito, H.; Fathman, C. G. CD45RBhigh CD4+ T cells from IFNgamma knockout mice do not induce wasting disease. J. Autoimmun., 1997, 10, 455-459.
44. Reinisch, W.; Hommes, D. W.; Van Assche, G.; Colombel, J. F.; Gendre, J. P.; Oldenburg, B.; Teml, A.; Geboes, K.; Ding, H.; Zhang, L.; Tang, M.; Cheng, M.; van Deventer, S. J.; Rutgeerts, P.; Pearce, T. 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.
45. Reinisch, W.; de Villiers, W.; Bene, L.; Simon, L.; Racz, I.; Katz, S.; Altorjay, I.; Feagan, B.; Riff, D.; Bernstein, C. N.; Hommes, D.; Rutgeerts, P.; Cortot, A.; Gaspari, M.; Cheng, M.; Pearce, T.; Sands, B. E. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multipledose study. Inflamm. Bowel Dis., 2010, 16, 233-242.
46. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol., 2003, 3, 133-146.
47. Cooper, A. M.; Khader, S. A. IL-12p40: an inherently agonistic cytokine. Trends. Immunol., 2007, 28, 33-38.
48. Oppmann, B.; Lesley, R.; Blom, B.; Timans, J. C.; Xu, Y.; Hunte, B.; Vega, F.; Yu, N.; Wang, J.; Singh, K.; Zonin, F.; Vaisberg, E.; Churakova, T.; Liu, M.; Gorman, D.; Wagner, J.; Zurawski, S.; Liu, Y.; Abrams, J. S.; Moore, K. W.; Rennick, D.; de Waal-Malefyt, R.; Hannum, C.; Bazan, J. F.; Kastelein, R. A. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, 2000, 13, 715-725.
49. Goriely, S.; Neurath, M. F.; Goldman, M. How microorganisms tip the balance between interleukin-12 family members. Nat. Rev. Immunol., 2008, 8, 81-86.
50. Stritesky, G. L.; Yeh, N.; Kaplan, M. H. IL-23 promotes maintenance but not commitment to the Th17 lineage. J. Immunol., 2008, 181, 5948-5955.
51. Kobayashi, T.; Okamoto, S.; Hisamatsu, T.; Kamada, N.; Chinen, H.; Saito, R.; Kitazume, M. T.; 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.
52. Monteleone, G.; Biancone, L.; Marasco, R.; Morrone, G.; Marasco, O.; Luzza, F.; Pallone, F. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology, 1997, 112, 1169-1178.
53. Schmidt, C.; Giese, T.; Ludwig, B.; Mueller-Molaian, I.; Marth, T.; Zeuzem, S.; Meuer, S. C.; Stallmach, A. Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm. Bowel Dis., 2005, 11, 16-23.
54. Neurath, M. F.; Fuss, I.; Kelsall, B. L.; Stuber, E.; Strober, W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med., 1995, 182, 1281-1290.
55. Yen, D.; Cheung, J.; Scheerens, H.; Poulet, F.; McClanahan, T.; McKenzie, B.; Kleinschek, M. A.; Owyang, A.; Mattson, J.; Blumenschein, W.; Murphy, E.; Sathe, M.; Cua, D. J.; Kastelein, R. A.; Rennick, D. 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.
56. Becker, C.; Dornhoff, H.; Neufert, C.; Fantini, M. C.; Wirtz, S.; Huebner, S.; Nikolaev, A.; Lehr, H. A.; Murphy, A. J.; Valenzuela, D. M.; Yancopoulos, G. D.; Galle, P. R.; Karow, M.; Neurath, M. F. Cutting edge: IL-23 cross-regulates IL-12 production in T celldependent experimental colitis. J. Immunol., 2006, 177, 2760-2764.
57. Hue, S.; Ahern, P.; Buonocore, S.; Kullberg, M. C.; Cua, D. J.; McKenzie, B. S.; Powrie, F.; Maloy, K. J. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med., 2006, 203, 2473-2483.
58. Fuss, I. J.; Becker, C.; Yang, Z.; Groden, C.; Hornung, R. L.; Heller, F.; Neurath, M. F.; Strober, W.; Mannon, P. J. 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.
59. Billich, A. Drug evaluation: apilimod, an oral IL-12/IL-23 inhibitor for the treatment of autoimmune diseases and common variable immunodeficiency. IDrugs, 2007, 10, 53-59.
60. Wada, Y.; Lu, R.; Zhou, D.; Chu, J.; Przewloka, T.; Zhang, S.; Li, L.; Wu, Y.; Qin, J.; Balasubramanyam, V.; Barsoum, J.; Ono, M. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor. Blood, 2007, 109, 1156-1164.
61. Sands, B. E.; Jacobson, E. W.; Sylwestrowicz, T.; Younes, Z.; Dryden, G.; Fedorak, R.; Greenbloom, S. Randomized, doubleblind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn's disease. Inflamm. Bowel Dis., 2010, 16, 1209-1218.
62. Nishimoto, N.; Kishimoto, T. Interleukin 6: from bench to bedside. Nat. Clin. Pract. Rheumatol., 2006, 2, 619-626.
63. Zhou, L.; Ivanov, II; Spolski, R.; Min, R.; Shenderov, K.; Egawa, T.; Levy, D. E.; Leonard, W. J.; Littman, D. R. 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.
64. Mudter, J.; Neurath, M. F. Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm. Bowel Dis., 2007, 13, 1016-1023.
65. Mitsuyama, K.; Sasaki, E.; Toyonaga, A.; Ikeda, H.; Tsuruta, O.; Irie, A.; Arima, N.; Oriishi, T.; Harada, K.; Fujisaki, K.; et al. Colonic mucosal interleukin-6 in inflammatory bowel disease. Digestion, 1991, 50, 104-111.
66. Naito, Y.; Takagi, T.; Uchiyama, K.; Kuroda, M.; Kokura, S.; Ichikawa, H.; Yanagisawa, R.; Inoue, K.; Takano, H.; Satoh, M.; Yoshida, N.; Okanoue, T.; Yoshikawa, T. Reduced intestinal inflammation induced by dextran sodium sulfate in interleukin-6-deficient mice. Int. J. Mol. Med., 2004, 14, 191-196.
67. Ito, H.; Hirotani, T.; Yamamoto, M.; Ogawa, H.; Kishimoto, T. Anti-IL-6 receptor monoclonal antibody inhibits leukocyte recruitment and promotes T-cell apoptosis in a murine model of Crohn's disease. J. Gastroenterol., 2002, 37(Suppl 14), 56-61.
68. Ito, H.; Takazoe, M.; Fukuda, Y.; Hibi, T.; Kusugami, K.; Andoh, A.; Matsumoto, T.; Yamamura, T.; Azuma, J.; Nishimoto, N.; Yoshizaki, K.; Shimoyama, T.; Kishimoto, T. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology, 2004, 126, 989-996; discussion 947.
69. Maloy, K. J.; Kullberg, M. C. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol., 2008, 1, 339-349.
70. Fina, D.; Sarra, M.; Fantini, M. C.; Rizzo, A.; Caruso, R.; Caprioli, F.; Stolfi, C.; Cardolini, I.; Dottori, M.; Boirivant, M.; Pallone, F.; Macdonald, T. T.; Monteleone, G. Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology, 2008, 134, 1038-1048.
71. Monteleone, G.; Monteleone, I.; Fina, D.; Vavassori, P.; Del Vecchio Blanco, G.; Caruso, R.; Tersigni, R.; Alessandroni, L.; Biancone, L.; Naccari, G. C.; MacDonald, T. T.; Pallone, F. Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. Gastroenterology, 2005, 128, 687-694.
72. Fridman, J. S.; Scherle, P. A.; Collins, R.; Burn, T. C.; Li, Y.; Li, J.; Covington, M. B.; Thomas, B.; Collier, P.; Favata, M. F.; Wen, X.; Shi, J.; McGee, R.; Haley, P. J.; Shepard, S.; Rodgers, J. D.; Yeleswaram, S.; Hollis, G.; Newton, R. C.; Metcalf, B.; Friedman, S. M.; Vaddi, K. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J. Immunol., 184, 5298-5307.
73. Nowell, M. A.; Williams, A. S.; Carty, S. A.; Scheller, J.; Hayes, A. J.; Jones, G. W.; Richards, P. J.; Slinn, S.; Ernst, M.; Jenkins, B. J.; Topley, N.; Rose-John, S.; Jones, S. A. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J. Immunol., 2009, 182, 613-622.
74. Murase, A.; Okumura, T.; Sakakibara, A.; Tonai-Kachi, H.; Nakao, K.; Takada, J. Effect of prostanoid EP4 receptor antagonist, CJ-042,794, in rat models of pain and inflammation. Eur. J. Pharmacol., 2008, 580, 116-21.
75. Kay, J.; Matteson, E. L.; Dasgupta, B.; Nash, P.; Durez, P.; Hall, S.; Hsia, E. C.; Han, J.; Wagner, C.; Xu, Z.; Visvanathan, S.; Rahman, M. U. Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum., 2008, 58, 964-975.