Emerging biologic therapies in inflammatory bowel disease

Reviews in Gastroenterological Disorders

Volumn 4, Issue 2, 2004, Pages 66-85

  Lim, Wee Chian ^a   Hanuer, Stephen B ^a  

^a UNIVERSITY OF CHICAGO MEDICAL CENTER   (United States)

Author keywords

Anti TNF; Biologic therapy; Crohn's disease; Inflammatory bowel disease; Ulcerative colitis

Indexed keywords

ADALIMUMAB; ADENOVIRUS VECTOR; ALICAFORSEN; ALPHA INTERFERON; ALPHA2A INTERFERON; ALPHA2B INTERFERON; AZATHIOPRINE; BASILIXIMAB; BETA INTERFERON; CD40 LIGAND MONOCLONAL ANTIBODY; CERTOLIZUMAB PEGOL; CORTICOSTEROID; ETANERCEPT; GAMMA INTERFERON ANTIBODY; GELATIN; INFLIXIMAB; INTEGRIN; INTERLEUKIN 12 ANTIBODY; INTERLEUKIN 8 ANTIBODY; MLN 02; MONOCLONAL ANTIBODY IDEC 131; NATALIZUMAB; OKT 4; ONERCEPT; PLACEBO; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; RECOMBINANT GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; RECOMBINANT INTERLEUKIN 10; RECOMBINANT INTERLEUKIN 11; REPIFERMIN; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; UNINDEXED DRUG; VISILIZUMAB; GASTROINTESTINAL AGENT; MONOCLONAL ANTIBODY;

ACUTE GRAFT REJECTION; BIOLOGICAL THERAPY; CLINICAL TRIAL; CROHN DISEASE; DISEASE PREDISPOSITION; DRUG ABSORPTION; DRUG APPROVAL; ENTERITIS; HEREDITY; HUMAN; IMMUNE RESPONSE; IMMUNOPATHOGENESIS; IMMUNOREGULATION; LYMPHOCYTOPENIA; MEDICAL RESEARCH; NONHUMAN; REVIEW; THROMBOEMBOLISM; ULCERATIVE COLITIS; VIRUS INFECTION; VIRUS REACTIVATION; COMPARATIVE STUDY; CONTROLLED CLINICAL TRIAL; FEMALE; FORECASTING; HOSPITALIZATION; MALE; PROGNOSIS; RANDOMIZED CONTROLLED TRIAL; STANDARD; TREATMENT OUTCOME;

ANTIBODIES, MONOCLONAL; BIOLOGICAL THERAPY; COLITIS, ULCERATIVE; CROHN DISEASE; FEMALE; FORECASTING; GASTROINTESTINAL AGENTS; HUMANS; INFLAMMATORY BOWEL DISEASES; MALE; PROGNOSIS; RANDOMIZED CONTROLLED TRIALS; SEVERITY OF ILLNESS INDEX; TREATMENT OUTCOME;

EID: 2942638009     PISSN: 1533001X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (201)

1. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2001;347:417-429.
2. Hanauer SB, Present DH. The state of the art in the management of inflammatory bowel disease. Rep Gastroenterol Disord. 2003;3:81-92.
3. Hanauer SB, Sandborn W; Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol. 2001;96:635-643.
4. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 1997;97:204-211.
5. Stein RB, Hanauer SB. Medical therapy for inflammatory bowel disease. Gastroenterol Clin North Am. 1999;28:297-321.
6. Sandborn WJ, Feagan BG. Review article: mild to moderate Crohn's disease-defining the basis for a new treatment algorithm. Aliment Pharmacol Ther. 2003;18:263-277.
7. Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn's disease : a meta-analysis adjusted for confounding variables. Gastroenterology. 1997; 113:1465-1473.
8. Lochs H, Mayer M, Fleig WE, et al. Prophylaxis of postoperative relapse in Crohn's disease with mesalamine: European Cooperative Crohn's Disease Study VI. Gastroenterology. 2000; 118:264-273.
9. Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology. 2001;123:255-260.
10. Ardizzone S, Molteni P, Imbesi V, et al. Azathioprine in steroid-resistant and steroid-dependent ulcerative colitis. J Clin Gastroenterol. 1997;26:330-333.
11. Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med. 1995;123:132-142.
12. Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine for maintaining remission of Crohn's disease. Cochrane Database Syst Rev. 2000;(2):CD000067.
13. D'Haens G, Lemmens L, Geboes K, et al. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology. 2001;120:1323-1329.
14. Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111:641-649.
15. Bayless TM, Hanauer SB. Adpanced Therapy of Inflammatory Bowel Disease. Hamilton, Ontario, Canada: B.C. Decker.;2001:670.
16. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med. 1995;332:292-297.
17. Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. N Engl J Med. 2000;342: 1627-1632.
18. Laroux FS, Pavlick KP, Wolf RE, Grisham MB. Dysregulation of intestinal mucosal immunity: implications in inflammatory bowel disease. News Physiol Sci. 2001;16:272-277.
19. Rath HC, Schultz M, Freitag R, et al. Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice. Infect Immun. 2001;69:2277-2285.
20. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411:599-603.
21. Bonen DK, Cho JH. The genetics of inflammatory bowel disease. Gastroenterology. 2003; 124:521-536.
22. Plevy S. The immunology of inflammatory bowel disease. Gastroenterol Clin North Am. 2002;31:77-92.
23. Goke M, Podolsky DK. Regulation of the mucosal epithelial barrier. Baillieres Clin Gastroenterol. 1996;10:393-405.
24. Strober W, Ludviksson BR, Fuss IJ. The pathogenesis of mucosal inflammation in murine models of inflammatory bowel disease and Crohn disease. Ann Intern Med. 1998; 128:848-856.
25. Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157:1261-1270.
26. Strober W, Ludviksson BR, Fuss IJ. The pathogenesis of mucosal inflammation in routine models of inflammatory bowel disease and Crohn disease. Ann Intern Med. 1998; 128:848-856.
27. Monteleone G, Trapasso F, Parrello T, et al. Bioactive IL-18 expression is up-regulated in Crohn's disease. J Immunol. 1999;163:143-147.
28. Pizarro TT, Michie MH, Bentz M, et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. J Immunol. 1999;162:6829-6835.
29. Halstensen TS, Das KM, Brandtzaeg P. Epithelial deposits of immunoglobulin G1 and activated complement colocalise with the M(r) 40 kD putative autoantigen in ulcerative colitis. Gut. 1993;34:650-657.
30. Marotta PJ, LaRusso NF, Wiesner RH. Sclerosing cholangitis. Baillieres Clin Gastroenterol. 1997; 11:781-800.
31. Saxon A, Shanahan F, Landers C, et al. A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease. J Allergy Clin Immunol. 1990;86:202-210.
32. Das KM, Dasgupta A, Mandal A, Geng X. Autoimmunity to cytoskeletal protein tropomyosin. A clue to the pathogenetic mechanism for ulcerative colitis. J Immunol. 1993; 150:2487-2493.
33. Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science. 1996;272:60-66.
34. Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol. 1993;94:174-181.
35. Reimund JM, Wittersheim C, Dumont S, et al. Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn's disease. J Clin Immunol. 1996;16:144-150.
36. Neurath ME, Fuss I, Pasparakis M, et al. Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice. Eur J Immunol. 1997;27:1743-1750.
37. Braegger CP, Nicholls S, Murch SH, et al. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet. 1992;339:89-91.
38. Targan SR, Hanauer SB, van Deventer SJ, et al. 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.
39. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359:1541-1549.
40. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999;340:1398-1405.
41. Sandborn WJ, Hanauer SB. Infliximab in the treatment of Crohn's disease: a user's guide for clinicians. Am J Gastroenterol. 2002;97: 2962-2972.
42. Sands B, Van Deventer S, Bernstein C, et al. Long-term treatment of fistulizing Crohn's disease: response to Infliximab in the ACCENT II trial through 54 weeks [abstract]. Gastroenterology. 2002;122:A81.
43. Centocor, Inc. FDA approves Remicade (Infliximab) for long-term use in fistulizing Crohn's patients using 8-week maintenance dosing. Available at: http://www.remicade-crohns.com/contact/highlights_c.jsp;accessed March 22, 2004.
44. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis. 1999; 5:119-133.
45. Sandborn WJ. Optimizing anti-tumor necrosis factor strategies in inflammatory bowel disease. Curr Gastroenterol Rep. 2003;5:501-505.
46. Stack WA, Mann SD, Roy AJ, et al. Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn's disease. Lancet. 1997;349:521-524.
47. Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human antibody to TNF (CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial. Gastroenterology. 2001;120:1330-1338.
48. Feagan BG, Sandborn WJ, Baker J, et al. A randomized, double-blind, placebo-controlled, multi-center trial of the engineered human antibody to TNF (CDP571) for steroid sparing and maintenance of remission in patients with steroid dependent Crohn's disease [abstract]. Gastroenterology. 2000;118:A655.
49. Sandborn W, Feagan B, Radford-Smith G, et al. Randomized, placebo-controlled trial of CDP571, a humanized monoclonal antibody to TNF-a, in patients with moderate to severe Crohn's disease [abstract]. Gastroenterology. 2003;124:A61.
50. Hanauer S, Present D, Targan SR, et al. CDP571, a humanized monoclonal antibody to TNF-a, is well tolerated in Crohn's disease patients with previous hypersensitivity to Infliximab [abstract]. Gastroenterology. 2003;124:A517.
51. Novis. Celltech books long run at Lonza facility. Available at: http://www.inpharma.com/news/news-NG.asp?id=26643. Accessed March 22, 2004.
52. Schreiber S, Rutgeerts P, Fedorak R, et al. CDP870, a humanized anti-TNF antibody fragment, induces clinical response with remission in patients with active Crohn's disease (CD) [abstract]. The CDP870 Crohn's Disease Study Group. Gastroenterology. 2003;124:A61.
53. Schreiber S, Rutgeerts P, Innes A, et al. CDP870, a pegylated humanized anti-TNF antibody fragment, offers particular benefit to Crohn's disease patients with elevated C-reactive protein [abstract]. Am J Gastroenterol. 2003; 98:S245.
54. Winter T, Wright J, Ghosh S, et al. Intravenous CDP870, a humanized Anti-TNF antibody fragment, in patients with active Crohn's disease-an exploratory study [abstract]. Gastroenterology. 2003;124:A377.
55. Schreiber S, Winter T, Innes A, et al. Safety of CDP870, a pegylated humanized anti-TNF antibody fragment in Crohn's disease [abstract]. The CDP870 Crohn's Disease Study Group. Am J Gastroenterol. 2003;98:S246.
56. D'Haens G, Swijsen C, Noman M, et al. Etanercept in the treatment of active refractory Crohn's disease: a single-center pilot trial. Am J Gastroenterol. 2001;96:2564-2568.
57. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2001;121:1088-1094.
58. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology. 2003;124:1774-1785.
59. Rutgeerts P, Lemmens L, Van Assche G, et al. Treatment of active Crohn's disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomized, open-label, pilot study. Aliment Pharmacol Ther. 2003;17:185-192.
60. Lorenz HM. Technology evaluation: adalimumab, Abbott laboratories. Curr Opin Mol Ther. 2002;4:185-190.
61. Kishimoto T. The biology of interleukin-6. Blood. 1980;74:1-10.
62. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993; 54:1-78.
63. Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol. 2000;164:4878-4882.
64. Atreya R, Mudter J, Finotto S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat Med. 2000;6:583-588.
65. Ito H, Takazoe M, Fukuda Y, et al. Effective treatment of active Crohn's disease with humanized monoclonal antibody MRA to interleukin-6 receptor: a randomized placebo-controlled trial [abstract]. Gastroenterology. 2003; 124:A25.
66. Fiorentino DF, Bond AM, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989;170:2081-2095.
67. Kucharzik T, Stoll R, Lugering N, Domschke W. Circulating antiinflammatory cytokine IL-10 in patients with inflammatory bowel disease (IBD). Clin Exp Immunol. 1995;100:452-456.
68. Kuhn R, Lohler J, Rennick D, et al. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263-274.
69. Rennick DM, Fort MM. Lessons from genetically engineered animal models. XII. IL-10-deficient (IL-10(-/-) mice and intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2000;278:G829-GB33.
70. van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group. Gastroenterology. 1997;113:383-389.
71. Fedorak RN, Gangl A, Elson CO, et al. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology. 2000;119:1473-1482.
72. Schreiber S, Fedorak RN, Nielsen OH, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group. Gastroenterology. 2000;119:1461-1472.
73. Fedorak R, Nielsen O, Williams N, et al. Human recombinant interleukin-10 is safe and well tolerated but does not induce remission in steroid dependent Crohn's disease [abstract]. Gastroenterology. 2001;120:A127.
74. Colgan SP, Hershberg RM, Furuta GT, Blumberg RS. Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling. Proc Natl Acad Sci U S A. 1999;96:13938-13943.
75. Steidler L, Hans W, Schotte L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000;289:1352-1355.
76. Lindsay JO, Ciesielski CJ, Scheinin T, et al. Local delivery of adenoviral vectors encoding murine interleukin 10 induces colonic interleukin 10 production and is therapeutic for murine colitis. Gut. 2003;52:981-987.
77. Nakase H, Okazaki K, Tabata Y, et al. New cytokine delivery system using gelatin microspheres containing interleukin-10 for experimental inflammatory bowel disease. J Pharmacol Exp Ther. 2002;301:59-65.
78. Schwertschlag US, Trepicchio WL, Dykstra KH, et al. Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. Leukemia. 1999;13:1307-1315.
79. Trepicchio WL, Bozza M, Pedneault G, Dorner AJ. Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production. J Immunol. 1996;157:3627-3634.
80. Keith JC Jr, Albert L, Sonis ST, et al. IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cells. 1994; 12(suppl 1):79-89; discussion 89-90.
81. Du XX, Doerschuk CM, Orazi A, Williams DA. A bone marrow stromal-derived growth factor, interleukin-11, stimulates recovery of small intestinal mucosal cells after cytoablative therapy. Blood. 1994;83:33-37.
82. Booth C, Porten CS. Effects of IL-11 on the growth of intestinal epithelial cells in vitro. Cell Prolif. 1995;28:581-594.
83. Porten CS. Protection of the small intestinal clonogenic stem cells from radiation-induced damage by pretreatment with interleukin 11 also increases murine survival time. Stem Cells. 1996;14:452-459.
84. Qiu BS, Pfeiffer CJ, Keith JC Jr. Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats. Dig Dis Sci. 1996;41:1625-1630.
85. Sands BE, Bank S, Sninsky CA. Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease. Gastroenterology. 1999; 117:58-64.
86. Sands BE, Winston BD, Salzberg B, et al. Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn's disease. Aliment Pharmacol Ther. 2002;16:399-406.
87. Talbot RW, Heppell J, Dozois RR, Beart RW Jr. Vascular complications of inflammatory bowel disease. Mayo Clin Proc. 1986;61:140-145.
88. Kaye JA, Loewy J, Blume J, et al. Recombinant human interleukin-eleven (Neumega rhIL-11 growth factor) increases plasma von Willebrand factor and fibrinogen concentrations in normal subjects [abstract]. Blood. 1994;84:276A.
89. Cotreau MM, Stonis L, Schwertschlag US. A phase 1, randomized, double-blind, placebo-controlled, dose-escalating, safety, tolerability, pharmacokinetic, and pharmacodynamic study of oral recombinant human interleukin eleven (O-rhIL-11) in normal healthy subjects [abstract]. Gastroenterology. 2003;124:A377.
90. Podolsky DK, Lobb R, King N, et al. Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonal antibody. J Clin Invest. 1993;92:372-380.
91. Gordon FH, Lai CW, Hamilton MI, et al. A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease. Gastroenterology. 2001;121:268-274.
92. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's disease. N Engl J Med. 2003;348:24-32.
93. Lew EA, Stoffel EM. Natalizumab for active Crohn's disease. N Engl J Med. 2003;348:1599; author reply 1599.
94. Farstad IN, Halstensen TS, Kvale D, et al. Topographic distribution of homing receptors on B and T cells in human gut-associated lymphoid tissue: relation of L-selectin and integrin alpha 4 beta 7 to naive and memory phenotypes. Am J Pathol. 1997;150:187-199.
95. Hesterberg PE, Winsor-Hines D, Briskin MJ, et al. Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a gut-homing integrin alpha 4 beta 7. Gastroenterology. 1996;111:1373-1380.
96. Feagan BG, Greenberg G, Wild G, et al. Efficacy and safety of a humanized alpha4 beta7 antibody in active Crohn's disease [abstract]. Gastroenterology. 2003;124:A25.
97. Bennett CF, Condon TP, Grimm S, et al. Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides. J Immunol. 1994;152:3530-3540.
98. Bennett CF, Kornbrust D, Henry S, et al. An ICAM-1 antisense oligonucleotide prevents and reverses dextran sulfate sodium-induced colitis in mice. J Pharmacol Exp Ther. 1997; 280:988-1000.
99. Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, et al. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Gastroenterology. 1998;114:1133-1142.
100. Schreiber S, Nikolaus S, Malchow H, et al. Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease. Gastroenterology. 2001;120:1339-1346.
101. Yacyshyn BR, Chey WY, Goff J, et al. 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;51:30-36.
102. Neurath MF, Fuss I, Kelsall BL, et al. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995; 182:1281-1290.
103. Fuss IJ, Marth T, Neurath MF, et al. Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice. Gastroenterology. 1999;117:1078-1088.
104. Duchmann R, Schmitt E, Knolle P, et al. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur J Immunol. 1996;26:934-938.
105. Rutgeerts P, Reinisch W, Colombel JF, et al. Preliminary results of a phase I/II study of Huzaf, an anti-IFN- monoclonal antibody, in patients with moderate to severe active Crohn's disease [abstract]. Gastroenterology. 2002:122:A61.
106. Siegmund B, Fantuzzi G, Rieder F, et al. Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production. Am J Physiol Regal Integr Comp Physiol. 2001;281:R1264-R1273.
107. Holmes S, Abrahamson JA, Al-Mahdi N, et al. Characterization of the in vitro and in vivo activity of monoclonal antibodies to human IL-18. Hybridoma. 2000;19:363-367.
108. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med. 2000;343:108-117.
109. BioPortfolio. IDEC ( NASDAQ: IDPH) has halted clinical trials of its therapeutic monoclonal antibody IDEC-131. Available at: http://www.bioportfolio.com/news/btech_061102_1.htm. Accessed March 22, 2004.
110. James SP. Remission of Crohn's disease after human immunodeficiency virus infection. Gastroenterology. 1988;95:1667-1669.
111. Deusch K, Reiter C, Mauthe B, et al. Chimeric monoclonal anti-CD4 antibody therapy proves effective for treating inflammatory bowel disease [abstract]. Gastroenterology. 1992;102:A615.
112. Deusch K, Mauthe B, Reiter C, et al. CD4-antibody treatment of inflammatory bowel disease: one year follow up [abstract]. Gastroenterology. 1993;104:A691
113. Stronkhorst A, Radema S, Yong SL, et al. CD4 antibody treatment in patients with active Crohn's disease: a phase 1 dose finding study. Gut. 1997;40:320-327.
114. Emmrich J, Seyfarth M, Fleig WE, Emmrich F. Treatment of inflammatory bowel disease with anti-CD4 monoclonal antibody. Lancet. 1991; 338:570-571.
115. Emmrich J, Seyfarth M, Fleig WE, Emmrich F. Treatment of inflammatory bowel disease with anti-CD4 monoclonal antibody [abstract]. Gastroenterology. 1992;102:A620.
116. Emmrich J, Seyfarth M, Liebe S, Emmrich F. Anti-CD4-antibody treatment in inflammatory bowel disease without a long CD4+- cell depletion [abstract]. Gastroenterology. 1995;108:A815.
117. Canva-Delcambre V, Jacquot S, Robinet F, et al. Treatment of severe Crohn's disease with anti-CD4 monoclonal antibody. Aliment Pharmacol Ther. 1996;10:721-727.
118. Williams KL, Fuller CR, Dieleman LA, et al. Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone. Gastroenterology. 2001;120:925-937.
119. Chen K, Nezu R, Inoue M, et al. Beneficial effects of growth hormone combined with parenteral nutrition in the management of inflammatory bowel disease: an experimental study. Surgery. 1997;121:212-218.
120. Slonim AE, Bulone L, Damore MB, et al. A preliminary study of growth hormone therapy for Crohn's disease. N Engl J Med. 2000; 342:1633-1637.
121. Sartor RB. New therapeutic approaches to Crohn's disease. N Engl J Med. 2000; 342:1664-1666.
122. Korzenik JR, Dieckgraefe BK. Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease. Dig Dis Sci. 2000; 45:1121-1129.
123. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001; 411:603-606.
124. Vaughan D, Drumm B. Treatment of fistulas with granulocyte colony-stimulating factor in a patient with Crohn's disease. N Engl J Med. 1999;340:239-240.
125. Korzenik J, Dieckgraefe B. Immunostimulation in Crohn's disease: results of a pilot study of GCSF (R-Methug-CSF) in mucosal and fistulizing Crohn's disease [abstract]. Gastroenterology. 2000;118:AB74.
126. Dieckgraefe BK, Korzenik JR. Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor. Lancet. 2002;360:1478-1480.
127. Korzenik J, Pittler A, Dieckgraefe B. Immunostimulation in Crohn's disease: retreatment and maintenance therapy with GM-CSF [abstract]. Gastroenterology. 2002;122:A423.
128. Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Annu Rev Biochem. 1987;56:727-777.
129. Ransohoff RM. Cellular responses to interferons and other cytokines: the JAK-STAT paradigm. N Engl J Med. 1998;338:616-618.
130. Hanauer S, Baert F, Robinson M. Interferon treatment in mild to moderate active Crohn's disease: preliminary results of an open label pilot study [abstract]. Gastroenterology. 1994;106:A696.
131. Hadziselimovic F, Schaub U, Emmons LR. Interferon alpha-2A (roferon) as a treatment of inflammatory bowel disease in children and adolescents. Adv Exp Med Biol. 1995;371B: 1323-1326.
132. Wirth HP, Zala G, Meyenberger C, et al. [Alpha-interferon therapy in Crohn's disease: initial clinical results]. Schweiz Med Wochenschr. 1993;123:1384-1388.
133. Davidsen B, Munkholm P, Schlichting P, et al. Tolerability of interferon alpha-2b, a possible new treatment of active Crohn's disease. Aliment Pharmacol Ther. 1995;9:75-79.
134. Gasche C, Reinisch W, Vogelsang H, et al. Prospective evaluation of interferon-alpha in treatment of chronic active Crohn's disease. Dig Dis Sci. 1995;40:800-804.
135. Vantrappen G, Coremans G, Billiau A, De Somer P. Treatment of Crohn's disease with interferon. A preliminary clinical trial. Acta Clin Belg. 1980;35:238-242.
136. Masuda H, Iwai S, Tanaka T, Hayakawa S. Expression of IL-8, TNF-alpha and IFN-gamma m-RNA in ulcerative colitis, particularly in patients with inactive phase. J Clin Lab Immunol. 1995;46:111-123.
137. Nielsen OH, Gionchetti P, Ainsworth M, et al. Rectal dialysate and fecal concentrations of neutrophil gelatinase-associated lipocalin, interleukin-8, and tumor necrosis factor-alpha in ulcerative colitis. Am J Gastroenterol. 1999;94:2923-2928.
138. Saiki T, Mitsuyama K, Toyonaga A, et al. Detection of pro- and anti-inflammatory cytokines in stools of patients with inflammatory bowel disease. Scand J Gastroenterol. 1998;33:616-622.
139. Watkins PE, Warren BE, Stephens S, et al. Treatment of ulcerative colitis in the cottontop tamarin using antibody to tumour necrosis factor alpha. Gut. 1997;40:628-633.
140. Evans RC, Clarke L, Heath P, et al. Treatment of ulcerative colitis with an engineered human anti-TNFalpha antibody CDP571. Aliment Pharmacol Ther. 1997;11:1031-1035.
141. Sands BE, Tremaine WJ, Sandborn WJ, et al. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis. 2001;7:83-88.
142. Chey WY, Hussain A, Ryan C, et al. Infliximab for refractory ulcerative colitis. Am J Gastroenterol. 2001;96:2373-2381.
143. Chey WY. Infliximab for patients with refractory ulcerative colitis. Inflamm Bowel Dis. 2001;7(suppl 1):S30-S33.
144. Kaser A, Mairinger T, Vogel W, Tilg H. Infliximab in severe steroid-refractory ulcerative colitis: a pilot study. Wien Klin Wochenschr. 2001;113:930-933.
145. Kohn A, Prantera C, Pera A, et al. Anti-tumour necrosis factor alpha (infliximab) in the treatment of severe ulcerative colitis: result of an open study on 13 patients. Dig Liver Dis. 2002;34:626-630.
146. Su C, Salzberg BA, Lewis JD, et al. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol. 2002;97:2577-2584.
147. Kiafer C, Ramirez FC, Shernoff N. Anti-tumor necrosis factor therapy for patients with refractory ulcerative colitis [abstract]. Am J Gastroenterol. 2003; 98:S255.
148. Ochsenkuhn T, Sackmann M, Goeke B. Infliximab for acute severe ulcerative colitis: a randomized pilot study in non steroid refractory patients [abstract]. Gastroenterology. 2003;124:A62.
149. Actis GC, Bruno M, Pinna-Pintor M, et al. Infliximab for treatment of steroid-refractory ulcerative colitis. Dig Liver Dis. 2002;34:631-634.
150. Gornet JM, Couve S, Hassani Z, et al. Infliximab for refractory ulcerative colitis or indeterminate colitis: an open-label multicentre study. Aliment Pharmacol Ther. 2003;18:175-181.
151. Probert CS, Hearing SD, Schreiber S, et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut. 2003;52:998-1002.
152. Iyer S, Lahana R, Buelow R. Rational design and development of RDP58. Curr Pharm Des. 2002;8:2217-2229.
153. Iyer S, Kontoyiannis D, Chevrier D, et al. Inhibition of tumor necrosis factor mRNA translation by a rationally designed immunomodulatory peptide. J Biol Chem. 2000;275:17051-17057.
154. Murthy S, Flanigan A, Coppola D, Buelow R. RDP58, a locally active TNF inhibitor, is effective in the dextran sulphate mouse model of chronic colitis. Inflamm Res. 2002;51:522-531.
155. Boismenu R, Chen Y, Chou K, et al. Orally administered RDP58 reduces the severity of dextran sodium sulphate induced colitis. Ann Rheum Dis. 2002;61(suppl 2):ii19-ii24.
156. Bourreille A, Doubremelle M, de la Bletiere DR, et al. RDP58, a novel immunomodulatory peptide with anti-inflammatory effects. A pharmacological study in trinitrobenzene sulphonic acid colitis and Crohn disease. Scand J Gastroenterol. 2003;38:526-532.
157. Ganesan S, Iyer S, Travis S, et al. RDP-58, a new oral inhibitor of TNFa effectively treats primate models of colitis and is safe in man [abstract]. Gastroenterology. 2002;122:A6.
158. Travis SPL, Yap LM, Hawkey CJ, et al. RDP-58: novel and effective therapy for ulcerative colitis: results of parallel, prospective, placebo-controlled trials [abstract]. Am J Gastroenterol. 2003;98:S239.
159. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997; 336:1066-1071.
160. Neurath MF, Pettersson S, Meyer zum Buschenfelde KH, Strober W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med. 1996;2:998-1004.
161. Murano M, Maemura K, Hirata I, et al. Therapeutic effect of intracolonically administered nuclear factor kappa B (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis. Clin Exp Immunol. 2000;120:51-58.
162. Neurath MF, Fuss I, Schurmann G, et al. Cytokine gene transcription by NF-kappa B family members in patients with inflammatory bowel disease. Ann N Y Acad Sci. 1998; 859:149-159.
163. Loftberg R, Neurath M, Ost A, Pettersson S. Topical NF-kB p65 antisense oligonucleotides in patients with active distal colonic IBD. A randomized, controlled pilot trial [abstract]. Gastroenterology. 2002;122:A60.
164. Schreiber S, Fedorak R, Wild G, et al. Safety and tolerance of rHuIL-10 treatment in patients with mild/moderate active ulcerative colitis. Ulcerative Colitis IL-10 Cooperative Study Group [abstract]. Gastroenterology. 1998;114:A1080-A1081.
165. Gordon FH, Hamilton MI, Donoghue S, et al. A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin. Aliment Pharmacol Ther. 2002;16:699-705.
166. Feagan B, McDonald J, Greenberg G, et al. An ascending dose trial of humanized 4 7 antibody in ulcerative colitis (UC) [abstract]. Gastroenterology. 2000;118:A874.
167. Feagan B, Greenberg G, Wild G, et al. A randomized controlled trial of a humanized alpha4beta7 antibody in ulcerative colitis [abstract]. Am J Gastroenterol. 2003; 98:S248-S249.
168. Miner PB, Bane B, Bradley JD, et al. ICAM-1 antisense inhibition by enema improves pouchitis and suggests long-term mucosal healing in patients with chronic unremitting disease. Am J Gastroenterol. 2003;98:S246-S247.
169. Minami Y, Kono T, Miyazaki T, Taniguchi T. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol. 1993;11:245-26B.
170. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994; 330:1841-1845.
171. Van Assche G, D'Haens G, Noman M, et al. Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology. 2003;125:1025-1031.
172. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999;94:1587-1592.
173. Svanoni F, Bonassi U, Bagnolo F, et al. Effectiveness of cyclosporine A (CsA) in the treatment of active refractory ulcerative colitis (UC) [abstract]. Gastroenterology. 1998;114:A1096.
174. Hollander GA, Bierer BE, Burakoff SJ. Molecular and biological actions of cyclosporin A and FK506 on T cell development and function. Transfus Sci. 1994;15:207-220.
175. Van Assche G, Dalle I, Noman M, et al. A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis. Am J Gastroenterol. 2003;98:369-376.
176. Claessens C, Van Assche G, Dalle I, et al. Clinical improvement precedes mucosal healing in ulcerative colitis treated with Anti-IL-2 agents [abstract). Gastroenterology. 2002;122:A431.
177. Walker KB, Potter JM, House AK, Interleukin 2 synthesis in the presence of steroids: a model of steroid resistance. Clin Exp Immunol. 1987; 68:162-167.
178. Kam JC, Szefler SJ, Surs W, et al. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol. 1993;151:3460-3466.
179. Irusen E, Matthews JG, Takahashi A, et al. p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol. 2002; 109:649-657.
180. Jamieson CA, Yamamoto KR. Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling. Proc Natl Acad Sci U S A. 2000;109:7319-7324.
181. Creed TJ, Norman MR, Probert CS, et al. Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis. Aliment Pharmacol Ther. 2003;18:65-75.
182. Cole MS, Stellrecht KE, Shi JD, et al. HuM291, a humanized anti-CD3 antibody, is immunosuppressive to T cells while exhibiting reduced mitogenicity in vitro. Transplantation. 1999;68:563-571.
183. Plevy SE, Salzberg BA, Regueiro M, et al. A humanized anti-CD3 monoclonal antibody, visilizumab, for treatment of severe steroid-refractory ulcerative colitis: preliminary results of a phase I study [abstract]. Gastroenterology. 2003;124:A7.
184. Carpenter PA, Appelbaum FR, Corey L, et al. A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood. 2002;99:2712-2719.
185. Beck PL, Podolsky DK. Growth factors in inflammatory bowel disease. Inflamm Bowel Dis. 1999;5:44-60.
186. Werner S. Keratinocyte growth factor: a unique player in epithelial repair processes. Cytokine Growth Factor Rev. 1998;9:153-165.
187. Han DS, Li F, Holt L, et al. Keratinocyte growth factor-2 (FGF-10) promotes healing of experimental small intestinal ulceration in rats. Am J Physiol Gastrointest Liver Physiol. 2000;279: G1011-G1022.
188. Miceli R, Hubert M, Santiago G, et al. Efficacy of keratinocyte growth factor-2 in dextran sulfate sodium-induced routine colitis. J Pharmacol Exp Ther. 1999;290:464-471.
189. Byrne F, Farrell C, Aranda R, et al. Recombinant human keratinocyte growth factor (rHuKGF) ameliorates disease symptoms in both the DSS and CD45RB Hi cell transfer routine models of inflammatory bowel disease (IBD) [abstract]. Gastroenterology. 2001;2001:A689.
190. Sandborn WJ, Sands BE, Wolf DC, et al. Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Aliment Pharmacol Ther. 2003;17:1355-1364.
191. Heitz PU, Kasper M, van Noorden S, et al. Immunohistochemical localisation of urogastrone to human duodenal and submandibular glands. Gut. 1978;19:408-413.
192. Brown RL, Breeden MP, Greenhalgh DG. Enhancement of wound healing by topical treatment with epidermal growth factor. N Engl J Med. 1989;321:76-79.
193. Sullivan PB, Brueton MJ, Tabara ZB, et al. Epidermal growth factor in necrotising enteritis. Lancet. 1991;338:53-54.
194. Sinha A, Nightingale J, West KP, et al. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med. 2003;349:350-357.
195. Cottone M, Magliocco A, Trallori G, et al. Clinical course of inflammatory bowel disease during treatment with interferon for associated chronic active hepatitis. Ital J Gastroenterol. 1995;27:3-4.
196. Sumer N, Palabiyikoglu M. Induction of remission by interferon-alpha in patients with chronic active ulcerative colitis. Eur J Gastroenterol Hepatol. 1995;7:597-602.
197. Madsen SM, Schlichting P, Davidsen B, et al. An open-labeled, randomized study comparing systemic interferon-alpha-2A and prednisolone enemas in the treatment of left-sided ulcerative colitis. Am J Gastroenterol. 2001;96:1807-1815.
198. Tilg H, Vogelsang H, Ludwiczek O, et al. A randomized placebo-controlled trial of pegylated interferon alpha in active ulcerative colitis [abstract]. Gastroenterology. 2003;124:A62.
199. Musch E, Andus T, Malek M. Induction and maintenance of clinical remission by interferon-beta in patients with steroid-refractory active ulcerative colitis-an open long-term pilot trial. Aliment Pharmacol Ther. 2002;16:1233-1239.
200. Musch E, Raedler A, Andus T, et al. A phase II placebo-controlled, randomized, multicenter study to evaluate efficiency and safety of interferon beta-1a in patients with ulcerative colitis [abstract]. Gastroenterology. 2002;122:A431.
201. Nikolaus S, Rutgeerts P, Fedorak R, et al. Interferon beta-1a in ulcerative colitis: a placebo controlled, randomised, dose escalating study. Gut. 2003;52:1286-1290.