Mechanisms and efficacy of immunobiologic therapies for inflammatory bowel diseases

International Reviews of Immunology

Volumn 29, Issue 1, 2010, Pages 4-37

  Ghosh, Nilanjan ^a   Chaki, Rituparna ^a   Mandal, Vivekananda ^b   Lin, G David ^c   Mandal, Subhash C ^a,c  

^a Dr B C Roy College of Pharmacy and Allied Health Sciences   (India)

^b JADAVPUR UNIVERSITY   (India)

^c UNIVERSITY OF CANBERRA   (Australia)

Author keywords

Crohn's disease; Cytokines; Immunobiologic therapy; Ulcerative colitis

Indexed keywords

ABT 874; ADALIMUMAB; ALICAFORSEN; AZATHIOPRINE; BASILIXIMAB; CD40 LIGAND MONOCLONAL ANTIBODY; CERTOLIZUMAB PEGOL; CORTICOSTEROID; CYTOKINE; DACLIZUMAB; DEXTRO ARGINYL DEXTRO NORLEUCYL DEXTRO NORLEUCYL DEXTRO NORLEUCYL DEXTRO ARGINYL DEXTRO NORLEUCYL DEXTRO NORLEUCYL DEXTRO NORLEUCYLGLYCYL DEXTRO TYROSINAMIDE; FONTOLIZUMAB; GROWTH FACTOR; GROWTH HORMONE; INFLIXIMAB; INTERLEUKIN 2 RECEPTOR ANTIBODY; INTERLEUKIN 6 RECEPTOR ANTIBODY; MERCAPTOPURINE; MONOCLONAL ANTIBODY; NATALIZUMAB; PLACEBO; PREDNISOLONE; PROBIOTIC AGENT; RECOMBINANT GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; RECOMBINANT INTERLEUKIN 10; RECOMBINANT INTERLEUKIN 11; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; UNCLASSIFIED DRUG; USTEKINUMAB; VEDOLIZUMAB; VISILIZUMAB;

ASPERGILLOSIS; CD4+ T LYMPHOCYTE; CELL POLARITY; CLINICAL TRIAL; COLITIS; CROHN DISEASE; DELAYED HYPERSENSITIVITY; DEMYELINATION; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG FATALITY; DRUG HYPERSENSITIVITY; DRUG MECHANISM; ENTERITIS; ENVIRONMENTAL FACTOR; HEART FAILURE; HEREDITY; HISTOPLASMOSIS; HUMAN; IMMUNOPATHOGENESIS; INFECTION; LEUKOCYTE ADHERENCE; LISTERIOSIS; LUPUS VULGARIS; LYMPHOCYTE SUBPOPULATION; NONHUMAN; PNEUMOCYSTIS PNEUMONIA; PRIORITY JOURNAL; REMISSION; REVIEW; RISK FACTOR; SINGLE DRUG DOSE; T LYMPHOCYTE ACTIVATION; TH1 CELL; THROMBOEMBOLISM; TUBERCULOSIS; ULCERATIVE COLITIS; UNSPECIFIED SIDE EFFECT;

ANTIBODIES, MONOCLONAL; CLINICAL TRIALS AS TOPIC; COLITIS, ULCERATIVE; CROHN DISEASE; CYTOKINES; HUMANS; IMMUNOLOGIC FACTORS; INFLAMMATORY BOWEL DISEASES; TREATMENT OUTCOME;

EID: 76149107171     PISSN: 08830185     EISSN: 15635244     Source Type: Journal    
DOI: 10.3109/08830180903437212     Document Type: Review

References (114)

1. G Assche. Emerging drugs to treat Crohn's disease. Expert Opin Emerging Drugs 2007;12:49-59.
2. SB Hanauer and DH Present. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord 2003;3:81-92.
3. SB Hanauer and WJ Sandborn. Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol 2001;96:635-643.
4. WJ Sandborn and BG Feagan. Mild to moderate Crohn's disease-Defining the basis for a new treatment algorithm. Aliment Pharmacol Ther 2003;18:263-277.
5. C Camma, M Giunta, M Rosselli, and M Cottone. Mesalamine in the maintenance treatment of Crohn's disease: A meta-analysis adjusted for confounding variables. Gastroenterology 1997;113:1465-1473.
6. H Lochs, M Mayer, WE Fleig, et al. Prophylaxis of postoperative relapse in Crohn's disease: European Cooperative Crohn's Disease Study VI. Gastroenterology 2000;18:264-273
7. RB Stein and SB Hanauer. Medical therapy for inflammatory bowel disease. Gastroenterol Clin North Am 1999;28:297-321.
8. DC Pearson, GR May, GH Fick, and LR Sutherland. Azathiorprine and 6-mercaptopurine in Crohn's disease. A meta-analyisis. Ann Intern Med 1995;123:132-142.
9. GD Haens, L Lemmens, K Geboes, et al. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology 2001;120:1323-1329.
10. DH Present, SJ Meltzer, MP Krumholz, et al. 6-Mercaptopurine in the management of inflammatory bowel disease: Short-and long-term toxicity. Ann Intern Med 1989;111:641-649.
11. S Friedman. General principles of medical therapy of inflammatory bowel disease. Gastroenterol Clin North Am 2004;33:191-208.
12. BGFeagan, J Rochon, RNFedorak, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Disease Study Group Investigators. N Engl J Med 1995;332:292-297.
13. BG Feagan, RN Fedorak, EJ Irvine, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Disease Study Group Investigators. N Engl J Med 2000;342:1627-1632.
14. S Ardizzone, S Bollani,GManzionna, and GP Bianchi. Inflammatory bowel disease approaching the 3rd millennium: Pathogenesis and therapeutic implications? Eur J Gastroenterol Hepatol 1999;11:27-32.
15. C Fiocchi. Inflammatory bowel disease: Etiology and pathogenesis. Gastroenterology 1998;115:182-205.
16. FS Laroux, KP Pavlik, RE Wolf, and MB Grisham. Dysregulation of intestinal mucosal immunity: Implications in inflammatory bowel disease. News Physiol Sci 2001;16:272-277.
17. JP Hugot,MChamaillard, H Zouali, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001;411:599-603.
18. Y Ogura, DK Bonen, N Inohara, et al. A frame shift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001;411:603-606.
19. JH Cho. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 2008;8:458-466.
20. DA Heel, DP McGovern, and DP Jewell. Crohn's disease: Genetic susceptibility, bacteria, and innate immunity. Lancet 2001;357:1902-1904.
21. YR Mahida and S Johal. NF-κB may determine whether epithelial cell microbial interactions in the intestine are hostile or friendly. Clin Exp Immunol 2001;123:347-349.
22. B Beutler. Autoimmunity and apoptosis: The Crohn's connection. Immunity 2001;15:5-14.
23. JC Barrett, S Hansoul, DL Nicolae, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008;40:955-962.
24. F Shanahan. Crohn's disease. Lancet 2002;359:62-69.
25. DE Elliott, JF Urban, CK Argo, and JV Weinstock. Does the failure to acquire helmintic parasites predispose to Crohn's disease? FASEB J 2000;14:1848-1855.
26. S Franceschi, E Panza, C Vecchia, et al. Non-specific inflammatory bowel disease and smoking. Am J Epidemiol 1987;125:445-452.
27. E Lindberg, C Tysk, K Anderson, and G Jarnerot. Smoking and inflammatory bowel disease: A case control study. Gut 1988;29:352-357.
28. LG Miller, G Goldstein, M Murphy, and LC Ginns. Reversible alterations in immunoregulatory T cells in smoking: Analysis by monoclonal antibodies and flow cytometry. Chest 1982;82:526-529.
29. ED Srivastava, JR Barton, and S O'Mahony. Smoking, humoral immunity, and ulcerative colitis. Gut 1991;32:1016-1019.
30. GF Cope, RV Heatley, and JK Kelleher. Smoking and colonic mucus in ulcerative colitis. Br Med J 1986;293:481.
31. B Coulie, M Camilleri, AE Bharucha, et al. Colonic motility in chronic ulcerative proctosigmoiditis and the effects of nicotine on colonic motility in patients and healthy subjects. Aliment Pharmacol Ther 2001;15:653-663.
32. S Madretsma, LM Wolters, and JP van Dijk. In-vivo effect of nicotine on cytokine production by human non-adherent mononuclear cells. Eur J Gastroenterol Hepatol 1996;8:1017-1020.
33. S Plevy. The immunology of inflammatory bowel disease. Gastroenterol Clin North Am 2002;31:77-92.
34. M Goke and DK Podolsky. Regulation of the mucosal epithelial barrier. Baillieres Clin Gastroenterol 1996;10:393-405.
35. R Fabia, A Ar'Rajab, ML Johansson, et al. Impairment of bacterial flora in human ulcerative colitis and experimental colitis in the rat. Digestion 1993;54:248-255.
36. IJ Fuss, M Neurath, M Boirivant, 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.
37. JR Farrell and MA Peppercorn. Ulcerative colitis. Lancet 2002;359:331-340.
38. R Duchmann, E May, M Heike, et al. T cell specificity and cross reactivity towards enterobacteria, bacteroides, bifidobacterium, and antigens from resident intestinal flora in humans. Gut 1999;44:812-818.
39. D Schuppan and EG Hahn. MMPs in the gut: Inflammation hits the matrix. Gut 2000;47:12-14.
40. Y Naito and T Yoshikawa. Role of matrix metalloproteinases in inflammatory bowel disease. Mol Aspects Med 2005;26:379-390
41. F Powrie. T cells in inflammatory bowel disease: Protective and pathogenic roles. Immunity 1995;3:171-174.
42. M Boirivant, M Marini, GD Felice, et al. Lamina propria T cell in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis. Gastroenterology 1999;116:557-565.
43. K Ina, J Itoh, K Fukushima, et al. Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol 1999;163:1081-1090.
44. M Boirivant, R Pica, R DeMaria, et al. Stimulated human lamina propria T cells manifest enhanced Fas-mediated apoptosis. J Clin Invest 1996;98:2616-2622. (Pubitemid 26415084)
45. H Ueyama, T Kiyohara, N Sawada, et al. High Fas ligand expression on lymphocytes in lesions of ulcerative colitis. Gut 1998;43:48-55.
46. R Kuhn, J Löhler, D Rennick, et al. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993;75:263-274.
47. MS Gordon, WJ McCaskill-Stevens, LA Battiato, et al. A phase I trial of recombinant human interleukin-11 (neumega rhIl-11 growth factor) in women with breast cancer receiving chemotherapy. Blood 1996;87:3615-3624.
48. WL Trepicchio,M Bozza, G Pedneault, and AJ Dorner. 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.
49. BS Qiu, CJ Pfeiffer, and JC Keith. Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats. Dig Dis Sci 1996;41:1625-1630.
50. S Ardizzone and G Bianchi. Inflammatory bowel disease: New insights into pathogenesis and therapy. J Intern Med 2002;252:475-496.
51. MF Neurath, I Fuss, BL Kelsall, et al. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 1995;182:1281-1290.
52. TT MacDonald and G Monteleone. Interleukin-12 and Th1 immune responses in human Peyer's patches. Trends Immunol 2001;22:244-247.
53. TT Pizarro,MH Michie,MBentz, 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.
54. RB Sartor. Cytokines in intestinal inflammation: Pathophysiological and clinical considerations. Gastroenterology 1994;106:533-539.
55. L Alexopulou,MPasparikis, andGKollias. Amurine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling. Eur J Immunol 1997;27:2588-2592.
56. SJH Deventer. A place for TACE. Gut 2002;51:5-6.
57. ML Moss, SL Jin, and ME Milla. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 1997;385:733-735.
58. RA Black, CT Rauch, and CJ Kozlosky. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997;385:729-733.
59. J Brynskov, P Foegh, G Pedersen, et al. Tumor necrosis factor ?converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease. Gut 2002;51:37-43.
60. M Yamamoto, K Yoshozaki, T Kishimoto, and H Ito. IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol 2000;164:4878-4882.
61. R Atreya, J Mudter, S Finotto, et al. Blockade of interleukin 6 Trans signaling suppressor T cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn's disease and experimental colitis in vivo. Nat Med 2000;6:583-588.
62. EC Butcher and LJ Picker. Lymphocyte homing and homeostasis. Science 1996;272:60-66.
63. WJ Sandborn and TA Yednock. Novel approaches to treating inflammatory bowel disease: Targeting alpha-4 integrin. Am J Gastroenterol 2003;98:2372-2382.
64. PJ Delves and IM Roitt. The immune system. Second of two parts. N Engl J Med 2000;343:108-117.
65. FJ Dumont. IDEC-131. IDEC/Eisai. Curr Opin Investig Drugs 2002;3:725-734.
66. S Danese, F Scaldaferri, S Vetrano, et al. Critical role of CD40 CD40 ligand pathway in regulating mucosal inflammation driven angiogenesis in inflammatory bowel disease. Gut 2007;56:1248-1256.
67. PL Kozuch and SB Hanauer. General principles and pharmacology of biologics in inflammatory bowel disease. Gastroenterol Clin North Am 2006;35:757-773.
68. S Plevy, B Salzberg, G Assche, et al. A phase I study of visilizumab, a humanized anti-CD3 monoclonal antibody, for treatment of severe steroid-refractory ulcerative colitis. Gastroenterology 2007;133:1414-1422.
69. SJ van Deventer, CO Elson, and RN Fedorak. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's disease Study Group. Gastroenterology 1997;113:383-389.
70. S Schreiber, RN Fedorak, OH Nielsen, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Gastroenterology 2000;119:1461-1472. (Pubitemid 32198671)
71. L Steidler, W Hans, L Schotte, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000;289:1352-1355.
72. BE Sands, S Bank, CA Sninsky, et al. Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease. Gastroenterology 1999;117:58-64.
73. BE Sands, BD Winston, B Salzberg, et al. Randomized, controlled trial of recombinant human interleukin 11 in patients with active Crohn's disease. Aliment Pharmacol Ther 2002;16:399-406.
74. KR Herrlinger, T Witthoeft, A Raedler, et al. Randomized, double-blind, doubleblind, controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn's disease. Am J Gastroenterol 2006;101:793-797.
75. CA Papadakis and SA Targan. Tumor necrosis factor: Biology and therapeutic inhibitors. Gastroenterology 2000;119:1148-1157.
76. HM van Dullemen, SJ van Deventer, DW Hommes, et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109:129-135.
77. SR Targan, SB Hanauer, SJ van Deventer, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor αfor Crohn's disease. N Engl J Med 1997;337:1029-1035.
78. P Rutgeerts, GD Haens, S Targan, et al. Efficacy and safety or retreatment with anti-tumor necrosis factor antibody (Infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999;117:761-769.
79. SB Hanauer, BG Feagan, GR Lichtenstein, et al. Maintenance Infliximab for Crohn's disease: The ACCENT I randomised trial. Lancet 2002;359:1541-1549.
80. P Rutgeerts, WJ Sandborn, BG Feagan, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462-2476. (Pubitemid 41770166)
81. WJ Sandborn and WA Faubion. Biologics in inflammatory bowel disease: How much progress have we made? Gut 2004;53:1366-1373.
82. PS Puttini, S Ardizzone, G Manzionna, et al. Infliximab induced lupus in Crohn's disease: A case report. Dig Liver Dis 2003;35:814-817.
83. WJ Sandborn, BG Feagan, SB Hanauer, et al. An engineered human antibody to TNF (CDP571) for active Crohn's disease: A randomised, palcebo-controlled trial. Gastroenterology 2001;120:1330-1338.
84. BG Feagan, WJ Sandborn, G Lichtenstein, et al. CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for steroid-dependent Crohn's disease: A randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther 2006;23:617-628.
85. WJ Sandborn, BG Feagan, S Stoinov, et al. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med 2007;357:228-238.
86. S Schreiber, MK Kareemi, IC Lawrance, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med 2007;357:239-250. (Pubitemid 47080388)
87. S Iyer, D Kontoyiannis, D Chevrier, et al. Inhibition of tumor necrosis factor mRNA translation by a rationally designed immunomodulatory peptide. J Biol Chem 2000;275:17051-17057.
88. S Murthy, A Flanigan, D Coppola, and R Buelow. RDP58, a locally active TNF inhibitor, is effective in the dextran sulphatemouse model of chronic colitis. Inflamm Res 2002;51:522-531.
89. SPL Travis, LM Yap, CJ Hawkey, et al. RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Inflamm Bowel Dis 2005;11:713-719.
90. WJ Sandborn, S Hanauer, EV Loftus, et al. An open-label study of the human anti-TNFmonoclonal antibody adalimumab subjects with prior loss of response or intolerance to infliximab for Crohn's disease. Am J Gastroenterol 2004;99:1984-1989.
91. SB Hanauer, WJ Sandborn, P Rutgeerts, et al. Human anti-TNF monoclonal antibody (Adalimumab) in Crohn's disease: The CLASSIC I trial. Gastroenterology 2006;130:323-333.
92. WJSandborn, SBHanauer, P Rutgeerts, et al. Adalimumab formaintenance treatment of Crohn's disease: Results of the CLASSIC II trial. Gut 2007;56:1232-1239. (Pubitemid 47300424)
93. JF Colombel, WJ Sandborn, P Rutgeerts, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: The CHARM trial. Gastroenterology 2007;132:52-65.
94. H Ito, M Takazoe, Y Fukuda, et al. A pilot randomized trial of a human antiinterleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 2004;126:989-996.
95. G Assche, I Dalle, M Noman, et al. A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis. Am J Gastroenetrol 2003;98:369-376.
96. G Assche, WJ Sandborn, BG Feagan, et al. Daclizumab, a humanized monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: A randomized, double blind, placebo-controlled, dose ranging trial. Gut 2006;55:1568-1574.
97. TJ Creed, MR Norman, CS Probert, 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.
98. PJ Mannon, IJ Fuss, LMayer, et al. Anti-interleukin-12 antibody for activeCrohn's disease. N Engl J Med 2004;351:2069-2079.
99. P Rutgeerts, W Reinisch, and JF Colombel. 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. Gastroenterology 2002;122:A61.
100. G Assche and T Pearce. Fontolizumab, a humanized anti-IFN-gamma antibody, has clinical activity and excellent tolerability in moderate to severe Crohn's disease. Gut 2004;53:A48.
101. WJ Sandborn, BG Feagan, RN Fedorak, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 2008;135:1130-1141.
102. S Ghosh, E Goldin, FH Gordon, et al. Natalizumab for active Crohn's disease. N Engl J Med 2003;348:24-32.
103. BG Feagan, WJ Sandborn, S Hass, et al. Health-related quality of life during natalizumab maintenance therapy for Crohn's disease. Am J Gastroenterol 2007;102:2737-2746. (Pubitemid 350179328)
104. FH Gordon, MI Hamilton, S Donoghue, 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.
105. BG Feagan, G Greenberg, and G Wild. Efficacy and safety of humanized alpha 4 beta 7 antibody in active Crohn's disease. Gastroenterology 2003;124:A25.
106. CF Bennett, TP Condon, S Grimm, et al. Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides. J Immunol 1994;152:3530-3540.
107. BR Yacyshyn, MB Bowen-Yacyshyn, L Jewell, et al. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Gastroenterology 1998;114:113-142.
108. SJ VanDeventer, JA Tami, and MK Wedel. A randomised, controlled, doublebind, escalating dose study of alicaforsen enema in ulcerative colitis. Gut 2004;53:1646-1651.
109. PL Beck andDKPodolsky. Growth factors in inflammatory bowel disease. Inflamm Bowel Dis 1999;5:44-60.
110. AE Slonim, L Bulone, MB Damore, et al. A preliminary study of growth hormone therapy for Crohn's disease. N Engl J Med 2000;342:1633-1637.
111. A Sinha, J Nightingale, KPWest, 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.
112. JR Korzenic and BK Dieckgraefe. 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.
113. BK Dieckgraefe and JR Korzenik. Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor. Lancet 2002;360:1478-1480.
114. JR Korzenik, BK Dieckgraefe, JF Valentine, et al. Sargramostim for active Crohn's disease. N Engl J Med 2005;352:2193-2201.