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Biologic therapy of inflammatory bowel disease

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Presentation on theme: "Biologic therapy of inflammatory bowel disease"— Presentation transcript:

1 Biologic therapy of inflammatory bowel disease
William J. Sandborn, Stephan R. Targan  Gastroenterology  Volume 122, Issue 6, Pages (May 2002) DOI: /gast Copyright © 2002 American Gastroenterological Association Terms and Conditions

2 Fig. 1 Role of CD40 in T cell activation. Antigen recognition by T cells induces the expression of CD40 ligand (CD40L). CD40L engages CD40 on the APCs and stimulates the expression of B7 molecules and the secretion of cytokines that activate T cells. Thus, CD40L on the T cells makes the APCs “better” APCs. T cells can express CD40L on antigen recognition even without costimulation, but sustained expression of CD40L requires B7-CD28 costimulation, as well as antigen. Thus, the B7 and CD40 pathways stimulate each other. APC, antigen-presenting cell. Reprinted with permission from Abbas AK, Lichtman AH, Pober JS, eds. Activation of T lymphocytes. In: Cellular and molecular immunology. Philadelphia, PA: Saunders, 2000:169. Gastroenterology  , DOI: ( /gast ) Copyright © 2002 American Gastroenterological Association Terms and Conditions

3 Fig. 2 The Th1/Th2 paradigm. Modified with permission from Romagnani S. TH1/TH2 Cells. Inflamm Bowel Dis 1999;5:285–294. Gastroenterology  , DOI: ( /gast ) Copyright © 2002 American Gastroenterological Association Terms and Conditions

4 Fig. 3 Activation pathways leading to TNF production. Each activation pathway may vary depending on the cell type, for example macrophage or T cell, and the type of extracellular stimulus. Each step in the TNF production and secretion pathway is a potential target for therapeutic manipulation using specific inhibitors (shown in circled numbers). (1) TNF gene expression can be regulated by cAMP (cyclic adenosine monophosphate) modulation or MAPK (mitogen-activated protein kinases) including p38, p42/44 extracellular signal-regulated kinases (ERKs), and JNK. Pentoxyfylline increases cAMP and blocks TNF secretion by macrophages. The MAP-kinase inhibitor CNI-1493 inhibits p38 and JNK pathways. (2) TNF expression is induced via activation of the transcription factor NF-κB. NF-κB can be inhibited by sulfasalazine, mesalamine, and p65 oligonucleotides. (3) Modulation of TNF expression via the transcription factors AP-1, AP-2, nuclear factor-activated T cells (NF-AT), Ets, SP-1, C/EBPβ, and cAMP response element (CRE). (4) Splicing of TNF mRNA. (5) Translation of TNF mRNA via adenosine-uracil multimer-rich elements (ARE). (6) Degradation of TNF mRNA. Thalidomide acts to prevent degradation of TNF mRNA. (7) Cleavage of pro-TNF to TNF by TNF-α-converting-enzyme (TACE). This step can be inhibited by metalloproteinase inhibitors. (8) Binding of soluble and transmembrane TNF by monoclonal antibodies to TNF such as infliximab and CDP571. (9) Binding of soluble TNF by TNF receptor fusion proteins such as etanercept. (10) Binding of soluble TNF by soluble TNF receptors such as onercept. Modified with permission from Papadakis KA, Targan SR. Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology 2000;119:1148–1157. Gastroenterology  , DOI: ( /gast ) Copyright © 2002 American Gastroenterological Association Terms and Conditions

5 Fig. 4 Schematic diagram of NF-κB activation. Activation of NF-κB involves the phosphorylation and subsequent proteolytic degradation of the inhibitory protein I-κB by specific I-κB kinases. The free NF-κB (a heterodimer of p50 and p65) then passes into the nucleus, where it binds to κB sites in the promoter regions of genes for inflammatory proteins such as cytokines, enzymes, and adhesion molecules. P denotes protein, and mRNA messenger RNA. Modified with permission from Barnes PJ, Karin M. Nuclear factor-κB – a pivotal transcription factor in chronic inflammatory diseases. Copyright © 1997 Massachusetts Medical Society. All rights reserved (N Engl J Med 1997;336:1066–1071). Gastroenterology  , DOI: ( /gast ) Copyright © 2002 American Gastroenterological Association Terms and Conditions


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