An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo
Identifieur interne : 000B09 ( Istex/Corpus ); précédent : 000B08; suivant : 000B10An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo
Auteurs : A. Stallmach ; T. Marth ; B. Wei ; B M Wittig ; A. Hombach ; C. Schmidt ; M. Neurath ; M. Zeitz ; S. Zeuzem ; H. AbkenSource :
- Gut [ 0017-5749 ] ; 2004-03.
English descriptors
- KwdEn :
- 5-ASA, 5-aminosalicylic acid, CD, Crohn’s disease, Crohn’s disease, IFN-γ, interferon γ, IL, interleukin, LPMNC, lamina propria mononuclear cells, PBL, peripheral blood lymphocytes, PBMNC, peripheral blood mononuclear cells, PBS, phosphate buffered saline, PCR, polymerase chain reaction, PMA, phorbol myristate acetate, TNBS, 2,4,6,-trinitrobenzene sulphonic acid, TNF-α, tumour necrosis factor α, fusion protein, inflammatory bowel disease, interleukin 12, mAb, monoclonal antibody.
- Teeft :
- Active disease, Apoptosis, Apoptotic, Apoptotic cells, Bowel, Cdna, Cell proliferation, Colitis, Colitis mice, Colon specimens, Colonic, Conglomerate, Cytokine, Deficient mice, Experimental models, Facs analysis, Flow cytometry, Fusion, Fusion protein, Gastroenterology, Glucocorticoid, High concentrations, Igg2b, Ileocaecal, Ileocaecal conglomerate tumour, Ileocaecal part resection, Immune response, Immunol, Independent experiments, Inflammation, Inflammatory, Inflammatory bowel disease, Interleukin, Internal medicine, Intestinal, Intestinal inflammation, Intracellular cytokines, Lamina, Lamina propria, Lpmnc, Lymphocyte, Mouse, Mucosal, Peripheral blood lymphocytes, Phorbol myristate acetate, Positive cells, Primer, Propria, Receptor, Receptor binding site, Recombinant, Resection, Stallmach, Stricture, Stricture resection, Subunit, Sulphonic acid, Terminal ileum, Tnbs, Tnbs colitic mice, Tnbs colitis, Tnbs colitis mice, Tumour, Tumour necrosis factor.
Abstract
Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn’s disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation. Methods: We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro. Results: Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10−7 M, it acted as an IL-12 antagonist as it inhibited interferon γ (IFN-γ) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10−6 M, IL-12(p40)-IgG2b increased IFN-γ secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor α, and increased IL-10 secretion. Conclusions: The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.
Url:
DOI: 10.1136/gut.2003.020107
Links to Exploration step
ISTEX:68EA40E2B9E8CE5BC0812327B7D680310BDAEAAALe document en format XML
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Wei</name><affiliation><mods:affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Wittig, B M" sort="Wittig, B M" uniqKey="Wittig B" first="B M" last="Wittig">B M Wittig</name><affiliation><mods:affiliation>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hombach, A" sort="Hombach, A" uniqKey="Hombach A" first="A" last="Hombach">A. Hombach</name><affiliation><mods:affiliation>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</mods:affiliation></affiliation></author><author><name sortKey="Schmidt, C" sort="Schmidt, C" uniqKey="Schmidt C" first="C" last="Schmidt">C. Schmidt</name><affiliation><mods:affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Neurath, M" sort="Neurath, M" uniqKey="Neurath M" first="M" last="Neurath">M. Neurath</name><affiliation><mods:affiliation>I Medical Clinic, University of Mainz, Germany</mods:affiliation></affiliation></author><author><name sortKey="Zeitz, M" sort="Zeitz, M" uniqKey="Zeitz M" first="M" last="Zeitz">M. Zeitz</name><affiliation><mods:affiliation>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</mods:affiliation></affiliation></author><author><name sortKey="Zeuzem, S" sort="Zeuzem, S" uniqKey="Zeuzem S" first="S" last="Zeuzem">S. Zeuzem</name><affiliation><mods:affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Abken, H" sort="Abken, H" uniqKey="Abken H" first="H" last="Abken">H. Abken</name><affiliation><mods:affiliation>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Gut</title><title level="j" type="abbrev">Gut</title><idno type="ISSN">0017-5749</idno><idno type="eISSN">1468-3288</idno><imprint><publisher>BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><date type="published" when="2004-03">2004-03</date><biblScope unit="volume">53</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="339">339</biblScope></imprint><idno type="ISSN">0017-5749</idno></series><idno type="istex">68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA</idno><idno type="DOI">10.1136/gut.2003.020107</idno><idno type="href">gutjnl-53-339.pdf</idno><idno type="PMID">14960512</idno><idno type="local">0530339</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0017-5749</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>5-ASA, 5-aminosalicylic acid</term><term>CD, Crohn’s disease</term><term>Crohn’s disease</term><term>IFN-γ, interferon γ</term><term>IL, interleukin</term><term>LPMNC, lamina propria mononuclear cells</term><term>PBL, peripheral blood lymphocytes</term><term>PBMNC, peripheral blood mononuclear cells</term><term>PBS, phosphate buffered saline</term><term>PCR, polymerase chain reaction</term><term>PMA, phorbol myristate acetate</term><term>TNBS, 2,4,6,-trinitrobenzene sulphonic acid</term><term>TNF-α, tumour necrosis factor α</term><term>fusion protein</term><term>inflammatory bowel disease</term><term>interleukin 12</term><term>mAb, monoclonal antibody</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Active disease</term><term>Apoptosis</term><term>Apoptotic</term><term>Apoptotic cells</term><term>Bowel</term><term>Cdna</term><term>Cell proliferation</term><term>Colitis</term><term>Colitis mice</term><term>Colon specimens</term><term>Colonic</term><term>Conglomerate</term><term>Cytokine</term><term>Deficient mice</term><term>Experimental models</term><term>Facs analysis</term><term>Flow cytometry</term><term>Fusion</term><term>Fusion protein</term><term>Gastroenterology</term><term>Glucocorticoid</term><term>High concentrations</term><term>Igg2b</term><term>Ileocaecal</term><term>Ileocaecal conglomerate tumour</term><term>Ileocaecal part resection</term><term>Immune response</term><term>Immunol</term><term>Independent experiments</term><term>Inflammation</term><term>Inflammatory</term><term>Inflammatory bowel disease</term><term>Interleukin</term><term>Internal medicine</term><term>Intestinal</term><term>Intestinal inflammation</term><term>Intracellular cytokines</term><term>Lamina</term><term>Lamina propria</term><term>Lpmnc</term><term>Lymphocyte</term><term>Mouse</term><term>Mucosal</term><term>Peripheral blood lymphocytes</term><term>Phorbol myristate acetate</term><term>Positive cells</term><term>Primer</term><term>Propria</term><term>Receptor</term><term>Receptor binding site</term><term>Recombinant</term><term>Resection</term><term>Stallmach</term><term>Stricture</term><term>Stricture resection</term><term>Subunit</term><term>Sulphonic acid</term><term>Terminal ileum</term><term>Tnbs</term><term>Tnbs colitic mice</term><term>Tnbs colitis</term><term>Tnbs colitis mice</term><term>Tumour</term><term>Tumour necrosis factor</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn’s disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation. Methods: We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro. Results: Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10−7 M, it acted as an IL-12 antagonist as it inhibited interferon γ (IFN-γ) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10−6 M, IL-12(p40)-IgG2b increased IFN-γ secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor α, and increased IL-10 secretion. Conclusions: The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.</div></front></TEI><istex><corpusName>bmj</corpusName><keywords><teeft><json:string>fusion protein</json:string><json:string>colitis</json:string><json:string>tnbs</json:string><json:string>lpmnc</json:string><json:string>receptor</json:string><json:string>ileocaecal</json:string><json:string>resection</json:string><json:string>tumour</json:string><json:string>immunol</json:string><json:string>propria</json:string><json:string>lamina</json:string><json:string>glucocorticoid</json:string><json:string>apoptotic</json:string><json:string>apoptosis</json:string><json:string>recombinant</json:string><json:string>bowel</json:string><json:string>lamina propria</json:string><json:string>conglomerate</json:string><json:string>tnbs colitis</json:string><json:string>stricture</json:string><json:string>cytokine</json:string><json:string>interleukin</json:string><json:string>gastroenterology</json:string><json:string>ileocaecal part resection</json:string><json:string>stallmach</json:string><json:string>ileocaecal conglomerate tumour</json:string><json:string>intestinal</json:string><json:string>inflammation</json:string><json:string>colonic</json:string><json:string>subunit</json:string><json:string>igg2b</json:string><json:string>lymphocyte</json:string><json:string>cdna</json:string><json:string>primer</json:string><json:string>positive cells</json:string><json:string>mucosal</json:string><json:string>tnbs colitis mice</json:string><json:string>inflammatory bowel disease</json:string><json:string>inflammatory</json:string><json:string>apoptotic cells</json:string><json:string>deficient mice</json:string><json:string>independent experiments</json:string><json:string>sulphonic acid</json:string><json:string>intestinal inflammation</json:string><json:string>facs analysis</json:string><json:string>phorbol myristate acetate</json:string><json:string>colitis mice</json:string><json:string>tumour necrosis factor</json:string><json:string>cell proliferation</json:string><json:string>fusion</json:string><json:string>experimental models</json:string><json:string>stricture resection</json:string><json:string>flow cytometry</json:string><json:string>terminal ileum</json:string><json:string>peripheral blood lymphocytes</json:string><json:string>colon specimens</json:string><json:string>receptor binding site</json:string><json:string>tnbs colitic mice</json:string><json:string>high concentrations</json:string><json:string>active disease</json:string><json:string>intracellular cytokines</json:string><json:string>internal medicine</json:string><json:string>immune response</json:string><json:string>mouse</json:string></teeft></keywords><author><json:item><name>A Stallmach</name><affiliations><json:string>Department of Internal Medicine II, Saarland University, Homburg, Germany</json:string></affiliations></json:item><json:item><name>T Marth</name><affiliations><json:string>Department of Internal Medicine II, Saarland University, Homburg, Germany</json:string></affiliations></json:item><json:item><name>B Weiß</name><affiliations><json:string>Department of Internal Medicine II, Saarland University, Homburg, Germany</json:string></affiliations></json:item><json:item><name>B M Wittig</name><affiliations><json:string>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</json:string></affiliations></json:item><json:item><name>A Hombach</name><affiliations><json:string>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</json:string></affiliations></json:item><json:item><name>C Schmidt</name><affiliations><json:string>Department of Internal Medicine II, Saarland University, Homburg, Germany</json:string></affiliations></json:item><json:item><name>M Neurath</name><affiliations><json:string>I Medical Clinic, University of Mainz, Germany</json:string></affiliations></json:item><json:item><name>M Zeitz</name><affiliations><json:string>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</json:string></affiliations></json:item><json:item><name>S Zeuzem</name><affiliations><json:string>Department of Internal Medicine II, Saarland University, Homburg, Germany</json:string></affiliations></json:item><json:item><name>H Abken</name><affiliations><json:string>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>interleukin 12</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>fusion protein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Crohn’s disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>inflammatory bowel disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>5-ASA, 5-aminosalicylic acid</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CD, Crohn’s disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TNBS, 2,4,6,-trinitrobenzene sulphonic acid</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>LPMNC, lamina propria mononuclear cells</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PBMNC, peripheral blood mononuclear cells</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IL, interleukin</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IFN-γ, interferon γ</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>mAb, monoclonal antibody</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PCR, polymerase chain reaction</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PBS, phosphate buffered saline</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PMA, phorbol myristate acetate</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PBL, peripheral blood lymphocytes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TNF-α, tumour necrosis factor α</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>other</json:string></originalGenre><abstract>Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn’s disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation. Methods: We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro. Results: Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations >10−7 M, it acted as an IL-12 antagonist as it inhibited interferon γ (IFN-γ) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10−6 M, IL-12(p40)-IgG2b increased IFN-γ secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor α, and increased IL-10 secretion. Conclusions: The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.</abstract><qualityIndicators><score>7.292</score><pdfVersion>1.2</pdfVersion><pdfPageSize>609.08 x 790.583 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>17</keywordCount><abstractCharCount>1365</abstractCharCount><pdfWordCount>5409</pdfWordCount><pdfCharCount>37744</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>191</abstractWordCount></qualityIndicators><title>An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo</title><pmid><json:string>14960512</json:string></pmid><genre><json:string>other</json:string></genre><host><title>Gut</title><language><json:string>unknown</json:string></language><issn><json:string>0017-5749</json:string></issn><eissn><json:string>1468-3288</json:string></eissn><volume>53</volume><issue>3</issue><pages><first>339</first></pages><genre><json:string>journal</json:string></genre></host><categories><wos><json:string>science</json:string><json:string>gastroenterology & hepatology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>gastroenterology & hepatology</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string><json:string>gastroenterologie. foie. pancreas. abdomen</json:string></inist></categories><publicationDate>2004</publicationDate><copyrightDate>2004</copyrightDate><doi><json:string>10.1136/gut.2003.020107</json:string></doi><id>68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><availability><p>Copyright 2004 by Gut</p></availability><date>2004-02-11</date></publicationStmt><notesStmt><note>Correspondence to:
Professor A Stallmach
Clinic for Gastroenterology and Hepatology, Catholic Clinics Essen-Nord, D-45329 Essen, Germany; a.stallmach@kken.de</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo</title><author xml:id="author-1"><persName><forename type="first">A</forename><surname>Stallmach</surname></persName><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation></author><author xml:id="author-2"><persName><forename type="first">T</forename><surname>Marth</surname></persName><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation></author><author xml:id="author-3"><persName><forename type="first">B</forename><surname>Weiß</surname></persName><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation></author><author xml:id="author-4"><persName><forename type="first">B M</forename><surname>Wittig</surname></persName><affiliation>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</affiliation></author><author xml:id="author-5"><persName><forename type="first">A</forename><surname>Hombach</surname></persName><affiliation>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</affiliation></author><author xml:id="author-6"><persName><forename type="first">C</forename><surname>Schmidt</surname></persName><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation></author><author xml:id="author-7"><persName><forename type="first">M</forename><surname>Neurath</surname></persName><affiliation>I Medical Clinic, University of Mainz, Germany</affiliation></author><author xml:id="author-8"><persName><forename type="first">M</forename><surname>Zeitz</surname></persName><affiliation>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</affiliation></author><author xml:id="author-9"><persName><forename type="first">S</forename><surname>Zeuzem</surname></persName><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation></author><author xml:id="author-10"><persName><forename type="first">H</forename><surname>Abken</surname></persName><affiliation>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</affiliation></author></analytic><monogr><title level="j">Gut</title><title level="j" type="abbrev">Gut</title><idno type="pISSN">0017-5749</idno><idno type="eISSN">1468-3288</idno><imprint><publisher>BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><date type="published" when="2004-03"></date><biblScope unit="volume">53</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="339">339</biblScope></imprint></monogr><idno type="istex">68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA</idno><idno type="DOI">10.1136/gut.2003.020107</idno><idno type="href">gutjnl-53-339.pdf</idno><idno type="PMID">14960512</idno><idno type="local">0530339</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2004-02-11</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn’s disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation. Methods: We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro. Results: Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10−7 M, it acted as an IL-12 antagonist as it inhibited interferon γ (IFN-γ) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10−6 M, IL-12(p40)-IgG2b increased IFN-γ secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor α, and increased IL-10 secretion. Conclusions: The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>KWD</head><item><term>interleukin 12</term></item><item><term>fusion protein</term></item><item><term>Crohn’s disease</term></item><item><term>inflammatory bowel disease</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><head>ABR</head><item><term>5-ASA, 5-aminosalicylic acid</term></item><item><term>CD, Crohn’s disease</term></item><item><term>TNBS, 2,4,6,-trinitrobenzene sulphonic acid</term></item><item><term>LPMNC, lamina propria mononuclear cells</term></item><item><term>PBMNC, peripheral blood mononuclear cells</term></item><item><term>IL, interleukin</term></item><item><term>IFN-γ, interferon γ</term></item><item><term>mAb, monoclonal antibody</term></item><item><term>PCR, polymerase chain reaction</term></item><item><term>PBS, phosphate buffered saline</term></item><item><term>PMA, phorbol myristate acetate</term></item><item><term>PBL, peripheral blood lymphocytes</term></item><item><term>TNF-α, tumour necrosis factor α</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2004-02-11">Created</change><change when="2004-03">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Archiving and Interchange DTD v2.3 20070202//EN" URI="archivearticle.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="other"><front><journal-meta><journal-id journal-id-type="hwp">gutjnl</journal-id><journal-id journal-id-type="nlm-ta">Gut</journal-id><journal-title>Gut</journal-title><abbrev-journal-title abbrev-type="publisher">Gut</abbrev-journal-title><issn pub-type="ppub">0017-5749</issn><issn pub-type="epub">1468-3288</issn><publisher><publisher-name>BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">0530339</article-id><article-id pub-id-type="doi">10.1136/gut.2003.020107</article-id><article-id pub-id-type="other">gutjnl;53/3/339</article-id><article-id pub-id-type="pmid">14960512</article-id><article-id pub-id-type="other">339</article-id><article-id pub-id-type="other">gut.2003.020107</article-id><article-categories><subj-group subj-group-type="heading"><subject>Inflammatory bowel disease</subject></subj-group></article-categories><title-group><article-title>An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Stallmach</surname><given-names>A</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Marth</surname><given-names>T</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Weiß</surname><given-names>B</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Wittig</surname><given-names>B M</given-names></name><xref rid="AFF2">2</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Hombach</surname><given-names>A</given-names></name><xref rid="AFF3">3</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Schmidt</surname><given-names>C</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Neurath</surname><given-names>M</given-names></name><xref rid="AFF4">4</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Zeitz</surname><given-names>M</given-names></name><xref rid="AFF2">2</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Zeuzem</surname><given-names>S</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Abken</surname><given-names>H</given-names></name><xref rid="AFF3">3</xref></contrib><aff id="AFF1"><label>1</label>Department of Internal Medicine II, Saarland University, Homburg, Germany</aff><aff id="AFF2"><label>2</label>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</aff><aff id="AFF3"><label>3</label>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</aff><aff id="AFF4"><label>4</label>I Medical Clinic, University of Mainz, Germany</aff></contrib-group><author-notes><corresp>Correspondence to:
Professor A Stallmach
Clinic for Gastroenterology and Hepatology, Catholic Clinics Essen-Nord, D-45329 Essen, Germany; <ext-link xlink:href="a.stallmachkken.de" ext-link-type="email" xlink:type="simple">a.stallmach@kken.de</ext-link></corresp></author-notes><pub-date pub-type="ppub"><month>3</month><year>2004</year></pub-date><pub-date pub-type="epub"><day>11</day><month>2</month><year>2004</year></pub-date><volume>53</volume><volume-id pub-id-type="other">53</volume-id><volume-id pub-id-type="other">53</volume-id><issue>3</issue><issue-id pub-id-type="other">gutjnl;53/3</issue-id><issue-id pub-id-type="other">3</issue-id><issue-id pub-id-type="other">53/3</issue-id><fpage>339</fpage><history><date date-type="accepted"><day>13</day><month>10</month><year>2003</year></date></history><permissions><copyright-statement>Copyright 2004 by Gut</copyright-statement><copyright-year>2004</copyright-year></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="gutjnl-53-339.pdf"></self-uri><abstract xml:lang="en"><p><bold>Background and aims:</bold> Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn’s disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation.</p><p><bold>Methods:</bold> We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro.</p><p><bold>Results:</bold> Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10<sup>−7</sup> M, it acted as an IL-12 antagonist as it inhibited interferon γ (IFN-γ) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10<sup>−6</sup> M, IL-12(p40)-IgG2b increased IFN-γ secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% <italic>v</italic> 68%), prevented body weight loss, reduced tumour necrosis factor α, and increased IL-10 secretion.</p><p><bold>Conclusions:</bold> The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.</p></abstract><kwd-group kwd-group-type="KWD" xml:lang="en"><kwd>interleukin 12</kwd><kwd>fusion protein</kwd><kwd>Crohn’s disease</kwd><kwd>inflammatory bowel disease</kwd></kwd-group><kwd-group kwd-group-type="ABR" xml:lang="en"><kwd>5-ASA, 5-aminosalicylic acid</kwd><kwd>CD, Crohn’s disease</kwd><kwd>TNBS, 2,4,6,-trinitrobenzene sulphonic acid</kwd><kwd>LPMNC, lamina propria mononuclear cells</kwd><kwd>PBMNC, peripheral blood mononuclear cells</kwd><kwd>IL, interleukin</kwd><kwd>IFN-γ, interferon γ</kwd><kwd>mAb, monoclonal antibody</kwd><kwd>PCR, polymerase chain reaction</kwd><kwd>PBS, phosphate buffered saline</kwd><kwd>PMA, phorbol myristate acetate</kwd><kwd>PBL, peripheral blood lymphocytes</kwd><kwd>TNF-α, tumour necrosis factor α</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo</title></titleInfo><name type="personal"><namePart type="given">A</namePart><namePart type="family">Stallmach</namePart><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">T</namePart><namePart type="family">Marth</namePart><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B</namePart><namePart type="family">Weiß</namePart><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B M</namePart><namePart type="family">Wittig</namePart><affiliation>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Hombach</namePart><affiliation>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Schmidt</namePart><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Neurath</namePart><affiliation>I Medical Clinic, University of Mainz, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Zeitz</namePart><affiliation>Department of Internal Medicine I, Free University Berlin, Berlin, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Zeuzem</namePart><affiliation>Department of Internal Medicine II, Saarland University, Homburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H</namePart><namePart type="family">Abken</namePart><affiliation>Tumour Genetics, Clinic I for Internal Medicine, University of Cologne, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="other" displayLabel="other"></genre><originInfo><publisher>BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><dateIssued encoding="w3cdtf">2004-03</dateIssued><dateCreated encoding="w3cdtf">2004-02-11</dateCreated><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn’s disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation. Methods: We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro. Results: Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10−7 M, it acted as an IL-12 antagonist as it inhibited interferon γ (IFN-γ) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10−6 M, IL-12(p40)-IgG2b increased IFN-γ secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor α, and increased IL-10 secretion. Conclusions: The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.</abstract><note type="author-notes">Correspondence to:
Professor A Stallmach
Clinic for Gastroenterology and Hepatology, Catholic Clinics Essen-Nord, D-45329 Essen, Germany; a.stallmach@kken.de</note><subject lang="en"><genre>KWD</genre><topic>interleukin 12</topic><topic>fusion protein</topic><topic>Crohn’s disease</topic><topic>inflammatory bowel disease</topic></subject><subject lang="en"><genre>ABR</genre><topic>5-ASA, 5-aminosalicylic acid</topic><topic>CD, Crohn’s disease</topic><topic>TNBS, 2,4,6,-trinitrobenzene sulphonic acid</topic><topic>LPMNC, lamina propria mononuclear cells</topic><topic>PBMNC, peripheral blood mononuclear cells</topic><topic>IL, interleukin</topic><topic>IFN-γ, interferon γ</topic><topic>mAb, monoclonal antibody</topic><topic>PCR, polymerase chain reaction</topic><topic>PBS, phosphate buffered saline</topic><topic>PMA, phorbol myristate acetate</topic><topic>PBL, peripheral blood lymphocytes</topic><topic>TNF-α, tumour necrosis factor α</topic></subject><relatedItem type="host"><titleInfo><title>Gut</title></titleInfo><titleInfo type="abbreviated"><title>Gut</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0017-5749</identifier><identifier type="eISSN">1468-3288</identifier><identifier type="PublisherID-hwp">gutjnl</identifier><identifier type="PublisherID-nlm-ta">Gut</identifier><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>53</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>339</start></extent></part></relatedItem><identifier type="istex">68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA</identifier><identifier type="DOI">10.1136/gut.2003.020107</identifier><identifier type="href">gutjnl-53-339.pdf</identifier><identifier type="PMID">14960512</identifier><identifier type="local">0530339</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright 2004 by Gut</accessCondition><recordInfo><recordContentSource>BMJ</recordContentSource></recordInfo></mods></metadata><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/68EA40E2B9E8CE5BC0812327B7D680310BDAEAAA/annexes/jpeg</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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