Immunotoxicity profile of natalizumab
Natalizumab is a monoclonal antibody to human α4 integrin indicated for treatment of multiple sclerosis and Crohn's disease that prevents extravasation of leukocytes into surrounding tissues and their involvement in inflammation. Because α4 integrins and their receptors are involved in hematopo...
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| Veröffentlicht in: | Journal of immunotoxicology 2009-06, Vol.6 (2), p.115-129 |
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| creator | Wehner, Nancy G. Gasper, Carolyn Shopp, George Nelson, Joyce Draper, Ken Parker, Suezanne Clarke, Janet |
| description | Natalizumab is a monoclonal antibody to human α4 integrin indicated for treatment of multiple sclerosis and Crohn's disease that prevents extravasation of leukocytes into surrounding tissues and their involvement in inflammation. Because α4 integrins and their receptors are involved in hematopoiesis and immune cell trafficking, natalizumab may interfere with these processes. We evaluated the effects of natalizumab on immune function in monkeys using in vitro and in vivo studies. Consistent with the pharmacologic effects of natalizumab, dose-related increases in white blood cell counts and spleen weights were observed. Administration to monkeys did not result in statistically significant alterations in the percentages of circulating B-cells, T-cells, T-cell subsets (CD4, CD8), or stem cells (CD34). A modest and highly variable delay in the primary humoral response to T-cell-dependent antigens was observed. Ex vivo studies using cells from natalizumab-treated monkeys demonstrated that treatment did not alter immune regulatory or effector cell functions in blood lymphocytes or spleen cells. A similar lack of effect on these functions was observed in vitro following treatment of PBMC and monocytes from human donors. Overall, natalizumab was well tolerated in monkeys, demonstrated the expected pharmacologic effect on cell trafficking, and showed no adverse effect on immune cell function. |
| doi_str_mv | 10.1080/15476910902977381 |
| format | Article |
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Because α4 integrins and their receptors are involved in hematopoiesis and immune cell trafficking, natalizumab may interfere with these processes. We evaluated the effects of natalizumab on immune function in monkeys using in vitro and in vivo studies. Consistent with the pharmacologic effects of natalizumab, dose-related increases in white blood cell counts and spleen weights were observed. Administration to monkeys did not result in statistically significant alterations in the percentages of circulating B-cells, T-cells, T-cell subsets (CD4, CD8), or stem cells (CD34). A modest and highly variable delay in the primary humoral response to T-cell-dependent antigens was observed. Ex vivo studies using cells from natalizumab-treated monkeys demonstrated that treatment did not alter immune regulatory or effector cell functions in blood lymphocytes or spleen cells. A similar lack of effect on these functions was observed in vitro following treatment of PBMC and monocytes from human donors. Overall, natalizumab was well tolerated in monkeys, demonstrated the expected pharmacologic effect on cell trafficking, and showed no adverse effect on immune cell function.</description><identifier>ISSN: 1547-691X</identifier><identifier>EISSN: 1547-6901</identifier><identifier>DOI: 10.1080/15476910902977381</identifier><identifier>PMID: 19589098</identifier><language>eng</language><publisher>England: Informa UK Ltd</publisher><subject>Animals ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - adverse effects ; Antibodies, Monoclonal, Humanized ; Antibody Formation - drug effects ; Antigens, CD - metabolism ; B-Lymphocytes - drug effects ; B-Lymphocytes - immunology ; B-Lymphocytes - metabolism ; B-Lymphocytes - pathology ; Cell Movement - drug effects ; Cell Proliferation - drug effects ; Clinical Trials as Topic ; Crohn Disease - immunology ; Crohn Disease - therapy ; Cytokines - secretion ; Cytotoxicity, Immunologic - drug effects ; Hematopoiesis - drug effects ; Humans ; immune function ; Immunotherapy ; Integrin alpha4 - immunology ; K562 Cells ; Leukocyte Count ; Lymphocyte Activation - drug effects ; Macaca fascicularis ; Macaca mulatta ; monoclonal antibody ; Multiple Sclerosis - immunology ; Multiple Sclerosis - therapy ; Natalizumab ; Organ Size ; Stem Cells - drug effects ; Stem Cells - immunology ; Stem Cells - metabolism ; Stem Cells - pathology ; T-Lymphocyte Subsets - drug effects ; T-Lymphocyte Subsets - immunology ; T-Lymphocyte Subsets - metabolism ; T-Lymphocyte Subsets - pathology ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; T-Lymphocytes - pathology ; α4 integrin</subject><ispartof>Journal of immunotoxicology, 2009-06, Vol.6 (2), p.115-129</ispartof><rights>2009 Informa UK Ltd 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-660f504202ed73481362af201de2d731bbf395613625740a607ed7f93c9698683</citedby><cites>FETCH-LOGICAL-c435t-660f504202ed73481362af201de2d731bbf395613625740a607ed7f93c9698683</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.tandfonline.com/doi/pdf/10.1080/15476910902977381$$EPDF$$P50$$Ginformaworld$$H</linktopdf><linktohtml>$$Uhttps://www.tandfonline.com/doi/full/10.1080/15476910902977381$$EHTML$$P50$$Ginformaworld$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,59647,60436,61221,61402</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19589098$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wehner, Nancy G.</creatorcontrib><creatorcontrib>Gasper, Carolyn</creatorcontrib><creatorcontrib>Shopp, George</creatorcontrib><creatorcontrib>Nelson, Joyce</creatorcontrib><creatorcontrib>Draper, Ken</creatorcontrib><creatorcontrib>Parker, Suezanne</creatorcontrib><creatorcontrib>Clarke, Janet</creatorcontrib><title>Immunotoxicity profile of natalizumab</title><title>Journal of immunotoxicology</title><addtitle>J Immunotoxicol</addtitle><description>Natalizumab is a monoclonal antibody to human α4 integrin indicated for treatment of multiple sclerosis and Crohn's disease that prevents extravasation of leukocytes into surrounding tissues and their involvement in inflammation. Because α4 integrins and their receptors are involved in hematopoiesis and immune cell trafficking, natalizumab may interfere with these processes. We evaluated the effects of natalizumab on immune function in monkeys using in vitro and in vivo studies. Consistent with the pharmacologic effects of natalizumab, dose-related increases in white blood cell counts and spleen weights were observed. Administration to monkeys did not result in statistically significant alterations in the percentages of circulating B-cells, T-cells, T-cell subsets (CD4, CD8), or stem cells (CD34). A modest and highly variable delay in the primary humoral response to T-cell-dependent antigens was observed. Ex vivo studies using cells from natalizumab-treated monkeys demonstrated that treatment did not alter immune regulatory or effector cell functions in blood lymphocytes or spleen cells. A similar lack of effect on these functions was observed in vitro following treatment of PBMC and monocytes from human donors. Overall, natalizumab was well tolerated in monkeys, demonstrated the expected pharmacologic effect on cell trafficking, and showed no adverse effect on immune cell function.</description><subject>Animals</subject><subject>Antibodies, Monoclonal - administration & dosage</subject><subject>Antibodies, Monoclonal - adverse effects</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Antibody Formation - drug effects</subject><subject>Antigens, CD - metabolism</subject><subject>B-Lymphocytes - drug effects</subject><subject>B-Lymphocytes - immunology</subject><subject>B-Lymphocytes - metabolism</subject><subject>B-Lymphocytes - pathology</subject><subject>Cell Movement - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Clinical Trials as Topic</subject><subject>Crohn Disease - immunology</subject><subject>Crohn Disease - therapy</subject><subject>Cytokines - secretion</subject><subject>Cytotoxicity, Immunologic - drug effects</subject><subject>Hematopoiesis - drug effects</subject><subject>Humans</subject><subject>immune function</subject><subject>Immunotherapy</subject><subject>Integrin alpha4 - immunology</subject><subject>K562 Cells</subject><subject>Leukocyte Count</subject><subject>Lymphocyte Activation - drug effects</subject><subject>Macaca fascicularis</subject><subject>Macaca mulatta</subject><subject>monoclonal antibody</subject><subject>Multiple Sclerosis - immunology</subject><subject>Multiple Sclerosis - therapy</subject><subject>Natalizumab</subject><subject>Organ Size</subject><subject>Stem Cells - drug effects</subject><subject>Stem Cells - immunology</subject><subject>Stem Cells - metabolism</subject><subject>Stem Cells - pathology</subject><subject>T-Lymphocyte Subsets - drug effects</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocyte Subsets - metabolism</subject><subject>T-Lymphocyte Subsets - pathology</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><subject>T-Lymphocytes - pathology</subject><subject>α4 integrin</subject><issn>1547-691X</issn><issn>1547-6901</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9LAzEUxIMotlY_gBfpRW-rL5vdbIJeSvFPoeBFwVvI7iY0JbupyS5aP70pLYoIPb3H8JthGITOMVxjYHCD86ygHAOHlBcFYfgADTdaQjngw58fvw3QSQhLiBgmcIwGmOeMA2dDdDlrmr51nfs0lenW45V32lg1dnrcyk5a89U3sjxFR1raoM52d4ReH-5fpk_J_PlxNp3MkyojeZdQCjqHLIVU1QXJGCY0lToFXKs0CrgsNeE53ch5kYGkUERQc1JxyhllZISutrmxxnuvQicaEyplrWyV64OIUYzknEQQb8HKuxC80mLlTSP9WmAQm23Ev22i52IX3peNqn8duzEicLcFTKudb-SH87YWnVxb57WXbWWCIPvyb__YF0rablFJr8TS9b6Nw-1p9w1Xc4H4</recordid><startdate>200906</startdate><enddate>200906</enddate><creator>Wehner, Nancy G.</creator><creator>Gasper, Carolyn</creator><creator>Shopp, George</creator><creator>Nelson, Joyce</creator><creator>Draper, Ken</creator><creator>Parker, Suezanne</creator><creator>Clarke, Janet</creator><general>Informa UK Ltd</general><general>Taylor & Francis</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope></search><sort><creationdate>200906</creationdate><title>Immunotoxicity profile of natalizumab</title><author>Wehner, Nancy G. ; Gasper, Carolyn ; Shopp, George ; Nelson, Joyce ; Draper, Ken ; Parker, Suezanne ; Clarke, Janet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c435t-660f504202ed73481362af201de2d731bbf395613625740a607ed7f93c9698683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal - administration & dosage</topic><topic>Antibodies, Monoclonal - adverse effects</topic><topic>Antibodies, Monoclonal, Humanized</topic><topic>Antibody Formation - drug effects</topic><topic>Antigens, CD - metabolism</topic><topic>B-Lymphocytes - drug effects</topic><topic>B-Lymphocytes - immunology</topic><topic>B-Lymphocytes - metabolism</topic><topic>B-Lymphocytes - pathology</topic><topic>Cell Movement - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Clinical Trials as Topic</topic><topic>Crohn Disease - immunology</topic><topic>Crohn Disease - therapy</topic><topic>Cytokines - secretion</topic><topic>Cytotoxicity, Immunologic - drug effects</topic><topic>Hematopoiesis - drug effects</topic><topic>Humans</topic><topic>immune function</topic><topic>Immunotherapy</topic><topic>Integrin alpha4 - immunology</topic><topic>K562 Cells</topic><topic>Leukocyte Count</topic><topic>Lymphocyte Activation - drug effects</topic><topic>Macaca fascicularis</topic><topic>Macaca mulatta</topic><topic>monoclonal antibody</topic><topic>Multiple Sclerosis - immunology</topic><topic>Multiple Sclerosis - therapy</topic><topic>Natalizumab</topic><topic>Organ Size</topic><topic>Stem Cells - drug effects</topic><topic>Stem Cells - immunology</topic><topic>Stem Cells - metabolism</topic><topic>Stem Cells - pathology</topic><topic>T-Lymphocyte Subsets - drug effects</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocyte Subsets - metabolism</topic><topic>T-Lymphocyte Subsets - pathology</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><topic>T-Lymphocytes - pathology</topic><topic>α4 integrin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wehner, Nancy G.</creatorcontrib><creatorcontrib>Gasper, Carolyn</creatorcontrib><creatorcontrib>Shopp, George</creatorcontrib><creatorcontrib>Nelson, Joyce</creatorcontrib><creatorcontrib>Draper, Ken</creatorcontrib><creatorcontrib>Parker, Suezanne</creatorcontrib><creatorcontrib>Clarke, Janet</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Journal of immunotoxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wehner, Nancy G.</au><au>Gasper, Carolyn</au><au>Shopp, George</au><au>Nelson, Joyce</au><au>Draper, Ken</au><au>Parker, Suezanne</au><au>Clarke, Janet</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Immunotoxicity profile of natalizumab</atitle><jtitle>Journal of immunotoxicology</jtitle><addtitle>J Immunotoxicol</addtitle><date>2009-06</date><risdate>2009</risdate><volume>6</volume><issue>2</issue><spage>115</spage><epage>129</epage><pages>115-129</pages><issn>1547-691X</issn><eissn>1547-6901</eissn><abstract>Natalizumab is a monoclonal antibody to human α4 integrin indicated for treatment of multiple sclerosis and Crohn's disease that prevents extravasation of leukocytes into surrounding tissues and their involvement in inflammation. Because α4 integrins and their receptors are involved in hematopoiesis and immune cell trafficking, natalizumab may interfere with these processes. We evaluated the effects of natalizumab on immune function in monkeys using in vitro and in vivo studies. Consistent with the pharmacologic effects of natalizumab, dose-related increases in white blood cell counts and spleen weights were observed. Administration to monkeys did not result in statistically significant alterations in the percentages of circulating B-cells, T-cells, T-cell subsets (CD4, CD8), or stem cells (CD34). A modest and highly variable delay in the primary humoral response to T-cell-dependent antigens was observed. Ex vivo studies using cells from natalizumab-treated monkeys demonstrated that treatment did not alter immune regulatory or effector cell functions in blood lymphocytes or spleen cells. A similar lack of effect on these functions was observed in vitro following treatment of PBMC and monocytes from human donors. Overall, natalizumab was well tolerated in monkeys, demonstrated the expected pharmacologic effect on cell trafficking, and showed no adverse effect on immune cell function.</abstract><cop>England</cop><pub>Informa UK Ltd</pub><pmid>19589098</pmid><doi>10.1080/15476910902977381</doi><tpages>15</tpages></addata></record> |
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| subjects | Animals Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - adverse effects Antibodies, Monoclonal, Humanized Antibody Formation - drug effects Antigens, CD - metabolism B-Lymphocytes - drug effects B-Lymphocytes - immunology B-Lymphocytes - metabolism B-Lymphocytes - pathology Cell Movement - drug effects Cell Proliferation - drug effects Clinical Trials as Topic Crohn Disease - immunology Crohn Disease - therapy Cytokines - secretion Cytotoxicity, Immunologic - drug effects Hematopoiesis - drug effects Humans immune function Immunotherapy Integrin alpha4 - immunology K562 Cells Leukocyte Count Lymphocyte Activation - drug effects Macaca fascicularis Macaca mulatta monoclonal antibody Multiple Sclerosis - immunology Multiple Sclerosis - therapy Natalizumab Organ Size Stem Cells - drug effects Stem Cells - immunology Stem Cells - metabolism Stem Cells - pathology T-Lymphocyte Subsets - drug effects T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism T-Lymphocyte Subsets - pathology T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes - pathology α4 integrin |
| title | Immunotoxicity profile of natalizumab |
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