Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count
Background: Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes. Objectives: To characterize changes in B- and T-cell phenotype and function...
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| Veröffentlicht in: | Multiple sclerosis 2018-05, Vol.24 (6), p.728-738 |
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| container_title | Multiple sclerosis |
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| creator | Longbrake, Erin E Cantoni, Claudia Chahin, Salim Cignarella, Francesca Cross, Anne H Piccio, Laura |
| description | Background:
Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes.
Objectives:
To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes.
Methods:
Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC |
| doi_str_mv | 10.1177/1352458517707069 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5665729</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sage_id>10.1177_1352458517707069</sage_id><sourcerecordid>2043540662</sourcerecordid><originalsourceid>FETCH-LOGICAL-c462t-40a371a34ed1f297f8a6e24a551b720293b1c4fe0baf2ec967f3a7ba67e24ba03</originalsourceid><addsrcrecordid>eNp1kc1r3DAQxUVpaNJt7z0VQS-9uJFkfdiXQpt-BQK9pGcx1o7WDra0tayA__tq2TRNA7loBt5vnuYxhLzh7APnxpzzWgmpGlV6Zphun5EzLo2pWGvY89IXuTrop-RlSjeMMWNq9YKcikY2zLTyjKxfhgmXfh2pzxPMsCAdwjY7TNT1EHalDoF-riiELb2uxnXa99GtBfM5uGWI4cDjHssTFho9XXqk6D26JdGiQpfimAv_YNTFHJZX5MTDmPD1Xd2QX9--Xl_8qK5-fr-8-HRVOanFUkkGteFQS9xyL1rjG9AoJCjFOyOYaOuOO-mRdeAFulYbX4PpQJtCdcDqDfl49N3nbsKtK2vOMNr9PJS8q40w2P-VMPR2F2-t0lqZ4r8h7-8M5vg7Y1rsNCSH4wgBY06WN62WnCupCvruEXoT8xxKPCuYrJVkWotCsSPl5pjSjP5-Gc7s4a728V3LyNuHIe4H_h6yANURSLDDf78-afgHkuWs2w</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2043540662</pqid></control><display><type>article</type><title>Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count</title><source>Access via SAGE</source><source>MEDLINE</source><creator>Longbrake, Erin E ; Cantoni, Claudia ; Chahin, Salim ; Cignarella, Francesca ; Cross, Anne H ; Piccio, Laura</creator><creatorcontrib>Longbrake, Erin E ; Cantoni, Claudia ; Chahin, Salim ; Cignarella, Francesca ; Cross, Anne H ; Piccio, Laura</creatorcontrib><description>Background:
Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes.
Objectives:
To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes.
Methods:
Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC < 800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed.
Results:
DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4+ CXCR5+) and mucosal invariant T-cells (CD8+ CD161+) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients.
Conclusion:
These data implicate DMF-induced changes in lymphocytes as an important component of the drug’s efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.</description><identifier>ISSN: 1352-4585</identifier><identifier>EISSN: 1477-0970</identifier><identifier>DOI: 10.1177/1352458517707069</identifier><identifier>PMID: 28480794</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Adult ; B-Lymphocytes - drug effects ; CD4 antigen ; CD8 antigen ; Cell activation ; Cell death ; Cell number ; Cross-Sectional Studies ; CXCR5 protein ; Cytokines ; Dimethyl Fumarate - therapeutic use ; Female ; Flow cytometry ; Helper cells ; Humans ; Immunological memory ; Immunosuppressive Agents - therapeutic use ; Inflammation ; Ionomycin ; Learning ; Leukocytes (mononuclear) ; Lymphocyte Count ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Lymphopenia ; Lymphopenia - chemically induced ; Male ; Memory cells ; Middle Aged ; Mucosa ; Multiple sclerosis ; Multiple Sclerosis, Relapsing-Remitting - drug therapy ; Multiple Sclerosis, Relapsing-Remitting - immunology ; Peripheral blood mononuclear cells ; Phenotypes ; T cell receptors ; T-Lymphocytes - drug effects</subject><ispartof>Multiple sclerosis, 2018-05, Vol.24 (6), p.728-738</ispartof><rights>The Author(s), 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-40a371a34ed1f297f8a6e24a551b720293b1c4fe0baf2ec967f3a7ba67e24ba03</citedby><cites>FETCH-LOGICAL-c462t-40a371a34ed1f297f8a6e24a551b720293b1c4fe0baf2ec967f3a7ba67e24ba03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/1352458517707069$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/1352458517707069$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>230,314,780,784,885,21819,27924,27925,43621,43622</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28480794$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Longbrake, Erin E</creatorcontrib><creatorcontrib>Cantoni, Claudia</creatorcontrib><creatorcontrib>Chahin, Salim</creatorcontrib><creatorcontrib>Cignarella, Francesca</creatorcontrib><creatorcontrib>Cross, Anne H</creatorcontrib><creatorcontrib>Piccio, Laura</creatorcontrib><title>Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count</title><title>Multiple sclerosis</title><addtitle>Mult Scler</addtitle><description>Background:
Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes.
Objectives:
To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes.
Methods:
Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC < 800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed.
Results:
DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4+ CXCR5+) and mucosal invariant T-cells (CD8+ CD161+) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients.
Conclusion:
These data implicate DMF-induced changes in lymphocytes as an important component of the drug’s efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.</description><subject>Adult</subject><subject>B-Lymphocytes - drug effects</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell activation</subject><subject>Cell death</subject><subject>Cell number</subject><subject>Cross-Sectional Studies</subject><subject>CXCR5 protein</subject><subject>Cytokines</subject><subject>Dimethyl Fumarate - therapeutic use</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Helper cells</subject><subject>Humans</subject><subject>Immunological memory</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Inflammation</subject><subject>Ionomycin</subject><subject>Learning</subject><subject>Leukocytes (mononuclear)</subject><subject>Lymphocyte Count</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>Lymphopenia</subject><subject>Lymphopenia - chemically induced</subject><subject>Male</subject><subject>Memory cells</subject><subject>Middle Aged</subject><subject>Mucosa</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis, Relapsing-Remitting - drug therapy</subject><subject>Multiple Sclerosis, Relapsing-Remitting - immunology</subject><subject>Peripheral blood mononuclear cells</subject><subject>Phenotypes</subject><subject>T cell receptors</subject><subject>T-Lymphocytes - drug effects</subject><issn>1352-4585</issn><issn>1477-0970</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1r3DAQxUVpaNJt7z0VQS-9uJFkfdiXQpt-BQK9pGcx1o7WDra0tayA__tq2TRNA7loBt5vnuYxhLzh7APnxpzzWgmpGlV6Zphun5EzLo2pWGvY89IXuTrop-RlSjeMMWNq9YKcikY2zLTyjKxfhgmXfh2pzxPMsCAdwjY7TNT1EHalDoF-riiELb2uxnXa99GtBfM5uGWI4cDjHssTFho9XXqk6D26JdGiQpfimAv_YNTFHJZX5MTDmPD1Xd2QX9--Xl_8qK5-fr-8-HRVOanFUkkGteFQS9xyL1rjG9AoJCjFOyOYaOuOO-mRdeAFulYbX4PpQJtCdcDqDfl49N3nbsKtK2vOMNr9PJS8q40w2P-VMPR2F2-t0lqZ4r8h7-8M5vg7Y1rsNCSH4wgBY06WN62WnCupCvruEXoT8xxKPCuYrJVkWotCsSPl5pjSjP5-Gc7s4a728V3LyNuHIe4H_h6yANURSLDDf78-afgHkuWs2w</recordid><startdate>20180501</startdate><enddate>20180501</enddate><creator>Longbrake, Erin E</creator><creator>Cantoni, Claudia</creator><creator>Chahin, Salim</creator><creator>Cignarella, Francesca</creator><creator>Cross, Anne H</creator><creator>Piccio, Laura</creator><general>SAGE Publications</general><general>Sage Publications Ltd</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>7TK</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180501</creationdate><title>Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count</title><author>Longbrake, Erin E ; Cantoni, Claudia ; Chahin, Salim ; Cignarella, Francesca ; Cross, Anne H ; Piccio, Laura</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-40a371a34ed1f297f8a6e24a551b720293b1c4fe0baf2ec967f3a7ba67e24ba03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>B-Lymphocytes - drug effects</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cell activation</topic><topic>Cell death</topic><topic>Cell number</topic><topic>Cross-Sectional Studies</topic><topic>CXCR5 protein</topic><topic>Cytokines</topic><topic>Dimethyl Fumarate - therapeutic use</topic><topic>Female</topic><topic>Flow cytometry</topic><topic>Helper cells</topic><topic>Humans</topic><topic>Immunological memory</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Inflammation</topic><topic>Ionomycin</topic><topic>Learning</topic><topic>Leukocytes (mononuclear)</topic><topic>Lymphocyte Count</topic><topic>Lymphocytes</topic><topic>Lymphocytes B</topic><topic>Lymphocytes T</topic><topic>Lymphopenia</topic><topic>Lymphopenia - chemically induced</topic><topic>Male</topic><topic>Memory cells</topic><topic>Middle Aged</topic><topic>Mucosa</topic><topic>Multiple sclerosis</topic><topic>Multiple Sclerosis, Relapsing-Remitting - drug therapy</topic><topic>Multiple Sclerosis, Relapsing-Remitting - immunology</topic><topic>Peripheral blood mononuclear cells</topic><topic>Phenotypes</topic><topic>T cell receptors</topic><topic>T-Lymphocytes - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Longbrake, Erin E</creatorcontrib><creatorcontrib>Cantoni, Claudia</creatorcontrib><creatorcontrib>Chahin, Salim</creatorcontrib><creatorcontrib>Cignarella, Francesca</creatorcontrib><creatorcontrib>Cross, Anne H</creatorcontrib><creatorcontrib>Piccio, Laura</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>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Multiple sclerosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Longbrake, Erin E</au><au>Cantoni, Claudia</au><au>Chahin, Salim</au><au>Cignarella, Francesca</au><au>Cross, Anne H</au><au>Piccio, Laura</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count</atitle><jtitle>Multiple sclerosis</jtitle><addtitle>Mult Scler</addtitle><date>2018-05-01</date><risdate>2018</risdate><volume>24</volume><issue>6</issue><spage>728</spage><epage>738</epage><pages>728-738</pages><issn>1352-4585</issn><eissn>1477-0970</eissn><abstract>Background:
Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes.
Objectives:
To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes.
Methods:
Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC < 800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed.
Results:
DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4+ CXCR5+) and mucosal invariant T-cells (CD8+ CD161+) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients.
Conclusion:
These data implicate DMF-induced changes in lymphocytes as an important component of the drug’s efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>28480794</pmid><doi>10.1177/1352458517707069</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Multiple sclerosis, 2018-05, Vol.24 (6), p.728-738 |
| issn | 1352-4585 1477-0970 |
| language | eng |
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| source | Access via SAGE; MEDLINE |
| subjects | Adult B-Lymphocytes - drug effects CD4 antigen CD8 antigen Cell activation Cell death Cell number Cross-Sectional Studies CXCR5 protein Cytokines Dimethyl Fumarate - therapeutic use Female Flow cytometry Helper cells Humans Immunological memory Immunosuppressive Agents - therapeutic use Inflammation Ionomycin Learning Leukocytes (mononuclear) Lymphocyte Count Lymphocytes Lymphocytes B Lymphocytes T Lymphopenia Lymphopenia - chemically induced Male Memory cells Middle Aged Mucosa Multiple sclerosis Multiple Sclerosis, Relapsing-Remitting - drug therapy Multiple Sclerosis, Relapsing-Remitting - immunology Peripheral blood mononuclear cells Phenotypes T cell receptors T-Lymphocytes - drug effects |
| title | Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count |
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