JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms
Summary Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT‐signalling is known to be involved in the regulation of CD4+ T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4+ T cell re...
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| Veröffentlicht in: | British journal of haematology 2015-06, Vol.169 (6), p.824-833 |
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| creator | Parampalli Yajnanarayana, Sowmya Stübig, Thomas Cornez, Isabelle Alchalby, Haefaa Schönberg, Kathrin Rudolph, Janna Triviai, Ioanna Wolschke, Christine Heine, Annkristin Brossart, Peter Kröger, Nicolaus Wolf, Dominik |
| description | Summary
Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT‐signalling is known to be involved in the regulation of CD4+ T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4+ T cell responses, we undertook an in‐depth analysis of CD4+ T cell function upon ruxolitinib exposure. We observed a decrease in total CD3+ cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro‐inflammatory T‐helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor‐α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P |
| doi_str_mv | 10.1111/bjh.13373 |
| format | Article |
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Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT‐signalling is known to be involved in the regulation of CD4+ T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4+ T cell responses, we undertook an in‐depth analysis of CD4+ T cell function upon ruxolitinib exposure. We observed a decrease in total CD3+ cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro‐inflammatory T‐helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor‐α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0·05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2‐dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4+ T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib‐treated patients.</description><identifier>ISSN: 0007-1048</identifier><identifier>EISSN: 1365-2141</identifier><identifier>DOI: 10.1111/bjh.13373</identifier><identifier>PMID: 25824483</identifier><language>eng</language><publisher>England</publisher><subject>Aged ; Cell Differentiation - drug effects ; Cell Differentiation - immunology ; Cell Proliferation - drug effects ; Cytokines - biosynthesis ; Humans ; Immunophenotyping ; immunotherapy ; Janus Kinase 1 - antagonists & inhibitors ; Janus Kinase 1 - metabolism ; Janus Kinase 2 - antagonists & inhibitors ; Janus Kinase 2 - metabolism ; Janus kinases inhibitor ; Lymphocyte Activation - drug effects ; Lymphocyte Activation - immunology ; Lymphocyte Count ; Middle Aged ; myeloproliferative disease ; Myeloproliferative Disorders - drug therapy ; Myeloproliferative Disorders - immunology ; Myeloproliferative Disorders - metabolism ; Phenotype ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Pyrazoles - pharmacology ; Pyrazoles - therapeutic use ; Receptors, Antigen, T-Cell - metabolism ; ruxolitinib ; Signal Transduction - drug effects ; STAT5 Transcription Factor - metabolism ; T cells ; T-Lymphocyte Subsets - drug effects ; T-Lymphocyte Subsets - immunology ; T-Lymphocyte Subsets - metabolism ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism</subject><ispartof>British journal of haematology, 2015-06, Vol.169 (6), p.824-833</ispartof><rights>2015 John Wiley & Sons Ltd</rights><rights>2015 John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2753-1f212353c15affbf83448c3b89e51a6c47017588326c9355a4e1279a0375c76e3</citedby><cites>FETCH-LOGICAL-c2753-1f212353c15affbf83448c3b89e51a6c47017588326c9355a4e1279a0375c76e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbjh.13373$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbjh.13373$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25824483$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Parampalli Yajnanarayana, Sowmya</creatorcontrib><creatorcontrib>Stübig, Thomas</creatorcontrib><creatorcontrib>Cornez, Isabelle</creatorcontrib><creatorcontrib>Alchalby, Haefaa</creatorcontrib><creatorcontrib>Schönberg, Kathrin</creatorcontrib><creatorcontrib>Rudolph, Janna</creatorcontrib><creatorcontrib>Triviai, Ioanna</creatorcontrib><creatorcontrib>Wolschke, Christine</creatorcontrib><creatorcontrib>Heine, Annkristin</creatorcontrib><creatorcontrib>Brossart, Peter</creatorcontrib><creatorcontrib>Kröger, Nicolaus</creatorcontrib><creatorcontrib>Wolf, Dominik</creatorcontrib><title>JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms</title><title>British journal of haematology</title><addtitle>Br J Haematol</addtitle><description>Summary
Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT‐signalling is known to be involved in the regulation of CD4+ T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4+ T cell responses, we undertook an in‐depth analysis of CD4+ T cell function upon ruxolitinib exposure. We observed a decrease in total CD3+ cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro‐inflammatory T‐helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor‐α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0·05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2‐dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4+ T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib‐treated patients.</description><subject>Aged</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Differentiation - immunology</subject><subject>Cell Proliferation - drug effects</subject><subject>Cytokines - biosynthesis</subject><subject>Humans</subject><subject>Immunophenotyping</subject><subject>immunotherapy</subject><subject>Janus Kinase 1 - antagonists & inhibitors</subject><subject>Janus Kinase 1 - metabolism</subject><subject>Janus Kinase 2 - antagonists & inhibitors</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Janus kinases inhibitor</subject><subject>Lymphocyte Activation - drug effects</subject><subject>Lymphocyte Activation - immunology</subject><subject>Lymphocyte Count</subject><subject>Middle Aged</subject><subject>myeloproliferative disease</subject><subject>Myeloproliferative Disorders - drug therapy</subject><subject>Myeloproliferative Disorders - immunology</subject><subject>Myeloproliferative Disorders - metabolism</subject><subject>Phenotype</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrazoles - therapeutic use</subject><subject>Receptors, Antigen, T-Cell - metabolism</subject><subject>ruxolitinib</subject><subject>Signal Transduction - drug effects</subject><subject>STAT5 Transcription Factor - metabolism</subject><subject>T cells</subject><subject>T-Lymphocyte Subsets - drug effects</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocyte Subsets - metabolism</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><issn>0007-1048</issn><issn>1365-2141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kM9OAjEQxhujEUQPvoDpUQ8LnXa7LUckKiKJFzw33dINJfvP7SLhbXwWn8ziojfnMpmZX7588yF0DWQIoUbpZj0ExgQ7QX1gCY8oxHCK-oQQEQGJZQ9deL8hBBjhcI56lEsax5L1kZ1PXmBEsSvXLnWtq0rsilq7xuMlNjbPcbYtTbcvvz4_XNtUWJerMOFat86Wrcc7165xsbd5VTdV7jLbhMuHxaWt6lz7wl-is0zn3l4d-wC9PT4sp7No8fr0PJ0sIkMFZxFkFCjjzADXWZZmkgWThqVybDnoxMSCgOBSMpqYMeNcxxaoGGvCBDcisWyAbjvd4ON9a32rCucPX-hgZesVJJILToDQgN51qGkq7xubqbpxhW72Cog6pKpCquon1cDeHGW3aWFXf-RvjAEYdcDO5Xb_v5K6n886yW8TrIEA</recordid><startdate>201506</startdate><enddate>201506</enddate><creator>Parampalli Yajnanarayana, Sowmya</creator><creator>Stübig, Thomas</creator><creator>Cornez, Isabelle</creator><creator>Alchalby, Haefaa</creator><creator>Schönberg, Kathrin</creator><creator>Rudolph, Janna</creator><creator>Triviai, Ioanna</creator><creator>Wolschke, Christine</creator><creator>Heine, Annkristin</creator><creator>Brossart, Peter</creator><creator>Kröger, Nicolaus</creator><creator>Wolf, Dominik</creator><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>7X8</scope></search><sort><creationdate>201506</creationdate><title>JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms</title><author>Parampalli Yajnanarayana, Sowmya ; Stübig, Thomas ; Cornez, Isabelle ; Alchalby, Haefaa ; Schönberg, Kathrin ; Rudolph, Janna ; Triviai, Ioanna ; Wolschke, Christine ; Heine, Annkristin ; Brossart, Peter ; Kröger, Nicolaus ; Wolf, Dominik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2753-1f212353c15affbf83448c3b89e51a6c47017588326c9355a4e1279a0375c76e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aged</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Differentiation - immunology</topic><topic>Cell Proliferation - drug effects</topic><topic>Cytokines - biosynthesis</topic><topic>Humans</topic><topic>Immunophenotyping</topic><topic>immunotherapy</topic><topic>Janus Kinase 1 - antagonists & inhibitors</topic><topic>Janus Kinase 1 - metabolism</topic><topic>Janus Kinase 2 - antagonists & inhibitors</topic><topic>Janus Kinase 2 - metabolism</topic><topic>Janus kinases inhibitor</topic><topic>Lymphocyte Activation - drug effects</topic><topic>Lymphocyte Activation - immunology</topic><topic>Lymphocyte Count</topic><topic>Middle Aged</topic><topic>myeloproliferative disease</topic><topic>Myeloproliferative Disorders - drug therapy</topic><topic>Myeloproliferative Disorders - immunology</topic><topic>Myeloproliferative Disorders - metabolism</topic><topic>Phenotype</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrazoles - therapeutic use</topic><topic>Receptors, Antigen, T-Cell - metabolism</topic><topic>ruxolitinib</topic><topic>Signal Transduction - drug effects</topic><topic>STAT5 Transcription Factor - metabolism</topic><topic>T cells</topic><topic>T-Lymphocyte Subsets - drug effects</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocyte Subsets - metabolism</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Parampalli Yajnanarayana, Sowmya</creatorcontrib><creatorcontrib>Stübig, Thomas</creatorcontrib><creatorcontrib>Cornez, Isabelle</creatorcontrib><creatorcontrib>Alchalby, Haefaa</creatorcontrib><creatorcontrib>Schönberg, Kathrin</creatorcontrib><creatorcontrib>Rudolph, Janna</creatorcontrib><creatorcontrib>Triviai, Ioanna</creatorcontrib><creatorcontrib>Wolschke, Christine</creatorcontrib><creatorcontrib>Heine, Annkristin</creatorcontrib><creatorcontrib>Brossart, Peter</creatorcontrib><creatorcontrib>Kröger, Nicolaus</creatorcontrib><creatorcontrib>Wolf, Dominik</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>British journal of haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Parampalli Yajnanarayana, Sowmya</au><au>Stübig, Thomas</au><au>Cornez, Isabelle</au><au>Alchalby, Haefaa</au><au>Schönberg, Kathrin</au><au>Rudolph, Janna</au><au>Triviai, Ioanna</au><au>Wolschke, Christine</au><au>Heine, Annkristin</au><au>Brossart, Peter</au><au>Kröger, Nicolaus</au><au>Wolf, Dominik</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms</atitle><jtitle>British journal of haematology</jtitle><addtitle>Br J Haematol</addtitle><date>2015-06</date><risdate>2015</risdate><volume>169</volume><issue>6</issue><spage>824</spage><epage>833</epage><pages>824-833</pages><issn>0007-1048</issn><eissn>1365-2141</eissn><abstract>Summary
Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT‐signalling is known to be involved in the regulation of CD4+ T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4+ T cell responses, we undertook an in‐depth analysis of CD4+ T cell function upon ruxolitinib exposure. We observed a decrease in total CD3+ cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro‐inflammatory T‐helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor‐α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0·05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2‐dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4+ T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib‐treated patients.</abstract><cop>England</cop><pmid>25824483</pmid><doi>10.1111/bjh.13373</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Cell Differentiation - drug effects Cell Differentiation - immunology Cell Proliferation - drug effects Cytokines - biosynthesis Humans Immunophenotyping immunotherapy Janus Kinase 1 - antagonists & inhibitors Janus Kinase 1 - metabolism Janus Kinase 2 - antagonists & inhibitors Janus Kinase 2 - metabolism Janus kinases inhibitor Lymphocyte Activation - drug effects Lymphocyte Activation - immunology Lymphocyte Count Middle Aged myeloproliferative disease Myeloproliferative Disorders - drug therapy Myeloproliferative Disorders - immunology Myeloproliferative Disorders - metabolism Phenotype Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Pyrazoles - pharmacology Pyrazoles - therapeutic use Receptors, Antigen, T-Cell - metabolism ruxolitinib Signal Transduction - drug effects STAT5 Transcription Factor - metabolism T cells T-Lymphocyte Subsets - drug effects T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism |
| title | JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms |
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