Silencing T-bet Defines a Critical Role in the Differentiation of Autoreactive T Lymphocytes
As a means of developing therapies that target the pathogenic T cells in multiple sclerosis (MS) without compromising the immune system or eliciting systemic side effects, we investigated the use of T-bet-specific antisense oligonucleotides and small interfering RNAs (siRNA) to silence T-bet express...
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| Veröffentlicht in: | Immunity (Cambridge, Mass.) Mass.), 2004-11, Vol.21 (5), p.719-731 |
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| creator | Lovett-Racke, Amy E. Rocchini, Anne E. Choy, Judy Northrop, Sara C. Hussain, Rehana Z. Ratts, Robert B. Sikder, Devanjan Racke, Michael K. |
| description | As a means of developing therapies that target the pathogenic T cells in multiple sclerosis (MS) without compromising the immune system or eliciting systemic side effects, we investigated the use of T-bet-specific antisense oligonucleotides and small interfering RNAs (siRNA) to silence T-bet expression in autoreactive encephalitogenic T cells and evaluated the biological consequences of this suppression in experimental autoimmune encephalomyelitis, a model for MS. The T-bet-specific AS oligonucleotide and siRNA suppressed T-bet expression, IFNγ production, and STAT1 levels during antigen-specific T cell differentiation. In vitro suppression of T-bet during differentiation of myelin-specific T cells and in vivo administration of a T-bet-specific antisense oligonucleotide or siRNA inhibited disease. T-bet was shown to bind the
IFNγ and
STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNγ production in CD4+ T cells, but to a lesser extent in most other IFNγ-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases. |
| doi_str_mv | 10.1016/j.immuni.2004.09.010 |
| format | Article |
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IFNγ and
STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNγ production in CD4+ T cells, but to a lesser extent in most other IFNγ-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.</description><identifier>ISSN: 1074-7613</identifier><identifier>EISSN: 1097-4180</identifier><identifier>DOI: 10.1016/j.immuni.2004.09.010</identifier><identifier>PMID: 15539157</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Autoimmune diseases ; Cell Differentiation ; Deoxyribonucleic acid ; Disease ; DNA ; DNA-Binding Proteins - genetics ; Encephalomyelitis, Autoimmune, Experimental - immunology ; Encephalomyelitis, Autoimmune, Experimental - therapy ; Genes ; Interferon-gamma - genetics ; Interleukin-12 - pharmacology ; Lymphocytes ; Mice ; Oligonucleotides, Antisense - pharmacology ; Proteins ; Receptors, Interleukin - genetics ; Receptors, Interleukin-12 ; RNA, Small Interfering - pharmacology ; STAT1 Transcription Factor ; STAT4 Transcription Factor ; Studies ; T cell receptors ; T-Box Domain Proteins ; T-Lymphocytes - cytology ; Trans-Activators - genetics ; Transcription factors ; Transcription Factors - genetics ; Transcription Factors - physiology</subject><ispartof>Immunity (Cambridge, Mass.), 2004-11, Vol.21 (5), p.719-731</ispartof><rights>2004 Cell Press</rights><rights>Copyright Elsevier Limited Nov 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-dadf98bbccf7d75fdc808ea1576094162fdf3a18c8ea6bf1a13a27ec00d89263</citedby><cites>FETCH-LOGICAL-c463t-dadf98bbccf7d75fdc808ea1576094162fdf3a18c8ea6bf1a13a27ec00d89263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.immuni.2004.09.010$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15539157$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lovett-Racke, Amy E.</creatorcontrib><creatorcontrib>Rocchini, Anne E.</creatorcontrib><creatorcontrib>Choy, Judy</creatorcontrib><creatorcontrib>Northrop, Sara C.</creatorcontrib><creatorcontrib>Hussain, Rehana Z.</creatorcontrib><creatorcontrib>Ratts, Robert B.</creatorcontrib><creatorcontrib>Sikder, Devanjan</creatorcontrib><creatorcontrib>Racke, Michael K.</creatorcontrib><title>Silencing T-bet Defines a Critical Role in the Differentiation of Autoreactive T Lymphocytes</title><title>Immunity (Cambridge, Mass.)</title><addtitle>Immunity</addtitle><description>As a means of developing therapies that target the pathogenic T cells in multiple sclerosis (MS) without compromising the immune system or eliciting systemic side effects, we investigated the use of T-bet-specific antisense oligonucleotides and small interfering RNAs (siRNA) to silence T-bet expression in autoreactive encephalitogenic T cells and evaluated the biological consequences of this suppression in experimental autoimmune encephalomyelitis, a model for MS. The T-bet-specific AS oligonucleotide and siRNA suppressed T-bet expression, IFNγ production, and STAT1 levels during antigen-specific T cell differentiation. In vitro suppression of T-bet during differentiation of myelin-specific T cells and in vivo administration of a T-bet-specific antisense oligonucleotide or siRNA inhibited disease. T-bet was shown to bind the
IFNγ and
STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNγ production in CD4+ T cells, but to a lesser extent in most other IFNγ-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.</description><subject>Animals</subject><subject>Autoimmune diseases</subject><subject>Cell Differentiation</subject><subject>Deoxyribonucleic acid</subject><subject>Disease</subject><subject>DNA</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Encephalomyelitis, Autoimmune, Experimental - immunology</subject><subject>Encephalomyelitis, Autoimmune, Experimental - therapy</subject><subject>Genes</subject><subject>Interferon-gamma - genetics</subject><subject>Interleukin-12 - pharmacology</subject><subject>Lymphocytes</subject><subject>Mice</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Proteins</subject><subject>Receptors, Interleukin - genetics</subject><subject>Receptors, Interleukin-12</subject><subject>RNA, Small Interfering - pharmacology</subject><subject>STAT1 Transcription Factor</subject><subject>STAT4 Transcription Factor</subject><subject>Studies</subject><subject>T cell receptors</subject><subject>T-Box Domain Proteins</subject><subject>T-Lymphocytes - cytology</subject><subject>Trans-Activators - genetics</subject><subject>Transcription factors</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - physiology</subject><issn>1074-7613</issn><issn>1097-4180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkVuL1DAUgIso7rr6D0QCwr61nrRN0r4Iy6w3GBB0HoWQJiduhjYZk3Rh_r0ZZkDwQfNyQvjOJeerqtcUGgqUv9s3bllW75oWoG9gbIDCk-qawijqng7w9HQXfS047a6qFyntAWjPRnheXVHGupEycV39-O5m9Nr5n2RXT5jJPVrnMRFFNtFlp9VMvoUZifMkPyC5d9ZiRJ-dyi54Eiy5W3OIqHR2j0h2ZHtcDg9BHzOml9Uzq-aEry7xptp9_LDbfK63Xz992dxta93zLtdGGTsO06S1FUYwa_QAA6oyH4exp7y1xnaKDro88slSRTvVCtQAZhhb3t1Ut-eyhxh-rZiyXFzSOM_KY1iT5AJ4yxj9L0iFgKGcAr79C9yHNfryB0kZ9G0HLYNC9WdKx5BSRCsP0S0qHiUFeXIk9_LsSJ4cSRhlcVTS3lyKr9OC5k_SRUoB3p8BLDt7dBhl0q5IQuMi6ixNcP_u8BsmLaRW</recordid><startdate>20041101</startdate><enddate>20041101</enddate><creator>Lovett-Racke, Amy E.</creator><creator>Rocchini, Anne E.</creator><creator>Choy, Judy</creator><creator>Northrop, Sara C.</creator><creator>Hussain, Rehana Z.</creator><creator>Ratts, Robert B.</creator><creator>Sikder, Devanjan</creator><creator>Racke, Michael K.</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20041101</creationdate><title>Silencing T-bet Defines a Critical Role in the Differentiation of Autoreactive T Lymphocytes</title><author>Lovett-Racke, Amy E. ; 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IFNγ and
STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNγ production in CD4+ T cells, but to a lesser extent in most other IFNγ-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15539157</pmid><doi>10.1016/j.immuni.2004.09.010</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Autoimmune diseases Cell Differentiation Deoxyribonucleic acid Disease DNA DNA-Binding Proteins - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - therapy Genes Interferon-gamma - genetics Interleukin-12 - pharmacology Lymphocytes Mice Oligonucleotides, Antisense - pharmacology Proteins Receptors, Interleukin - genetics Receptors, Interleukin-12 RNA, Small Interfering - pharmacology STAT1 Transcription Factor STAT4 Transcription Factor Studies T cell receptors T-Box Domain Proteins T-Lymphocytes - cytology Trans-Activators - genetics Transcription factors Transcription Factors - genetics Transcription Factors - physiology |
| title | Silencing T-bet Defines a Critical Role in the Differentiation of Autoreactive T Lymphocytes |
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