Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells
Abstract Objective Recent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molec...
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| Veröffentlicht in: | Atherosclerosis 2012-02, Vol.220 (2), p.329-336 |
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| creator | Dietrich, Thore Hucko, Thomas Schneemann, Christiane Neumann, Marleen Menrad, Andreas Willuda, Joerg Atrott, Kirstin Stibenz, Dietger Fleck, Eckart Graf, Kristof Menssen, Hans D |
| description | Abstract Objective Recent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis. Methods and results L19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE−/− mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of pre-established atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls ( p < 0.01), whereas the macrophage marker Mac3 was significantly reduced ( p < 0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control ( p < 0.03). Conclusion L19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE−/− mice resulting in significant plaque size reduction mediated by local Tregs. |
| doi_str_mv | 10.1016/j.atherosclerosis.2011.09.050 |
| format | Article |
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Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis. Methods and results L19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE−/− mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of pre-established atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls ( p < 0.01), whereas the macrophage marker Mac3 was significantly reduced ( p < 0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control ( p < 0.03). Conclusion L19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE−/− mice resulting in significant plaque size reduction mediated by local Tregs.</description><identifier>ISSN: 0021-9150</identifier><identifier>EISSN: 1879-1484</identifier><identifier>DOI: 10.1016/j.atherosclerosis.2011.09.050</identifier><identifier>PMID: 22062588</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ireland Ltd</publisher><subject>Animals ; Aorta - drug effects ; Aorta - immunology ; Aorta - metabolism ; Aorta - pathology ; Aortic Diseases - genetics ; Aortic Diseases - immunology ; Aortic Diseases - metabolism ; Aortic Diseases - pathology ; Aortic Diseases - prevention & control ; apoE −/− mice ; Apolipoproteins E - deficiency ; Apolipoproteins E - genetics ; Atherosclerosis ; Atherosclerosis (general aspects, experimental research) ; Atherosclerosis - genetics ; Atherosclerosis - immunology ; Atherosclerosis - metabolism ; Atherosclerosis - pathology ; Atherosclerosis - prevention & control ; Biological and medical sciences ; Blood and lymphatic vessels ; Blood vessels and receptors ; Cardiology. Vascular system ; Cardiovascular ; Cardiovascular Agents - administration & dosage ; Cell Proliferation - drug effects ; Diet, High-Fat ; Disease Models, Animal ; Extracellular matrix ; Extradomain B fibronectin ; Fundamental and applied biological sciences. Psychology ; Humans ; Injections, Intravenous ; L19-IL2 ; Lipids - blood ; Macrophages - drug effects ; Macrophages - immunology ; Magnetic Resonance Imaging ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Recombinant Fusion Proteins - administration & dosage ; T-lymphocytes ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - immunology ; Time Factors ; Vertebrates: cardiovascular system</subject><ispartof>Atherosclerosis, 2012-02, Vol.220 (2), p.329-336</ispartof><rights>Elsevier Ireland Ltd</rights><rights>2011 Elsevier Ireland Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-d6b537fcafcc4d588d9d111cad80207d1b047745765897902d9e07cece15ad743</citedby><cites>FETCH-LOGICAL-c473t-d6b537fcafcc4d588d9d111cad80207d1b047745765897902d9e07cece15ad743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.atherosclerosis.2011.09.050$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25454999$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22062588$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dietrich, Thore</creatorcontrib><creatorcontrib>Hucko, Thomas</creatorcontrib><creatorcontrib>Schneemann, Christiane</creatorcontrib><creatorcontrib>Neumann, Marleen</creatorcontrib><creatorcontrib>Menrad, Andreas</creatorcontrib><creatorcontrib>Willuda, Joerg</creatorcontrib><creatorcontrib>Atrott, Kirstin</creatorcontrib><creatorcontrib>Stibenz, Dietger</creatorcontrib><creatorcontrib>Fleck, Eckart</creatorcontrib><creatorcontrib>Graf, Kristof</creatorcontrib><creatorcontrib>Menssen, Hans D</creatorcontrib><title>Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells</title><title>Atherosclerosis</title><addtitle>Atherosclerosis</addtitle><description>Abstract Objective Recent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis. Methods and results L19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE−/− mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of pre-established atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls ( p < 0.01), whereas the macrophage marker Mac3 was significantly reduced ( p < 0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control ( p < 0.03). Conclusion L19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE−/− mice resulting in significant plaque size reduction mediated by local Tregs.</description><subject>Animals</subject><subject>Aorta - drug effects</subject><subject>Aorta - immunology</subject><subject>Aorta - metabolism</subject><subject>Aorta - pathology</subject><subject>Aortic Diseases - genetics</subject><subject>Aortic Diseases - immunology</subject><subject>Aortic Diseases - metabolism</subject><subject>Aortic Diseases - pathology</subject><subject>Aortic Diseases - prevention & control</subject><subject>apoE −/− mice</subject><subject>Apolipoproteins E - deficiency</subject><subject>Apolipoproteins E - genetics</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - immunology</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - pathology</subject><subject>Atherosclerosis - prevention & control</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Blood vessels and receptors</subject><subject>Cardiology. Vascular system</subject><subject>Cardiovascular</subject><subject>Cardiovascular Agents - administration & dosage</subject><subject>Cell Proliferation - drug effects</subject><subject>Diet, High-Fat</subject><subject>Disease Models, Animal</subject><subject>Extracellular matrix</subject><subject>Extradomain B fibronectin</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Injections, Intravenous</subject><subject>L19-IL2</subject><subject>Lipids - blood</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - immunology</subject><subject>Magnetic Resonance Imaging</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Recombinant Fusion Proteins - administration & dosage</subject><subject>T-lymphocytes</subject><subject>T-Lymphocytes, Regulatory - drug effects</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Time Factors</subject><subject>Vertebrates: cardiovascular system</subject><issn>0021-9150</issn><issn>1879-1484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkkFv1DAQhS0EokvhL6BcKk4JM944jg8goYqWSitVgnK2vPYEvGTjxU5W7L-vo1162FMv9uV7b948DWNXCBUCNh83lRl_UwzJ9vPrU8UBsQJVgYAXbIGtVCXWbf2SLQA4lgoFXLA3KW0AoJbYvmYXnEPDRdsu2PdVsKYvHPV-T_FQhK64W5W8iOQmS6k4G1bsvSno384MyYdhpiP9mnozhqx9KCz1fXrLXnWmT_Tu9F-ynzdfH66_lav727vrL6vS1nI5lq5Zi6XsrOmsrV0O45RDRGtcCxykw3VOK2shG9EqqYA7RSAtWUJhnKyXl-zD0XcXw9-J0qi3Ps0JzEBhSlqhzOKszuSnI2nzEilSp3fRb008aAQ9t6o3-mxRPbeqQencata_P02a1ltyT-r_NWbg6gSYlOvsohls9njiRC1qpVTmbo8c5V72nqJO1tNgyflIdtQu-GdH-nzmZHs_-Dz8Dx0obcIUh1y-Rp24Bv1jPoX5EhABlGjk8hF0dbSL</recordid><startdate>20120201</startdate><enddate>20120201</enddate><creator>Dietrich, Thore</creator><creator>Hucko, Thomas</creator><creator>Schneemann, Christiane</creator><creator>Neumann, Marleen</creator><creator>Menrad, Andreas</creator><creator>Willuda, Joerg</creator><creator>Atrott, Kirstin</creator><creator>Stibenz, Dietger</creator><creator>Fleck, Eckart</creator><creator>Graf, Kristof</creator><creator>Menssen, Hans D</creator><general>Elsevier Ireland Ltd</general><general>Elsevier</general><scope>IQODW</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>7X8</scope></search><sort><creationdate>20120201</creationdate><title>Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells</title><author>Dietrich, Thore ; Hucko, Thomas ; Schneemann, Christiane ; Neumann, Marleen ; Menrad, Andreas ; Willuda, Joerg ; Atrott, Kirstin ; Stibenz, Dietger ; Fleck, Eckart ; Graf, Kristof ; Menssen, Hans D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-d6b537fcafcc4d588d9d111cad80207d1b047745765897902d9e07cece15ad743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Aorta - drug effects</topic><topic>Aorta - immunology</topic><topic>Aorta - metabolism</topic><topic>Aorta - pathology</topic><topic>Aortic Diseases - genetics</topic><topic>Aortic Diseases - immunology</topic><topic>Aortic Diseases - metabolism</topic><topic>Aortic Diseases - pathology</topic><topic>Aortic Diseases - prevention & control</topic><topic>apoE −/− mice</topic><topic>Apolipoproteins E - deficiency</topic><topic>Apolipoproteins E - genetics</topic><topic>Atherosclerosis</topic><topic>Atherosclerosis (general aspects, experimental research)</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - immunology</topic><topic>Atherosclerosis - metabolism</topic><topic>Atherosclerosis - pathology</topic><topic>Atherosclerosis - prevention & control</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Blood vessels and receptors</topic><topic>Cardiology. Vascular system</topic><topic>Cardiovascular</topic><topic>Cardiovascular Agents - administration & dosage</topic><topic>Cell Proliferation - drug effects</topic><topic>Diet, High-Fat</topic><topic>Disease Models, Animal</topic><topic>Extracellular matrix</topic><topic>Extradomain B fibronectin</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Injections, Intravenous</topic><topic>L19-IL2</topic><topic>Lipids - blood</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - immunology</topic><topic>Magnetic Resonance Imaging</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Recombinant Fusion Proteins - administration & dosage</topic><topic>T-lymphocytes</topic><topic>T-Lymphocytes, Regulatory - drug effects</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Time Factors</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dietrich, Thore</creatorcontrib><creatorcontrib>Hucko, Thomas</creatorcontrib><creatorcontrib>Schneemann, Christiane</creatorcontrib><creatorcontrib>Neumann, Marleen</creatorcontrib><creatorcontrib>Menrad, Andreas</creatorcontrib><creatorcontrib>Willuda, Joerg</creatorcontrib><creatorcontrib>Atrott, Kirstin</creatorcontrib><creatorcontrib>Stibenz, Dietger</creatorcontrib><creatorcontrib>Fleck, Eckart</creatorcontrib><creatorcontrib>Graf, Kristof</creatorcontrib><creatorcontrib>Menssen, Hans D</creatorcontrib><collection>Pascal-Francis</collection><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>Atherosclerosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dietrich, Thore</au><au>Hucko, Thomas</au><au>Schneemann, Christiane</au><au>Neumann, Marleen</au><au>Menrad, Andreas</au><au>Willuda, Joerg</au><au>Atrott, Kirstin</au><au>Stibenz, Dietger</au><au>Fleck, Eckart</au><au>Graf, Kristof</au><au>Menssen, Hans D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells</atitle><jtitle>Atherosclerosis</jtitle><addtitle>Atherosclerosis</addtitle><date>2012-02-01</date><risdate>2012</risdate><volume>220</volume><issue>2</issue><spage>329</spage><epage>336</epage><pages>329-336</pages><issn>0021-9150</issn><eissn>1879-1484</eissn><abstract>Abstract Objective Recent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis. Methods and results L19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE−/− mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of pre-established atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls ( p < 0.01), whereas the macrophage marker Mac3 was significantly reduced ( p < 0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control ( p < 0.03). Conclusion L19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE−/− mice resulting in significant plaque size reduction mediated by local Tregs.</abstract><cop>Amsterdam</cop><pub>Elsevier Ireland Ltd</pub><pmid>22062588</pmid><doi>10.1016/j.atherosclerosis.2011.09.050</doi><tpages>8</tpages></addata></record> |
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| subjects | Animals Aorta - drug effects Aorta - immunology Aorta - metabolism Aorta - pathology Aortic Diseases - genetics Aortic Diseases - immunology Aortic Diseases - metabolism Aortic Diseases - pathology Aortic Diseases - prevention & control apoE −/− mice Apolipoproteins E - deficiency Apolipoproteins E - genetics Atherosclerosis Atherosclerosis (general aspects, experimental research) Atherosclerosis - genetics Atherosclerosis - immunology Atherosclerosis - metabolism Atherosclerosis - pathology Atherosclerosis - prevention & control Biological and medical sciences Blood and lymphatic vessels Blood vessels and receptors Cardiology. Vascular system Cardiovascular Cardiovascular Agents - administration & dosage Cell Proliferation - drug effects Diet, High-Fat Disease Models, Animal Extracellular matrix Extradomain B fibronectin Fundamental and applied biological sciences. Psychology Humans Injections, Intravenous L19-IL2 Lipids - blood Macrophages - drug effects Macrophages - immunology Magnetic Resonance Imaging Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Recombinant Fusion Proteins - administration & dosage T-lymphocytes T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - immunology Time Factors Vertebrates: cardiovascular system |
| title | Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells |
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