Immunoengineering of the Vascular Endothelium to Silence MHC Expression During Normothermic Ex Vivo Lung Perfusion
Disparities at the major histocompatibility complex (MHC) antigens and associated minor antigens trigger harmful immune responses, leading to graft rejection after transplantation. We showed that MHC-silenced cells and tissues are efficiently protected against rejection. In complex vascularized orga...
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| Veröffentlicht in: | Human gene therapy 2019-04, Vol.30 (4), p.485-496 |
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| creator | Figueiredo, Constanca Carvalho Oliveira, Marco Chen-Wacker, Chen Jansson, Katharina Höffler, Klaus Yuzefovych, Yuliia Pogozhykh, Olena Jin, Zhu Kühnel, Mark Jonigk, Danny Wiegmann, Bettina Sommer, Wiebke Haverich, Axel Warnecke, Gregor Blasczyk, Rainer |
| description | Disparities at the major histocompatibility complex (MHC) antigens and associated minor antigens trigger harmful immune responses, leading to graft rejection after transplantation. We showed that MHC-silenced cells and tissues are efficiently protected against rejection. In complex vascularized organs, the endothelium is the major interface between donor and recipient. This study therefore aimed to reduce the immunogenicity of the lung by silencing MHC expression on the endothelium. In porcine lungs, short-hairpin RNAs targeting beta-2-microglobulin and class II-transactivator transcripts were delivered by lentiviral vectors during normothermic ex vivo perfusion to silence swine leukocyte antigen (SLA) I and II expression permanently. The results demonstrated the feasibility of genetically engineering all lung regions, achieving a targeted silencing effect for SLA I and II of 67% and 52%, respectively, without affecting cell viability or tissue integrity. This decrease in immunogenicity carries the potential to generate immunologically invisible organs to counteract the burden of rejection and immunosuppression. |
| doi_str_mv | 10.1089/hum.2018.117 |
| format | Article |
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We showed that MHC-silenced cells and tissues are efficiently protected against rejection. In complex vascularized organs, the endothelium is the major interface between donor and recipient. This study therefore aimed to reduce the immunogenicity of the lung by silencing MHC expression on the endothelium. In porcine lungs, short-hairpin RNAs targeting beta-2-microglobulin and class II-transactivator transcripts were delivered by lentiviral vectors during normothermic ex vivo perfusion to silence swine leukocyte antigen (SLA) I and II expression permanently. The results demonstrated the feasibility of genetically engineering all lung regions, achieving a targeted silencing effect for SLA I and II of 67% and 52%, respectively, without affecting cell viability or tissue integrity. This decrease in immunogenicity carries the potential to generate immunologically invisible organs to counteract the burden of rejection and immunosuppression.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.2018.117</identifier><identifier>PMID: 30261752</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Animals ; Antigens ; Cell viability ; Endothelial Cells - metabolism ; Endothelium ; Endothelium, Vascular - metabolism ; Feasibility studies ; Gene Expression ; Gene Silencing ; Gene Transfer Techniques ; Genes, Reporter ; Genetic Engineering ; Genetic Vectors - genetics ; Graft rejection ; Histocompatibility Antigens - genetics ; Histocompatibility Antigens Class I - genetics ; Histocompatibility Antigens Class I - metabolism ; Histocompatibility Antigens Class II - genetics ; Histocompatibility Antigens Class II - metabolism ; Immune response ; Immunogenicity ; Immunosuppression ; Lentivirus - genetics ; Leukocytes ; Livestock ; Lung - metabolism ; Lung - pathology ; Lungs ; Major histocompatibility complex ; Organs ; Perfusion ; Rejection ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Silence ; Swine ; Temperature ; Tissues ; Transduction, Genetic ; Transplantation</subject><ispartof>Human gene therapy, 2019-04, Vol.30 (4), p.485-496</ispartof><rights>Copyright Mary Ann Liebert, Inc. Apr 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c319t-21f54ad690a5b267c50c646b01a478d8c56a41226904b5ac5854d4ff500e29ab3</citedby><cites>FETCH-LOGICAL-c319t-21f54ad690a5b267c50c646b01a478d8c56a41226904b5ac5854d4ff500e29ab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30261752$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Figueiredo, Constanca</creatorcontrib><creatorcontrib>Carvalho Oliveira, Marco</creatorcontrib><creatorcontrib>Chen-Wacker, Chen</creatorcontrib><creatorcontrib>Jansson, Katharina</creatorcontrib><creatorcontrib>Höffler, Klaus</creatorcontrib><creatorcontrib>Yuzefovych, Yuliia</creatorcontrib><creatorcontrib>Pogozhykh, Olena</creatorcontrib><creatorcontrib>Jin, Zhu</creatorcontrib><creatorcontrib>Kühnel, Mark</creatorcontrib><creatorcontrib>Jonigk, Danny</creatorcontrib><creatorcontrib>Wiegmann, Bettina</creatorcontrib><creatorcontrib>Sommer, Wiebke</creatorcontrib><creatorcontrib>Haverich, Axel</creatorcontrib><creatorcontrib>Warnecke, Gregor</creatorcontrib><creatorcontrib>Blasczyk, Rainer</creatorcontrib><title>Immunoengineering of the Vascular Endothelium to Silence MHC Expression During Normothermic Ex Vivo Lung Perfusion</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>Disparities at the major histocompatibility complex (MHC) antigens and associated minor antigens trigger harmful immune responses, leading to graft rejection after transplantation. We showed that MHC-silenced cells and tissues are efficiently protected against rejection. In complex vascularized organs, the endothelium is the major interface between donor and recipient. This study therefore aimed to reduce the immunogenicity of the lung by silencing MHC expression on the endothelium. In porcine lungs, short-hairpin RNAs targeting beta-2-microglobulin and class II-transactivator transcripts were delivered by lentiviral vectors during normothermic ex vivo perfusion to silence swine leukocyte antigen (SLA) I and II expression permanently. The results demonstrated the feasibility of genetically engineering all lung regions, achieving a targeted silencing effect for SLA I and II of 67% and 52%, respectively, without affecting cell viability or tissue integrity. This decrease in immunogenicity carries the potential to generate immunologically invisible organs to counteract the burden of rejection and immunosuppression.</description><subject>Animals</subject><subject>Antigens</subject><subject>Cell viability</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Feasibility studies</subject><subject>Gene Expression</subject><subject>Gene Silencing</subject><subject>Gene Transfer Techniques</subject><subject>Genes, Reporter</subject><subject>Genetic Engineering</subject><subject>Genetic Vectors - genetics</subject><subject>Graft rejection</subject><subject>Histocompatibility Antigens - genetics</subject><subject>Histocompatibility Antigens Class I - genetics</subject><subject>Histocompatibility Antigens Class I - metabolism</subject><subject>Histocompatibility Antigens Class II - genetics</subject><subject>Histocompatibility Antigens Class II - metabolism</subject><subject>Immune response</subject><subject>Immunogenicity</subject><subject>Immunosuppression</subject><subject>Lentivirus - genetics</subject><subject>Leukocytes</subject><subject>Livestock</subject><subject>Lung - metabolism</subject><subject>Lung - pathology</subject><subject>Lungs</subject><subject>Major histocompatibility complex</subject><subject>Organs</subject><subject>Perfusion</subject><subject>Rejection</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Silence</subject><subject>Swine</subject><subject>Temperature</subject><subject>Tissues</subject><subject>Transduction, Genetic</subject><subject>Transplantation</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0ctPGzEQB2CrKioUuHFGlnrpoRv8XO8eqzSQSOEh8bhaXq-XOFrbwY4R_Pc4QHvoySPPNyPLPwBOMJpg1LRnq-wmBOFmgrH4Ag4w56ISjJCvpUaMVogysg--p7RGCFNei29gnyJSY8HJAYgL57IPxj9ab0y0_hGGAW5XBj6opPOoIpz5PpSL0WYHtwHe2tF4beDlfApnL5toUrLBwz_5ffgqRLfT0Vld2vDBPge4zKVzY-KQd_QI7A1qTOb48zwE9-ezu-m8Wl5fLKa_l5WmuN1WBA-cqb5ukeIdqYXmSNes7hBWTDR9o3mtGCakANZxpXnDWc-GgSNkSKs6egh-fuzdxPCUTdpKZ5M246i8CTlJgjGrWy6oKPTHf3QdcvTldZIQRLFgrWiL-vWhdAwpRTPITbROxVeJkdxlIUsWcpeFLFkUfvq5NHfO9P_w38-nb26zhGg</recordid><startdate>201904</startdate><enddate>201904</enddate><creator>Figueiredo, Constanca</creator><creator>Carvalho Oliveira, Marco</creator><creator>Chen-Wacker, Chen</creator><creator>Jansson, Katharina</creator><creator>Höffler, Klaus</creator><creator>Yuzefovych, Yuliia</creator><creator>Pogozhykh, Olena</creator><creator>Jin, Zhu</creator><creator>Kühnel, Mark</creator><creator>Jonigk, Danny</creator><creator>Wiegmann, Bettina</creator><creator>Sommer, Wiebke</creator><creator>Haverich, Axel</creator><creator>Warnecke, Gregor</creator><creator>Blasczyk, Rainer</creator><general>Mary Ann Liebert, Inc</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>7QO</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201904</creationdate><title>Immunoengineering of the Vascular Endothelium to Silence MHC Expression During Normothermic Ex Vivo Lung Perfusion</title><author>Figueiredo, Constanca ; Carvalho Oliveira, Marco ; Chen-Wacker, Chen ; Jansson, Katharina ; Höffler, Klaus ; Yuzefovych, Yuliia ; Pogozhykh, Olena ; Jin, Zhu ; Kühnel, Mark ; Jonigk, Danny ; Wiegmann, Bettina ; Sommer, Wiebke ; Haverich, Axel ; Warnecke, Gregor ; Blasczyk, Rainer</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c319t-21f54ad690a5b267c50c646b01a478d8c56a41226904b5ac5854d4ff500e29ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antigens</topic><topic>Cell viability</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelium</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Feasibility studies</topic><topic>Gene Expression</topic><topic>Gene Silencing</topic><topic>Gene Transfer Techniques</topic><topic>Genes, Reporter</topic><topic>Genetic Engineering</topic><topic>Genetic Vectors - genetics</topic><topic>Graft rejection</topic><topic>Histocompatibility Antigens - genetics</topic><topic>Histocompatibility Antigens Class I - genetics</topic><topic>Histocompatibility Antigens Class I - metabolism</topic><topic>Histocompatibility Antigens Class II - genetics</topic><topic>Histocompatibility Antigens Class II - metabolism</topic><topic>Immune response</topic><topic>Immunogenicity</topic><topic>Immunosuppression</topic><topic>Lentivirus - genetics</topic><topic>Leukocytes</topic><topic>Livestock</topic><topic>Lung - metabolism</topic><topic>Lung - pathology</topic><topic>Lungs</topic><topic>Major histocompatibility complex</topic><topic>Organs</topic><topic>Perfusion</topic><topic>Rejection</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Silence</topic><topic>Swine</topic><topic>Temperature</topic><topic>Tissues</topic><topic>Transduction, Genetic</topic><topic>Transplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Figueiredo, Constanca</creatorcontrib><creatorcontrib>Carvalho Oliveira, Marco</creatorcontrib><creatorcontrib>Chen-Wacker, Chen</creatorcontrib><creatorcontrib>Jansson, Katharina</creatorcontrib><creatorcontrib>Höffler, Klaus</creatorcontrib><creatorcontrib>Yuzefovych, Yuliia</creatorcontrib><creatorcontrib>Pogozhykh, Olena</creatorcontrib><creatorcontrib>Jin, Zhu</creatorcontrib><creatorcontrib>Kühnel, Mark</creatorcontrib><creatorcontrib>Jonigk, Danny</creatorcontrib><creatorcontrib>Wiegmann, Bettina</creatorcontrib><creatorcontrib>Sommer, Wiebke</creatorcontrib><creatorcontrib>Haverich, Axel</creatorcontrib><creatorcontrib>Warnecke, Gregor</creatorcontrib><creatorcontrib>Blasczyk, Rainer</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Figueiredo, Constanca</au><au>Carvalho Oliveira, Marco</au><au>Chen-Wacker, Chen</au><au>Jansson, Katharina</au><au>Höffler, Klaus</au><au>Yuzefovych, Yuliia</au><au>Pogozhykh, Olena</au><au>Jin, Zhu</au><au>Kühnel, Mark</au><au>Jonigk, Danny</au><au>Wiegmann, Bettina</au><au>Sommer, Wiebke</au><au>Haverich, Axel</au><au>Warnecke, Gregor</au><au>Blasczyk, Rainer</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Immunoengineering of the Vascular Endothelium to Silence MHC Expression During Normothermic Ex Vivo Lung Perfusion</atitle><jtitle>Human gene therapy</jtitle><addtitle>Hum Gene Ther</addtitle><date>2019-04</date><risdate>2019</risdate><volume>30</volume><issue>4</issue><spage>485</spage><epage>496</epage><pages>485-496</pages><issn>1043-0342</issn><eissn>1557-7422</eissn><abstract>Disparities at the major histocompatibility complex (MHC) antigens and associated minor antigens trigger harmful immune responses, leading to graft rejection after transplantation. We showed that MHC-silenced cells and tissues are efficiently protected against rejection. In complex vascularized organs, the endothelium is the major interface between donor and recipient. This study therefore aimed to reduce the immunogenicity of the lung by silencing MHC expression on the endothelium. In porcine lungs, short-hairpin RNAs targeting beta-2-microglobulin and class II-transactivator transcripts were delivered by lentiviral vectors during normothermic ex vivo perfusion to silence swine leukocyte antigen (SLA) I and II expression permanently. The results demonstrated the feasibility of genetically engineering all lung regions, achieving a targeted silencing effect for SLA I and II of 67% and 52%, respectively, without affecting cell viability or tissue integrity. This decrease in immunogenicity carries the potential to generate immunologically invisible organs to counteract the burden of rejection and immunosuppression.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>30261752</pmid><doi>10.1089/hum.2018.117</doi><tpages>12</tpages></addata></record> |
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| subjects | Animals Antigens Cell viability Endothelial Cells - metabolism Endothelium Endothelium, Vascular - metabolism Feasibility studies Gene Expression Gene Silencing Gene Transfer Techniques Genes, Reporter Genetic Engineering Genetic Vectors - genetics Graft rejection Histocompatibility Antigens - genetics Histocompatibility Antigens Class I - genetics Histocompatibility Antigens Class I - metabolism Histocompatibility Antigens Class II - genetics Histocompatibility Antigens Class II - metabolism Immune response Immunogenicity Immunosuppression Lentivirus - genetics Leukocytes Livestock Lung - metabolism Lung - pathology Lungs Major histocompatibility complex Organs Perfusion Rejection RNA, Messenger - genetics RNA, Messenger - metabolism Silence Swine Temperature Tissues Transduction, Genetic Transplantation |
| title | Immunoengineering of the Vascular Endothelium to Silence MHC Expression During Normothermic Ex Vivo Lung Perfusion |
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