Identification of the murine AAVrh32.33 capsid‐specific CD8+ T cell epitopes
Identifieur interne : 000216 ( Istex/Corpus ); précédent : 000215; suivant : 000217Identification of the murine AAVrh32.33 capsid‐specific CD8+ T cell epitopes
Auteurs : Lauren E. Mays ; James M. WilsonSource :
- The Journal of Gene Medicine [ 1099-498X ] ; 2009-12.
English descriptors
- Teeft :
- Aav2, Amino, Amino acids, Bimas, Capsid, Capsid protein, Cell epitope, Cell epitopes, Cell population, Copyright, Cytometric analysis, Dominant capsid epitopes, Dominant epitope, Elispot, Epitope, Fine mapping, Gene therapy, Gene transfer, Immune activation, Immunodominant, Immunodominant epitope, Individual peptides, Intracellular cytokine staining, Ipasggnal, John wiley sons, Kipasggnal, Mechanistic studies, Mhci, Mhci molecule, Monoclonal antibodies, Mouse, Murine, Murine models, Negative control, Peptide, Peptide pools, Small animal model, Splenocytes, Ssyelpyvm, Syfpeithi, Transgene, Virus vectors.
Abstract
Background: Adeno‐associated virus (AAV) is an ideal gene therapy vector and is non‐immunogenic in many small animal models. The stable gene expression commonly seen in murine models does not necessarily translate to nonhuman primates and higher‐order species, highlighting the need for a better understanding of immune activation to these vectors. One capsid variant, AAVrh32.33, demonstrates a unique phenotype in murine muscle, reminiscent of what is often seen in higher‐order species. AAVrh32.33 generates a strong CD8+ T‐cell response to both capsid and encoded transgene antigens in a manner independent of transgene product or major histocompatability complex haplotype, making it an ideal candidate for studying immune activation to AAV in the mouse. Methods: To map the H‐2b and H‐2d dominant epitopes of the AAVrh32.33 capsid, C57BL/6 or Balb/C mice received an intramuscular injection of 1 × 1011 genome copies of AAV2/rh32.33.CB.nLacZ. Three weeks later, splenocytes were harvested and stimulated in vitro with pooled or individual peptides from the AAVrh32.33 capsid peptide library and analysed by an interferon (IFN)‐γ enzyme‐linked immunosorbent spot assay or intracellular cytokine staining. Results: The immunodominant epitopes within the AAVrh32.33 capsid responsible for driving CD8+ T‐cell responses to the capsid protein in C57BL/6 (SSYELPYVM) and Balb/C (KIPASGGNAL) mice were defined. Conclusions: Identification of dominant capsid epitopes will make it possible to monitor cellular responses to the AAV capsid in vivo, facilitating mechanistic studies critical to defining how cellular immunity to the AAV capsid arises and, ultimately, how the generation of capsid‐specific T cells can be avoided to ensure safety in a gene therapy setting. Copyright © 2009 John Wiley & Sons, Ltd.
Url:
DOI: 10.1002/jgm.1402
Links to Exploration step
ISTEX:9DDC47DCC02F4E0AD7610B746E2730CE21768BB9Le document en format XML
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The stable gene expression commonly seen in murine models does not necessarily translate to nonhuman primates and higher‐order species, highlighting the need for a better understanding of immune activation to these vectors. One capsid variant, AAVrh32.33, demonstrates a unique phenotype in murine muscle, reminiscent of what is often seen in higher‐order species. AAVrh32.33 generates a strong CD8+ T‐cell response to both capsid and encoded transgene antigens in a manner independent of transgene product or major histocompatability complex haplotype, making it an ideal candidate for studying immune activation to AAV in the mouse. Methods: To map the H‐2b and H‐2d dominant epitopes of the AAVrh32.33 capsid, C57BL/6 or Balb/C mice received an intramuscular injection of 1 × 1011 genome copies of AAV2/rh32.33.CB.nLacZ. Three weeks later, splenocytes were harvested and stimulated in vitro with pooled or individual peptides from the AAVrh32.33 capsid peptide library and analysed by an interferon (IFN)‐γ enzyme‐linked immunosorbent spot assay or intracellular cytokine staining. Results: The immunodominant epitopes within the AAVrh32.33 capsid responsible for driving CD8+ T‐cell responses to the capsid protein in C57BL/6 (SSYELPYVM) and Balb/C (KIPASGGNAL) mice were defined. Conclusions: Identification of dominant capsid epitopes will make it possible to monitor cellular responses to the AAV capsid in vivo, facilitating mechanistic studies critical to defining how cellular immunity to the AAV capsid arises and, ultimately, how the generation of capsid‐specific T cells can be avoided to ensure safety in a gene therapy setting. Copyright © 2009 John Wiley & Sons, Ltd.</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>capsid</json:string><json:string>epitope</json:string><json:string>peptide</json:string><json:string>splenocytes</json:string><json:string>ssyelpyvm</json:string><json:string>elispot</json:string><json:string>transgene</json:string><json:string>immunodominant</json:string><json:string>syfpeithi</json:string><json:string>mhci</json:string><json:string>capsid protein</json:string><json:string>john wiley sons</json:string><json:string>kipasggnal</json:string><json:string>copyright</json:string><json:string>aav2</json:string><json:string>bimas</json:string><json:string>murine</json:string><json:string>ipasggnal</json:string><json:string>cell epitopes</json:string><json:string>gene transfer</json:string><json:string>gene therapy</json:string><json:string>individual peptides</json:string><json:string>murine models</json:string><json:string>mhci molecule</json:string><json:string>immune activation</json:string><json:string>peptide pools</json:string><json:string>dominant capsid epitopes</json:string><json:string>negative control</json:string><json:string>intracellular cytokine staining</json:string><json:string>cell epitope</json:string><json:string>amino</json:string><json:string>dominant epitope</json:string><json:string>cell population</json:string><json:string>cytometric analysis</json:string><json:string>small animal model</json:string><json:string>amino acids</json:string><json:string>mechanistic studies</json:string><json:string>immunodominant epitope</json:string><json:string>fine mapping</json:string><json:string>monoclonal antibodies</json:string><json:string>virus vectors</json:string><json:string>mouse</json:string></teeft></keywords><author><json:item><name>Lauren E. Mays</name><affiliations><json:string>Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</json:string></affiliations></json:item><json:item><name>James M. Wilson</name><affiliations><json:string>Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</json:string><json:string>E-mail: wilsonjm@mail.med.upenn.edu</json:string><json:string>Correspondence address: 125 S. 31st Street, TRL, Suite 2000, Philadelphia, PA 19104‐3403, USA.</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>AAV</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>capsid epitope</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>gene therapy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>T cells</value></json:item></subject><articleId><json:string>JGM1402</json:string></articleId><arkIstex>ark:/67375/WNG-TRK4MWXW-R</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Background: Adeno‐associated virus (AAV) is an ideal gene therapy vector and is non‐immunogenic in many small animal models. The stable gene expression commonly seen in murine models does not necessarily translate to nonhuman primates and higher‐order species, highlighting the need for a better understanding of immune activation to these vectors. One capsid variant, AAVrh32.33, demonstrates a unique phenotype in murine muscle, reminiscent of what is often seen in higher‐order species. AAVrh32.33 generates a strong CD8+ T‐cell response to both capsid and encoded transgene antigens in a manner independent of transgene product or major histocompatability complex haplotype, making it an ideal candidate for studying immune activation to AAV in the mouse. Methods: To map the H‐2b and H‐2d dominant epitopes of the AAVrh32.33 capsid, C57BL/6 or Balb/C mice received an intramuscular injection of 1 × 1011 genome copies of AAV2/rh32.33.CB.nLacZ. Three weeks later, splenocytes were harvested and stimulated in vitro with pooled or individual peptides from the AAVrh32.33 capsid peptide library and analysed by an interferon (IFN)‐γ enzyme‐linked immunosorbent spot assay or intracellular cytokine staining. Results: The immunodominant epitopes within the AAVrh32.33 capsid responsible for driving CD8+ T‐cell responses to the capsid protein in C57BL/6 (SSYELPYVM) and Balb/C (KIPASGGNAL) mice were defined. Conclusions: Identification of dominant capsid epitopes will make it possible to monitor cellular responses to the AAV capsid in vivo, facilitating mechanistic studies critical to defining how cellular immunity to the AAV capsid arises and, ultimately, how the generation of capsid‐specific T cells can be avoided to ensure safety in a gene therapy setting. Copyright © 2009 John Wiley & Sons, Ltd.</abstract><qualityIndicators><score>9.27</score><pdfWordCount>4270</pdfWordCount><pdfCharCount>26989</pdfCharCount><pdfVersion>1.3</pdfVersion><pdfPageCount>8</pdfPageCount><pdfPageSize>595 x 859 pts</pdfPageSize><pdfWordsPerPage>534</pdfWordsPerPage><pdfText>true</pdfText><refBibsNative>true</refBibsNative><abstractWordCount>263</abstractWordCount><abstractCharCount>1808</abstractCharCount><keywordCount>4</keywordCount></qualityIndicators><title>Identification of the murine AAVrh32.33 capsid‐specific CD8+ T cell epitopes</title><pmid><json:string>19777488</json:string></pmid><genre><json:string>article</json:string></genre><host><title>The Journal of Gene Medicine</title><language><json:string>unknown</json:string></language><doi><json:string>10.1002/(ISSN)1521-2254</json:string></doi><issn><json:string>1099-498X</json:string></issn><eissn><json:string>1521-2254</json:string></eissn><publisherId><json:string>JGM</json:string></publisherId><volume>11</volume><issue>12</issue><pages><first>1095</first><last>1102</last><total>8</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Research Article</value></json:item><json:item><value>Research Articles</value></json:item></subject></host><namedEntities><unitex><date><json:string>2009</json:string><json:string>1600</json:string><json:string>2000</json:string></date><geogName></geogName><orgName><json:string>Sons, Ltd.</json:string><json:string>Use Committee of the University of Pennsylvania</json:string><json:string>Mediatech</json:string><json:string>University of Pennsylvania School of Medicine</json:string><json:string>Sons, Ltd</json:string><json:string>Department of Pathology and Laboratory</json:string><json:string>Translational Research Laboratories</json:string><json:string>University of Pennsylvania</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>E. 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science</json:string><json:string>2 - medicine, research & experimental</json:string><json:string>2 - genetics & heredity</json:string><json:string>2 - biotechnology & applied microbiology</json:string></wos><scienceMetrix><json:string>1 - applied sciences</json:string><json:string>2 - enabling & strategic technologies</json:string><json:string>3 - biotechnology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Genetics(clinical)</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>3 - Drug Discovery</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Genetics</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Molecular Biology</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Molecular Medicine</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences biologiques fondamentales et appliquees. psychologie</json:string></inist></categories><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1002/jgm.1402</json:string></doi><id>9DDC47DCC02F4E0AD7610B746E2730CE21768BB9</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-TRK4MWXW-R/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-TRK4MWXW-R/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/WNG-TRK4MWXW-R/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Identification of the murine AAVrh32.33 capsid‐specific CD8+ T cell epitopes</title><title level="a" type="short" xml:lang="en">Mapping the AAVrh32.33 capsid epitope</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>John Wiley & Sons, Ltd.</publisher><pubPlace>Chichester, UK</pubPlace><availability><licence>Copyright © 2009 John Wiley & Sons, Ltd.</licence></availability><date type="published" when="2009-12"></date></publicationStmt><notesStmt><note type="content-type" subtype="article" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Identification of the murine AAVrh32.33 capsid‐specific CD8+ T cell epitopes</title><title level="a" type="short" xml:lang="en">Mapping the AAVrh32.33 capsid epitope</title><author xml:id="author-0000"><persName><forename type="first">Lauren E.</forename><surname>Mays</surname></persName><affiliation><orgName type="group">Gene Therapy Program</orgName><orgName type="laboratory">Department of Pathology and Laboratory Medicine</orgName><orgName type="institution">University of Pennsylvania School of Medicine</orgName><address><addrLine>Philadelphia</addrLine><addrLine>PA, USA</addrLine><country key="US" xml:lang="en">UNITED STATES</country></address></affiliation></author><author xml:id="author-0001" role="corresp"><persName><forename type="first">James M.</forename><surname>Wilson</surname></persName><email>wilsonjm@mail.med.upenn.edu</email><affiliation><orgName type="group">Gene Therapy Program</orgName><orgName type="laboratory">Department of Pathology and Laboratory Medicine</orgName><orgName type="institution">University of Pennsylvania School of Medicine</orgName><address><addrLine>Philadelphia</addrLine><addrLine>PA, USA</addrLine><country key="US" xml:lang="en">UNITED STATES</country></address></affiliation></author><idno type="istex">9DDC47DCC02F4E0AD7610B746E2730CE21768BB9</idno><idno type="ark">ark:/67375/WNG-TRK4MWXW-R</idno><idno type="DOI">10.1002/jgm.1402</idno><idno type="unit">JGM1402</idno><idno type="toTypesetVersion">file:JGM.JGM1402.pdf</idno></analytic><monogr><title level="j" type="main">The Journal of Gene Medicine</title><title level="j" type="alt">JOURNAL OF GENE MEDICINE, THE</title><idno type="pISSN">1099-498X</idno><idno type="eISSN">1521-2254</idno><idno type="book-DOI">10.1002/(ISSN)1521-2254</idno><idno type="book-part-DOI">10.1002/jgm.v11:12</idno><idno type="product">JGM</idno><imprint><biblScope unit="vol">11</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="1095">1095</biblScope><biblScope unit="page" to="1102">1102</biblScope><biblScope unit="page-count">8</biblScope><publisher>John Wiley & Sons, Ltd.</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2009-12"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><encodingDesc><schemaRef type="ODD" url="https://xml-schema.delivery.istex.fr/tei-istex.odd"></schemaRef><appInfo><application ident="pub2tei" version="1.0.10" when="2019-12-20"><label>pub2TEI-ISTEX</label><desc>A set of style sheets for converting XML documents encoded in various scientific publisher formats into a common TEI format.
<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract xml:lang="en" style="main"><head>Abstract</head><head>Background</head><p>Adeno‐associated virus (AAV) is an ideal gene therapy vector and is non‐immunogenic in many small animal models. The stable gene expression commonly seen in murine models does not necessarily translate to nonhuman primates and higher‐order species, highlighting the need for a better understanding of immune activation to these vectors. One capsid variant, AAVrh32.33, demonstrates a unique phenotype in murine muscle, reminiscent of what is often seen in higher‐order species. AAVrh32.33 generates a strong CD8+ T‐cell response to both capsid and encoded transgene antigens in a manner independent of transgene product or major histocompatability complex haplotype, making it an ideal candidate for studying immune activation to AAV in the mouse.</p><head>Methods</head><p>To map the H‐2b and H‐2d dominant epitopes of the AAVrh32.33 capsid, C57BL/6 or Balb/C mice received an intramuscular injection of 1 × 10<hi rend="superscript">11</hi> genome copies of AAV2/rh32.33.CB.nLacZ. Three weeks later, splenocytes were harvested and stimulated <hi rend="italic">in vitro</hi> with pooled or individual peptides from the AAVrh32.33 capsid peptide library and analysed by an interferon (IFN)‐γ enzyme‐linked immunosorbent spot assay or intracellular cytokine staining.</p><head>Results</head><p>The immunodominant epitopes within the AAVrh32.33 capsid responsible for driving CD8+ T‐cell responses to the capsid protein in C57BL/6 (SSYELPYVM) and Balb/C (KIPASGGNAL) mice were defined.</p><head>Conclusions</head><p>Identification of dominant capsid epitopes will make it possible to monitor cellular responses to the AAV capsid <hi rend="italic">in vivo</hi>, facilitating mechanistic studies critical to defining how cellular immunity to the AAV capsid arises and, ultimately, how the generation of capsid‐specific T cells can be avoided to ensure safety in a gene therapy setting. Copyright © 2009 John Wiley & Sons, Ltd.</p></abstract><textClass><keywords xml:lang="en"><term xml:id="kwd1">AAV</term><term xml:id="kwd2">capsid epitope</term><term xml:id="kwd3">gene therapy</term><term xml:id="kwd4">T cells</term></keywords><keywords rend="articleCategory"><term>Research Article</term></keywords><keywords rend="tocHeading1"><term>Research Articles</term></keywords></textClass><langUsage><language ident="en"></language></langUsage></profileDesc><revisionDesc><change when="2019-12-20" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-TRK4MWXW-R/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>John Wiley & Sons, Ltd.</publisherName><publisherLoc>Chichester, UK</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1521-2254</doi><issn type="print">1099-498X</issn><issn type="electronic">1521-2254</issn><idGroup><id type="product" value="JGM"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="JOURNAL OF GENE MEDICINE, THE">The Journal of Gene Medicine</title><title type="subtitle">A cross‐disciplinary journal for research on the science of gene transfer and its clinical applications</title><title type="short">J. Gene Med.</title></titleGroup></publicationMeta><publicationMeta level="part" position="120"><doi origin="wiley" registered="yes">10.1002/jgm.v11:12</doi><numberingGroup><numbering type="journalVolume" number="11">11</numbering><numbering type="journalIssue">12</numbering></numberingGroup><coverDate startDate="2009-12">December 2009</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="40" status="forIssue"><doi origin="wiley" registered="yes">10.1002/jgm.1402</doi><idGroup><id type="unit" value="JGM1402"></id></idGroup><countGroup><count type="pageTotal" number="8"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="publisher">Copyright © 2009 John Wiley & Sons, Ltd.</copyright><eventGroup><event type="manuscriptReceived" date="2009-07-08"></event><event type="manuscriptRevised" date="2009-08-20"></event><event type="manuscriptAccepted" date="2009-08-24"></event><event type="publishedOnlineEarlyUnpaginated" date="2009-09-23"></event><event type="firstOnline" date="2009-09-23"></event><event type="publishedOnlineFinalForm" date="2009-11-25"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.2 mode:FullText source:FullText result:FullText" date="2010-03-04"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-30"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-11-04"></event></eventGroup><numberingGroup><numbering type="pageFirst">1095</numbering><numbering type="pageLast">1102</numbering></numberingGroup><correspondenceTo>125 S. 31st Street, TRL, Suite 2000, Philadelphia, PA 19104‐3403, USA.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:JGM.JGM1402.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="4"></count><count type="tableTotal" number="2"></count><count type="referenceTotal" number="17"></count></countGroup><titleGroup><title type="main" xml:lang="en">Identification of the murine AAVrh32.33 capsid‐specific CD8+ T cell epitopes</title><title type="short" xml:lang="en">Mapping the AAVrh32.33 capsid epitope</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Lauren E.</givenNames><familyName>Mays</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1" corresponding="yes"><personName><givenNames>James M.</givenNames><familyName>Wilson</familyName></personName><contactDetails><email>wilsonjm@mail.med.upenn.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">AAV</keyword><keyword xml:id="kwd2">capsid epitope</keyword><keyword xml:id="kwd3">gene therapy</keyword><keyword xml:id="kwd4">T cells</keyword></keywordGroup><fundingInfo><fundingAgency>NIH</fundingAgency><fundingNumber>P01‐HL059407</fundingNumber><fundingNumber>P30‐DK47757</fundingNumber><fundingNumber>T32‐AR053461‐03</fundingNumber></fundingInfo><fundingInfo><fundingAgency>GSK</fundingAgency></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><section xml:id="abs1-1"><title type="main">Background</title><p>Adeno‐associated virus (AAV) is an ideal gene therapy vector and is non‐immunogenic in many small animal models. The stable gene expression commonly seen in murine models does not necessarily translate to nonhuman primates and higher‐order species, highlighting the need for a better understanding of immune activation to these vectors. One capsid variant, AAVrh32.33, demonstrates a unique phenotype in murine muscle, reminiscent of what is often seen in higher‐order species. AAVrh32.33 generates a strong CD8+ T‐cell response to both capsid and encoded transgene antigens in a manner independent of transgene product or major histocompatability complex haplotype, making it an ideal candidate for studying immune activation to AAV in the mouse.</p></section><section xml:id="abs1-2"><title type="main">Methods</title><p>To map the H‐2b and H‐2d dominant epitopes of the AAVrh32.33 capsid, C57BL/6 or Balb/C mice received an intramuscular injection of 1 × 10<sup>11</sup> genome copies of AAV2/rh32.33.CB.nLacZ. Three weeks later, splenocytes were harvested and stimulated <i>in vitro</i> with pooled or individual peptides from the AAVrh32.33 capsid peptide library and analysed by an interferon (IFN)‐γ enzyme‐linked immunosorbent spot assay or intracellular cytokine staining.</p></section><section xml:id="abs1-3"><title type="main">Results</title><p>The immunodominant epitopes within the AAVrh32.33 capsid responsible for driving CD8+ T‐cell responses to the capsid protein in C57BL/6 (SSYELPYVM) and Balb/C (KIPASGGNAL) mice were defined.</p></section><section xml:id="abs1-4"><title type="main">Conclusions</title><p>Identification of dominant capsid epitopes will make it possible to monitor cellular responses to the AAV capsid <i>in vivo</i>, facilitating mechanistic studies critical to defining how cellular immunity to the AAV capsid arises and, ultimately, how the generation of capsid‐specific T cells can be avoided to ensure safety in a gene therapy setting. Copyright © 2009 John Wiley & Sons, Ltd.</p></section></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Identification of the murine AAVrh32.33 capsid‐specific CD8+ T cell epitopes</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Mapping the AAVrh32.33 capsid epitope</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Identification of the murine AAVrh32.33 capsid‐specific CD8+ T cell epitopes</title></titleInfo><name type="personal"><namePart type="given">Lauren E.</namePart><namePart type="family">Mays</namePart><affiliation>Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">James M.</namePart><namePart type="family">Wilson</namePart><affiliation>Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</affiliation><affiliation>E-mail: wilsonjm@mail.med.upenn.edu</affiliation><affiliation>Correspondence address: 125 S. 31st Street, TRL, Suite 2000, Philadelphia, PA 19104‐3403, USA.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>John Wiley & Sons, Ltd.</publisher><place><placeTerm type="text">Chichester, UK</placeTerm></place><dateIssued encoding="w3cdtf">2009-12</dateIssued><dateCaptured encoding="w3cdtf">2009-07-08</dateCaptured><dateValid encoding="w3cdtf">2009-08-24</dateValid><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><extent unit="figures">4</extent><extent unit="tables">2</extent><extent unit="references">17</extent></physicalDescription><abstract lang="en">Background: Adeno‐associated virus (AAV) is an ideal gene therapy vector and is non‐immunogenic in many small animal models. The stable gene expression commonly seen in murine models does not necessarily translate to nonhuman primates and higher‐order species, highlighting the need for a better understanding of immune activation to these vectors. One capsid variant, AAVrh32.33, demonstrates a unique phenotype in murine muscle, reminiscent of what is often seen in higher‐order species. AAVrh32.33 generates a strong CD8+ T‐cell response to both capsid and encoded transgene antigens in a manner independent of transgene product or major histocompatability complex haplotype, making it an ideal candidate for studying immune activation to AAV in the mouse. Methods: To map the H‐2b and H‐2d dominant epitopes of the AAVrh32.33 capsid, C57BL/6 or Balb/C mice received an intramuscular injection of 1 × 1011 genome copies of AAV2/rh32.33.CB.nLacZ. Three weeks later, splenocytes were harvested and stimulated in vitro with pooled or individual peptides from the AAVrh32.33 capsid peptide library and analysed by an interferon (IFN)‐γ enzyme‐linked immunosorbent spot assay or intracellular cytokine staining. Results: The immunodominant epitopes within the AAVrh32.33 capsid responsible for driving CD8+ T‐cell responses to the capsid protein in C57BL/6 (SSYELPYVM) and Balb/C (KIPASGGNAL) mice were defined. Conclusions: Identification of dominant capsid epitopes will make it possible to monitor cellular responses to the AAV capsid in vivo, facilitating mechanistic studies critical to defining how cellular immunity to the AAV capsid arises and, ultimately, how the generation of capsid‐specific T cells can be avoided to ensure safety in a gene therapy setting. 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