Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1
Identifieur interne : 000400 ( Istex/Corpus ); précédent : 000399; suivant : 000401Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1
Auteurs : Geoffrey A. Pietersz ; Wenjun Li ; Carla Osinski ; Vasso Apostolopoulos ; Ian F. C MckenzieSource :
- Vaccine [ 0264-410X ] ; 2000.
English descriptors
- Teeft :
- Algorithm, Amino acids, Apostolopoulos, Assay, Avsmtssvl, Breast cancer, Cancer immunol immunother, Cell epitope, Cell epitopes, Cellular immunity, Ctlp, Ctlp frequencies, Ctlp frequency, Cytotoxic, Epitope, Extracellular, Extracellular peptides, Extracellular region, Fusion protein, Hmfg, Human muc1, Immune, Immune response, Immune responses, Immunisation, Immunised, Immunised mice, Immunising, Immunogenic, Immunol, Immunother, Intracellular, Intracellular peptides, Kbmuc1, Kbmuc1 mice, Lysis, Mannan, Mice immunised, Mouse, Muc1, Muc1 vntr, Mucin, Peptide, Pietersz, Synthetic peptides, Target cells, Transgenic, Transgenic mice, Tumour, Vaccine, Various peptides, Vntr, Vntr peptide, Vntr peptides, Vntr region, Whole hmfg.
Abstract
Abstract: Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/Kb and double transgenic HLA-A*0201/Kb×human MUC1 (A2 KbMUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 KbMUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.
Url:
DOI: 10.1016/S0264-410X(99)00515-0
Links to Exploration step
ISTEX:1E27E87D868943AC8CC7C000728469978D5F3BC6Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1</title><author><name sortKey="Pietersz, Geoffrey A" sort="Pietersz, Geoffrey A" uniqKey="Pietersz G" first="Geoffrey A" last="Pietersz">Geoffrey A. Pietersz</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: g.pietersz@ari.unimelb.edu.au</mods:affiliation></affiliation></author><author><name sortKey="Li, Wenjun" sort="Li, Wenjun" uniqKey="Li W" first="Wenjun" last="Li">Wenjun Li</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Osinski, Carla" sort="Osinski, Carla" uniqKey="Osinski C" first="Carla" last="Osinski">Carla Osinski</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Apostolopoulos, Vasso" sort="Apostolopoulos, Vasso" uniqKey="Apostolopoulos V" first="Vasso" last="Apostolopoulos">Vasso Apostolopoulos</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Mckenzie, Ian F C" sort="Mckenzie, Ian F C" uniqKey="Mckenzie I" first="Ian F. 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Pietersz</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: g.pietersz@ari.unimelb.edu.au</mods:affiliation></affiliation></author><author><name sortKey="Li, Wenjun" sort="Li, Wenjun" uniqKey="Li W" first="Wenjun" last="Li">Wenjun Li</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Osinski, Carla" sort="Osinski, Carla" uniqKey="Osinski C" first="Carla" last="Osinski">Carla Osinski</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Apostolopoulos, Vasso" sort="Apostolopoulos, Vasso" uniqKey="Apostolopoulos V" first="Vasso" last="Apostolopoulos">Vasso Apostolopoulos</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Mckenzie, Ian F C" sort="Mckenzie, Ian F C" uniqKey="Mckenzie I" first="Ian F. C" last="Mckenzie">Ian F. C Mckenzie</name><affiliation><mods:affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Vaccine</title><title level="j" type="abbrev">JVAC</title><idno type="ISSN">0264-410X</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2000">2000</date><biblScope unit="volume">18</biblScope><biblScope unit="issue">19</biblScope><biblScope unit="page" from="2059">2059</biblScope><biblScope unit="page" to="2071">2071</biblScope></imprint><idno type="ISSN">0264-410X</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0264-410X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Algorithm</term><term>Amino acids</term><term>Apostolopoulos</term><term>Assay</term><term>Avsmtssvl</term><term>Breast cancer</term><term>Cancer immunol immunother</term><term>Cell epitope</term><term>Cell epitopes</term><term>Cellular immunity</term><term>Ctlp</term><term>Ctlp frequencies</term><term>Ctlp frequency</term><term>Cytotoxic</term><term>Epitope</term><term>Extracellular</term><term>Extracellular peptides</term><term>Extracellular region</term><term>Fusion protein</term><term>Hmfg</term><term>Human muc1</term><term>Immune</term><term>Immune response</term><term>Immune responses</term><term>Immunisation</term><term>Immunised</term><term>Immunised mice</term><term>Immunising</term><term>Immunogenic</term><term>Immunol</term><term>Immunother</term><term>Intracellular</term><term>Intracellular peptides</term><term>Kbmuc1</term><term>Kbmuc1 mice</term><term>Lysis</term><term>Mannan</term><term>Mice immunised</term><term>Mouse</term><term>Muc1</term><term>Muc1 vntr</term><term>Mucin</term><term>Peptide</term><term>Pietersz</term><term>Synthetic peptides</term><term>Target cells</term><term>Transgenic</term><term>Transgenic mice</term><term>Tumour</term><term>Vaccine</term><term>Various peptides</term><term>Vntr</term><term>Vntr peptide</term><term>Vntr peptides</term><term>Vntr region</term><term>Whole hmfg</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/Kb and double transgenic HLA-A*0201/Kb×human MUC1 (A2 KbMUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 KbMUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.</div></front></TEI><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>muc1</json:string><json:string>peptide</json:string><json:string>hmfg</json:string><json:string>epitope</json:string><json:string>vntr</json:string><json:string>ctlp</json:string><json:string>mannan</json:string><json:string>lysis</json:string><json:string>immunised</json:string><json:string>pietersz</json:string><json:string>immunol</json:string><json:string>extracellular</json:string><json:string>mucin</json:string><json:string>kbmuc1</json:string><json:string>cytotoxic</json:string><json:string>intracellular</json:string><json:string>apostolopoulos</json:string><json:string>avsmtssvl</json:string><json:string>ctlp frequency</json:string><json:string>immune</json:string><json:string>transgenic</json:string><json:string>vaccine</json:string><json:string>target cells</json:string><json:string>immunother</json:string><json:string>immunisation</json:string><json:string>vntr peptides</json:string><json:string>tumour</json:string><json:string>transgenic mice</json:string><json:string>immunising</json:string><json:string>immunogenic</json:string><json:string>assay</json:string><json:string>immunised mice</json:string><json:string>cell epitopes</json:string><json:string>breast cancer</json:string><json:string>human muc1</json:string><json:string>mice immunised</json:string><json:string>intracellular peptides</json:string><json:string>cellular immunity</json:string><json:string>ctlp frequencies</json:string><json:string>extracellular region</json:string><json:string>immune responses</json:string><json:string>kbmuc1 mice</json:string><json:string>cell epitope</json:string><json:string>muc1 vntr</json:string><json:string>various peptides</json:string><json:string>extracellular peptides</json:string><json:string>amino acids</json:string><json:string>cancer immunol immunother</json:string><json:string>algorithm</json:string><json:string>mouse</json:string><json:string>synthetic peptides</json:string><json:string>whole hmfg</json:string><json:string>fusion protein</json:string><json:string>vntr peptide</json:string><json:string>immune response</json:string><json:string>vntr region</json:string></teeft></keywords><author><json:item><name>Geoffrey A Pietersz</name><affiliations><json:string>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</json:string><json:string>E-mail: g.pietersz@ari.unimelb.edu.au</json:string></affiliations></json:item><json:item><name>Wenjun Li</name><affiliations><json:string>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</json:string></affiliations></json:item><json:item><name>Carla Osinski</name><affiliations><json:string>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</json:string></affiliations></json:item><json:item><name>Vasso Apostolopoulos</name><affiliations><json:string>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</json:string></affiliations></json:item><json:item><name>Ian F.C McKenzie</name><affiliations><json:string>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Mucin 1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Epitopes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Immunotherapy</value></json:item></subject><arkIstex>ark:/67375/6H6-1SSX45ZR-5</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Abstract: Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/Kb and double transgenic HLA-A*0201/Kb×human MUC1 (A2 KbMUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 KbMUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.</abstract><qualityIndicators><score>9.928</score><pdfWordCount>5755</pdfWordCount><pdfCharCount>36900</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>13</pdfPageCount><pdfPageSize>595 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>244</abstractWordCount><abstractCharCount>1615</abstractCharCount><keywordCount>3</keywordCount></qualityIndicators><title>Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1</title><pmid><json:string>10706970</json:string></pmid><pii><json:string>S0264-410X(99)00515-0</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>Vaccine</title><language><json:string>unknown</json:string></language><publicationDate>2000</publicationDate><issn><json:string>0264-410X</json:string></issn><pii><json:string>S0264-410X(00)X0101-6</json:string></pii><volume>18</volume><issue>19</issue><pages><first>2059</first><last>2071</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>2000</json:string><json:string>2000 and 1/11,000</json:string><json:string>2880</json:string><json:string>4723</json:string></date><geogName></geogName><orgName><json:string>CSL</json:string><json:string>Elsevier Science Ltd.</json:string><json:string>Australia Received</json:string><json:string>Austin Research Institute</json:string><json:string>Commonwealth Serum Laboratories</json:string><json:string>Biotech, Sweden</json:string><json:string>Scripps Clinic and Research Foundation, La Jolla, CA</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>F.C. McKenzie</json:string><json:string>G.A. Pietersz</json:string><json:string>B. Acres</json:string><json:string>Carla Osinski</json:string><json:string>Kenneth Parker</json:string></persName><placeName><json:string>UK</json:string><json:string>Melbourne</json:string><json:string>Strasbourg</json:string><json:string>France</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>[9,11,20]</json:string><json:string>[21,22]</json:string><json:string>[12]</json:string><json:string>G.A. Pietersz et al.</json:string><json:string>[31,40,41]</json:string><json:string>[39]</json:string><json:string>[18,35]</json:string><json:string>[11,32]</json:string><json:string>[10]</json:string><json:string>[38]</json:string><json:string>[8,20]</json:string><json:string>[42]</json:string><json:string>[37]</json:string><json:string>[30]</json:string><json:string>[7]</json:string><json:string>[36]</json:string><json:string>[9]</json:string><json:string>[33,34]</json:string><json:string>[9,13,14]</json:string><json:string>[19]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/6H6-1SSX45ZR-5</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - medicine, research & experimental</json:string><json:string>2 - immunology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - virology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Infectious Diseases</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Public Health, Environmental and Occupational Health</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Veterinary</json:string><json:string>3 - General Veterinary</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Immunology and Microbiology</json:string><json:string>3 - General Immunology and Microbiology</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 medicales</json:string></inist></categories><publicationDate>2000</publicationDate><copyrightDate>2000</copyrightDate><doi><json:string>10.1016/S0264-410X(99)00515-0</json:string></doi><id>1E27E87D868943AC8CC7C000728469978D5F3BC6</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-1SSX45ZR-5/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-1SSX45ZR-5/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/6H6-1SSX45ZR-5/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a">Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">ELSEVIER</publisher><availability><licence><p>©2000 Elsevier Science Ltd</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</p></availability><date>2000</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note type="content">Fig. 1: Assay for HMFG and mannan. (a) Inhibition of binding of anti-MUC1 antibody to HMFG by competitor preparations of HMFG (○) and mannan–HMFG (⋅). (b) Binding of mannan–HMFG (⋅) and HMFG (○) to anti-MUC1 antibody and Con A detected by a radioimmunoassay.</note><note type="content">Fig. 2: A2 KbMUC1 double transgenic mice were immunised with mannan–HMFG and splenocytes were used in CTL assays. Cytotoxic activity of the effector cells were measured on 51Cr-labelled MCF7 with (■) or without cold K562 (⋅); BT20 (□) or ME272 (○).</note><note type="content">Fig. 3: C57BL/6 and BALB/c mice were immunised with mannan–HMFG and splenocytes were used in CTL assays. Lysis of P815 (a) or RMA (c) cells pulsed with various 9-mer peptides from the intracellular peptide 471–493; Lysis of P815 (b) or RMA (d) cells pulsed with various 9-mer peptides from the extracellular peptides 33–103 and 51–70 and (e) Lysis of P815 cells pulsed with YYQELQRDI and RMA-MUC1 cells pulsed with SAPDNRPAL. As controls for peptide pulsing and antigen-specific cell lysis, known peptide antigens were used and are shown in each panel and described in the text.</note><note type="content">Table 1: Diagramatic structure of MUC1 and sequences of the synthetic peptidesa</note><note type="content">Table 2: CTLp frequencies in spleens of mice immunised with mannan–HMFG</note><note type="content">Table 3: Mice immunised with mannan–HMFG: CTLp frequencies to various non-VNTR peptides and their predicted CTL epitopes</note><note type="content">Table 4: Experimentally determined and predicted mouse and human CTL epitopes in the MUC1 VNTR</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1</title><author xml:id="author-0000"><persName><forename type="first">Geoffrey A</forename><surname>Pietersz</surname></persName><email>g.pietersz@ari.unimelb.edu.au</email><note type="correspondence"><p>Corresponding author. Tel.: +1-613-9287-0666; fax: +1-613-9287-0600</p></note><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Wenjun</forename><surname>Li</surname></persName><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Carla</forename><surname>Osinski</surname></persName><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Vasso</forename><surname>Apostolopoulos</surname></persName><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Ian F.C</forename><surname>McKenzie</surname></persName><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation></author><idno type="istex">1E27E87D868943AC8CC7C000728469978D5F3BC6</idno><idno type="ark">ark:/67375/6H6-1SSX45ZR-5</idno><idno type="DOI">10.1016/S0264-410X(99)00515-0</idno><idno type="PII">S0264-410X(99)00515-0</idno></analytic><monogr><title level="j">Vaccine</title><title level="j" type="abbrev">JVAC</title><idno type="pISSN">0264-410X</idno><idno type="PII">S0264-410X(00)X0101-6</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2000"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">19</biblScope><biblScope unit="page" from="2059">2059</biblScope><biblScope unit="page" to="2071">2071</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2000</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/Kb and double transgenic HLA-A*0201/Kb×human MUC1 (A2 KbMUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 KbMUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Mucin 1</term></item><item><term>Epitopes</term></item><item><term>Immunotherapy</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1999-08-24">Modified</change><change when="2000">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-1SSX45ZR-5/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity><istex:entity SYSTEM="fx1" NDATA="IMAGE" name="fx1"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla"><item-info><jid>JVAC</jid><aid>1953</aid><ce:pii>S0264-410X(99)00515-0</ce:pii><ce:doi>10.1016/S0264-410X(99)00515-0</ce:doi><ce:copyright type="full-transfer" year="2000">Elsevier Science Ltd</ce:copyright></item-info><head><ce:title>Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1</ce:title><ce:author-group><ce:author><ce:given-name>Geoffrey A</ce:given-name><ce:surname>Pietersz</ce:surname><ce:cross-ref refid="CORR1">*</ce:cross-ref><ce:e-address>g.pietersz@ari.unimelb.edu.au</ce:e-address></ce:author><ce:author><ce:given-name>Wenjun</ce:given-name><ce:surname>Li</ce:surname></ce:author><ce:author><ce:given-name>Carla</ce:given-name><ce:surname>Osinski</ce:surname></ce:author><ce:author><ce:given-name>Vasso</ce:given-name><ce:surname>Apostolopoulos</ce:surname></ce:author><ce:author><ce:given-name>Ian F.C</ce:given-name><ce:surname>McKenzie</ce:surname></ce:author><ce:affiliation><ce:textfn>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author. Tel.: +1-613-9287-0666; fax: +1-613-9287-0600</ce:text></ce:correspondence></ce:author-group><ce:date-received day="17" month="6" year="1999"></ce:date-received><ce:date-revised day="24" month="8" year="1999"></ce:date-revised><ce:date-accepted day="18" month="10" year="1999"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/K<ce:sup>b</ce:sup> and double transgenic HLA-A*0201/K<ce:sup>b</ce:sup>×human MUC1 (A2 K<ce:sup>b</ce:sup>MUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 K<ce:sup>b</ce:sup>MUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>Mucin 1</ce:text></ce:keyword><ce:keyword><ce:text>Epitopes</ce:text></ce:keyword><ce:keyword><ce:text>Immunotherapy</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1</title></titleInfo><name type="personal"><namePart type="given">Geoffrey A</namePart><namePart type="family">Pietersz</namePart><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation><affiliation>E-mail: g.pietersz@ari.unimelb.edu.au</affiliation><description>Corresponding author. Tel.: +1-613-9287-0666; fax: +1-613-9287-0600</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wenjun</namePart><namePart type="family">Li</namePart><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carla</namePart><namePart type="family">Osinski</namePart><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vasso</namePart><namePart type="family">Apostolopoulos</namePart><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ian F.C</namePart><namePart type="family">McKenzie</namePart><affiliation>The Austin Research Institute, Studley Rd, Heidelberg, Victoria 3084, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">2000</dateIssued><dateModified encoding="w3cdtf">1999-08-24</dateModified><copyrightDate encoding="w3cdtf">2000</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Abstract: Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/Kb and double transgenic HLA-A*0201/Kb×human MUC1 (A2 KbMUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 KbMUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.</abstract><note type="content">Fig. 1: Assay for HMFG and mannan. (a) Inhibition of binding of anti-MUC1 antibody to HMFG by competitor preparations of HMFG (○) and mannan–HMFG (⋅). (b) Binding of mannan–HMFG (⋅) and HMFG (○) to anti-MUC1 antibody and Con A detected by a radioimmunoassay.</note><note type="content">Fig. 2: A2 KbMUC1 double transgenic mice were immunised with mannan–HMFG and splenocytes were used in CTL assays. Cytotoxic activity of the effector cells were measured on 51Cr-labelled MCF7 with (■) or without cold K562 (⋅); BT20 (□) or ME272 (○).</note><note type="content">Fig. 3: C57BL/6 and BALB/c mice were immunised with mannan–HMFG and splenocytes were used in CTL assays. Lysis of P815 (a) or RMA (c) cells pulsed with various 9-mer peptides from the intracellular peptide 471–493; Lysis of P815 (b) or RMA (d) cells pulsed with various 9-mer peptides from the extracellular peptides 33–103 and 51–70 and (e) Lysis of P815 cells pulsed with YYQELQRDI and RMA-MUC1 cells pulsed with SAPDNRPAL. As controls for peptide pulsing and antigen-specific cell lysis, known peptide antigens were used and are shown in each panel and described in the text.</note><note type="content">Table 1: Diagramatic structure of MUC1 and sequences of the synthetic peptidesa</note><note type="content">Table 2: CTLp frequencies in spleens of mice immunised with mannan–HMFG</note><note type="content">Table 3: Mice immunised with mannan–HMFG: CTLp frequencies to various non-VNTR peptides and their predicted CTL epitopes</note><note type="content">Table 4: Experimentally determined and predicted mouse and human CTL epitopes in the MUC1 VNTR</note><subject><genre>Keywords</genre><topic>Mucin 1</topic><topic>Epitopes</topic><topic>Immunotherapy</topic></subject><relatedItem type="host"><titleInfo><title>Vaccine</title></titleInfo><titleInfo type="abbreviated"><title>JVAC</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">2000</dateIssued></originInfo><identifier type="ISSN">0264-410X</identifier><identifier type="PII">S0264-410X(00)X0101-6</identifier><part><date>2000</date><detail type="volume"><number>18</number><caption>vol.</caption></detail><detail type="issue"><number>19</number><caption>no.</caption></detail><extent unit="issue-pages"><start>1971</start><end>2072</end></extent><extent unit="pages"><start>2059</start><end>2071</end></extent></part></relatedItem><identifier type="istex">1E27E87D868943AC8CC7C000728469978D5F3BC6</identifier><identifier type="ark">ark:/67375/6H6-1SSX45ZR-5</identifier><identifier type="DOI">10.1016/S0264-410X(99)00515-0</identifier><identifier type="PII">S0264-410X(99)00515-0</identifier><accessCondition type="use and reproduction" contentType="copyright">©2000 Elsevier Science Ltd</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource><recordOrigin>Elsevier Science Ltd, ©2000</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-1SSX45ZR-5/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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