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Transient Immunomodulation with Anti-CD40 Ligand Antibody and CTLA4Ig Enhances Persistence and Secondary Adenovirus-Mediated Gene Transfer into Mouse Liver
Although recombinant adenovirus vectors offer a very efficient means by which to transfer genetic information into cells in vivo, antigen-dependent immunity limits the duration of gene expression and prevents retreatment. Recombinant murine CTLA4Ig and anti-CD40 ligand antibody block costimulatory i...
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Published in: | Proceedings of the National Academy of Sciences - PNAS 1997-04, Vol.94 (9), p.4686-4691 |
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description | Although recombinant adenovirus vectors offer a very efficient means by which to transfer genetic information into cells in vivo, antigen-dependent immunity limits the duration of gene expression and prevents retreatment. Recombinant murine CTLA4Ig and anti-CD40 ligand antibody block costimulatory interactions between T cells and antigen presenting cells. We previously reported that murine CTLA4Ig prolongs adenoviral-mediated gene transfer, but does not allow for secondary expression after readministration of the vector. In studies described here, when anti-CD40 ligand and recombinant murine CTLA4Ig were coadministered around the time of primary vector administration (i) prolonged adenovirus-mediated gene expression (length of experiment up to 1 year) from the livers of >90% of treated mice was observed, and (ii) secondary adenovirus-mediated gene transfer was achieved in >50% of the mice even after the immunosuppressive effects of these agents were no longer present. Nearly two-thirds of these mice had persistent secondary gene expression lasting for at least 200-300 days. Neither agent alone allowed transduction after secondary vector administration. Treated mice had decreased immune responses to the vector as shown by markedly decreased production of neutralizing antibodies, diminished spleen proliferation responses and IFN-γ production in vitro, and reduced T cell infiltrates in the liver. These results suggest that it may be possible to obtain persistence as well as secondary adenoviral-mediated gene transfer with transient immunosuppressive therapies. |
doi_str_mv | 10.1073/pnas.94.9.4686 |
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Recombinant murine CTLA4Ig and anti-CD40 ligand antibody block costimulatory interactions between T cells and antigen presenting cells. We previously reported that murine CTLA4Ig prolongs adenoviral-mediated gene transfer, but does not allow for secondary expression after readministration of the vector. In studies described here, when anti-CD40 ligand and recombinant murine CTLA4Ig were coadministered around the time of primary vector administration (i) prolonged adenovirus-mediated gene expression (length of experiment up to 1 year) from the livers of >90% of treated mice was observed, and (ii) secondary adenovirus-mediated gene transfer was achieved in >50% of the mice even after the immunosuppressive effects of these agents were no longer present. Nearly two-thirds of these mice had persistent secondary gene expression lasting for at least 200-300 days. Neither agent alone allowed transduction after secondary vector administration. Treated mice had decreased immune responses to the vector as shown by markedly decreased production of neutralizing antibodies, diminished spleen proliferation responses and IFN-γ production in vitro, and reduced T cell infiltrates in the liver. These results suggest that it may be possible to obtain persistence as well as secondary adenoviral-mediated gene transfer with transient immunosuppressive therapies.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.94.9.4686</identifier><identifier>PMID: 9114052</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Abatacept ; Adenoviridae - genetics ; Adenoviridae - immunology ; adenovirus ; Adenoviruses ; Animals ; Antibodies ; Antibodies - pharmacology ; Antibodies, Viral - blood ; Antigen-Presenting Cells - immunology ; Antigens, CD ; Antigens, Differentiation - pharmacology ; Bacteriophages ; Biological Sciences ; CD40 Antigens - immunology ; CD40 Ligand ; Cellular biology ; CTLA-4 Antigen ; Female ; Gene expression ; Gene Expression - drug effects ; Gene therapy ; Gene Transfer Techniques ; Genetic Therapy - methods ; Genetic vectors ; Immunity (Disease) ; Immunoconjugates ; Immunosuppression - methods ; Immunosuppressive Agents - pharmacology ; Ligands ; Liver ; Liver - virology ; Membrane Glycoproteins - immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Neutralizing antibodies ; T lymphocytes ; T-Lymphocytes - immunology</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1997-04, Vol.94 (9), p.4686-4691</ispartof><rights>Copyright 1997 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Apr 29, 1997</rights><rights>Copyright © 1997, The National Academy of Sciences of the USA 1997</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-9b3015ba7cd8ba42e899a1f5505ba00853b8637cf45e926b61b258d67ffb84493</citedby><cites>FETCH-LOGICAL-c513t-9b3015ba7cd8ba42e899a1f5505ba00853b8637cf45e926b61b258d67ffb84493</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/94/9.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/42073$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/42073$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,58238,58471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9114052$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kay, Mark A.</creatorcontrib><creatorcontrib>Meuse, Leonard</creatorcontrib><creatorcontrib>Gown, Allen M.</creatorcontrib><creatorcontrib>Linsley, Peter</creatorcontrib><creatorcontrib>Hollenbaugh, Diane</creatorcontrib><creatorcontrib>Aruffo, Alejandro</creatorcontrib><creatorcontrib>Ochs, Hans D.</creatorcontrib><creatorcontrib>Wilson, Christopher B.</creatorcontrib><title>Transient Immunomodulation with Anti-CD40 Ligand Antibody and CTLA4Ig Enhances Persistence and Secondary Adenovirus-Mediated Gene Transfer into Mouse Liver</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Although recombinant adenovirus vectors offer a very efficient means by which to transfer genetic information into cells in vivo, antigen-dependent immunity limits the duration of gene expression and prevents retreatment. Recombinant murine CTLA4Ig and anti-CD40 ligand antibody block costimulatory interactions between T cells and antigen presenting cells. We previously reported that murine CTLA4Ig prolongs adenoviral-mediated gene transfer, but does not allow for secondary expression after readministration of the vector. In studies described here, when anti-CD40 ligand and recombinant murine CTLA4Ig were coadministered around the time of primary vector administration (i) prolonged adenovirus-mediated gene expression (length of experiment up to 1 year) from the livers of >90% of treated mice was observed, and (ii) secondary adenovirus-mediated gene transfer was achieved in >50% of the mice even after the immunosuppressive effects of these agents were no longer present. Nearly two-thirds of these mice had persistent secondary gene expression lasting for at least 200-300 days. Neither agent alone allowed transduction after secondary vector administration. Treated mice had decreased immune responses to the vector as shown by markedly decreased production of neutralizing antibodies, diminished spleen proliferation responses and IFN-γ production in vitro, and reduced T cell infiltrates in the liver. These results suggest that it may be possible to obtain persistence as well as secondary adenoviral-mediated gene transfer with transient immunosuppressive therapies.</description><subject>Abatacept</subject><subject>Adenoviridae - genetics</subject><subject>Adenoviridae - immunology</subject><subject>adenovirus</subject><subject>Adenoviruses</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies - pharmacology</subject><subject>Antibodies, Viral - blood</subject><subject>Antigen-Presenting Cells - immunology</subject><subject>Antigens, CD</subject><subject>Antigens, Differentiation - pharmacology</subject><subject>Bacteriophages</subject><subject>Biological Sciences</subject><subject>CD40 Antigens - immunology</subject><subject>CD40 Ligand</subject><subject>Cellular biology</subject><subject>CTLA-4 Antigen</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Gene therapy</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Therapy - methods</subject><subject>Genetic vectors</subject><subject>Immunity (Disease)</subject><subject>Immunoconjugates</subject><subject>Immunosuppression - methods</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Ligands</subject><subject>Liver</subject><subject>Liver - virology</subject><subject>Membrane Glycoproteins - immunology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C3H</subject><subject>Neutralizing antibodies</subject><subject>T lymphocytes</subject><subject>T-Lymphocytes - immunology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><recordid>eNp9UsGO0zAQtRBoWQpXDkhI1h64pdiJncQSl6osS6WuQKKcLSeZtK4Su9hOYb-Fn8VpS1UQ4mTNzHtv3owHoZeUTCkpsrc7o_xUsKmYsrzMH6FrSgRNcibIY3RNSFokJUvZU_TM-y0hRPCSXKErQSkjPL1GP1dOGa_BBLzo-8HY3jZDp4K2Bn_XYYNnJuhk_p4RvNRrZZpDorLNAx6D-Wo5Y4s1vjUbZWrw-DM4r32AGBwAX6C2plHuAc8aMHav3eCTe2i0CtDgOzCADw5acFibYPG9HTzEXntwz9GTVnUeXpzeCfr64XY1_5gsP90t5rNlUnOahURUGaG8UkXdlJViKZRCKNpyTmKSkJJnVZlnRd0yDiLNq5xWKS-bvGjbqmRMZBP07qi7G6oemjouw6lO7pzuo3FplZZ_VozeyLXdy5QUUX2C3pzozn4bwAfZa19D1ykDcRhZRD9UHPr8H0i54On4qRN08xdwawdn4g5iS5rRMqdj2-kRVDvrvYP2bJgSOarI8TSkYFLI8TQi4fXlmGf46RYu7I28c_U3X7ZD1wX4ES6E_gmM9VfH-tYH684AFteVZb8ADtbXcg</recordid><startdate>19970429</startdate><enddate>19970429</enddate><creator>Kay, Mark A.</creator><creator>Meuse, Leonard</creator><creator>Gown, Allen M.</creator><creator>Linsley, Peter</creator><creator>Hollenbaugh, Diane</creator><creator>Aruffo, Alejandro</creator><creator>Ochs, Hans D.</creator><creator>Wilson, Christopher B.</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><general>The National Academy of Sciences of the USA</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19970429</creationdate><title>Transient Immunomodulation with Anti-CD40 Ligand Antibody and CTLA4Ig Enhances Persistence and Secondary Adenovirus-Mediated Gene Transfer into Mouse Liver</title><author>Kay, Mark A. ; 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Recombinant murine CTLA4Ig and anti-CD40 ligand antibody block costimulatory interactions between T cells and antigen presenting cells. We previously reported that murine CTLA4Ig prolongs adenoviral-mediated gene transfer, but does not allow for secondary expression after readministration of the vector. In studies described here, when anti-CD40 ligand and recombinant murine CTLA4Ig were coadministered around the time of primary vector administration (i) prolonged adenovirus-mediated gene expression (length of experiment up to 1 year) from the livers of >90% of treated mice was observed, and (ii) secondary adenovirus-mediated gene transfer was achieved in >50% of the mice even after the immunosuppressive effects of these agents were no longer present. Nearly two-thirds of these mice had persistent secondary gene expression lasting for at least 200-300 days. Neither agent alone allowed transduction after secondary vector administration. Treated mice had decreased immune responses to the vector as shown by markedly decreased production of neutralizing antibodies, diminished spleen proliferation responses and IFN-γ production in vitro, and reduced T cell infiltrates in the liver. These results suggest that it may be possible to obtain persistence as well as secondary adenoviral-mediated gene transfer with transient immunosuppressive therapies.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>9114052</pmid><doi>10.1073/pnas.94.9.4686</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Abatacept Adenoviridae - genetics Adenoviridae - immunology adenovirus Adenoviruses Animals Antibodies Antibodies - pharmacology Antibodies, Viral - blood Antigen-Presenting Cells - immunology Antigens, CD Antigens, Differentiation - pharmacology Bacteriophages Biological Sciences CD40 Antigens - immunology CD40 Ligand Cellular biology CTLA-4 Antigen Female Gene expression Gene Expression - drug effects Gene therapy Gene Transfer Techniques Genetic Therapy - methods Genetic vectors Immunity (Disease) Immunoconjugates Immunosuppression - methods Immunosuppressive Agents - pharmacology Ligands Liver Liver - virology Membrane Glycoproteins - immunology Mice Mice, Inbred BALB C Mice, Inbred C3H Neutralizing antibodies T lymphocytes T-Lymphocytes - immunology |
title | Transient Immunomodulation with Anti-CD40 Ligand Antibody and CTLA4Ig Enhances Persistence and Secondary Adenovirus-Mediated Gene Transfer into Mouse Liver |
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