Reduced inflammatory response to plasmid DNA vectors by elimination and inhibition of immunostimulatory CpG motifs.
Identifieur interne : 000483 ( PubMed/Curation ); précédent : 000482; suivant : 000484Reduced inflammatory response to plasmid DNA vectors by elimination and inhibition of immunostimulatory CpG motifs.
Auteurs : N S Yew [États-Unis] ; H. Zhao ; I H Wu ; A. Song ; J D Tousignant ; M. Przybylska ; S H ChengSource :
- Molecular therapy : the journal of the American Society of Gene Therapy [ 1525-0016 ] ; 2000.
Descripteurs français
- KwdFr :
- ADN bactérien (génétique), ADN bactérien (immunologie), Administration par voie nasale, Animaux, Antipaludiques (immunologie), Antipaludiques (pharmacologie), Chloroquine (immunologie), Chloroquine (pharmacologie), Cytokines (antagonistes et inhibiteurs), Cytokines (biosynthèse), Délétion de séquence, Ilots CpG, Inflammation (immunologie), Interleukine-12 (antagonistes et inhibiteurs), Interleukine-12 (biosynthèse), Lipides, Liquide de lavage bronchoalvéolaire (immunologie), Mutagenèse dirigée, Mépacrine (immunologie), Mépacrine (pharmacologie), Plasmides, Poumon (métabolisme), Rate (métabolisme), Souris, Souris de lignée BALB C, Techniques de transfert de gènes, Vecteurs génétiques (génétique), Vecteurs génétiques (immunologie).
- MESH :
- antagonistes et inhibiteurs : Cytokines, Interleukine-12.
- biosynthèse : Cytokines, Interleukine-12.
- génétique : ADN bactérien, Vecteurs génétiques.
- immunologie : ADN bactérien, Antipaludiques, Chloroquine, Inflammation, Liquide de lavage bronchoalvéolaire, Mépacrine, Vecteurs génétiques.
- métabolisme : Poumon, Rate.
- pharmacologie : Antipaludiques, Chloroquine, Mépacrine.
- Administration par voie nasale, Animaux, Délétion de séquence, Ilots CpG, Lipides, Mutagenèse dirigée, Plasmides, Souris, Souris de lignée BALB C, Techniques de transfert de gènes.
English descriptors
- KwdEn :
- Administration, Intranasal, Animals, Antimalarials (immunology), Antimalarials (pharmacology), Bronchoalveolar Lavage Fluid (immunology), Chloroquine (immunology), Chloroquine (pharmacology), CpG Islands, Cytokines (antagonists & inhibitors), Cytokines (biosynthesis), DNA, Bacterial (genetics), DNA, Bacterial (immunology), Gene Transfer Techniques, Genetic Vectors (genetics), Genetic Vectors (immunology), Inflammation (immunology), Interleukin-12 (antagonists & inhibitors), Interleukin-12 (biosynthesis), Lipids, Lung (metabolism), Mice, Mice, Inbred BALB C, Mutagenesis, Site-Directed, Plasmids, Quinacrine (immunology), Quinacrine (pharmacology), Sequence Deletion, Spleen (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Cytokines, Interleukin-12.
- chemical , biosynthesis : Cytokines, Interleukin-12.
- chemical , genetics : DNA, Bacterial.
- chemical , immunology : Antimalarials, Chloroquine, DNA, Bacterial, Quinacrine.
- chemical , pharmacology : Antimalarials, Chloroquine, Quinacrine.
- genetics : Genetic Vectors.
- immunology : Bronchoalveolar Lavage Fluid, Genetic Vectors, Inflammation.
- metabolism : Lung, Spleen.
- Administration, Intranasal, Animals, CpG Islands, Gene Transfer Techniques, Lipids, Mice, Mice, Inbred BALB C, Mutagenesis, Site-Directed, Plasmids, Sequence Deletion.
Abstract
An inflammatory response is invariably associated with administration of gene transfer complexes composed of cationic lipids and plasmid DNA (pDNA). In the lung, an influx of neutrophils and elevated levels of several proinflammatory cytokines such as TNF-alpha, IFN-gamma, IL-6, and IL-12 characterize this dose-dependent response. The induction of these cytokines was shown previously to be due in part to the presence of unmethylated CpG dinucleotides in the bacterially derived pDNA. We have eliminated 270 of 526 CpG dinucleotides in a reporter plasmid (pCFA-CAT) and tested the inflammatory response to cationic lipid:pDNA complexes containing the modified vector (pGZA-CAT) after intravenous (i.v.) or intranasal (i.n.) delivery into BALB/c mice. Compared to the unmodified vector, the CpG-reduced pGZA-CAT was found to be significantly less immunostimulatory, as the levels of IL-12, IFN-gamma, and IL-6 in the serum 24 h after i.v. delivery were reduced by 40 to 75%. Similar reductions in cytokine levels were also observed in the bronchoalveolar lavage fluids (BALF) after i.n. administration, while the levels of reporter gene expression were not affected by the modifications. We have also investigated known inhibitors of the CpG signaling pathways in order to decrease the inflammatory response. Two such inhibitors, chloroquine and quinacrine, greatly reduced the induction of IL-12 from mouse spleen cells in vitro and inhibited cytokine production in the lung by approximately 50% without affecting gene expression. These results illustrate that use of a less immunostimulatory pDNA vector or inhibitors of CpG immunostimulation can reduce significantly the toxicity associated with cationic lipid:pDNA complexes thereby increasing the therapeutic index of this synthetic gene transfer vector.
DOI: 10.1006/mthe.2000.0036
PubMed: 10933941
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Song</name></author><author><name sortKey="Tousignant, J D" sort="Tousignant, J D" uniqKey="Tousignant J" first="J D" last="Tousignant">J D Tousignant</name></author><author><name sortKey="Przybylska, M" sort="Przybylska, M" uniqKey="Przybylska M" first="M" last="Przybylska">M. 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Zhao</name></author><author><name sortKey="Wu, I H" sort="Wu, I H" uniqKey="Wu I" first="I H" last="Wu">I H Wu</name></author><author><name sortKey="Song, A" sort="Song, A" uniqKey="Song A" first="A" last="Song">A. Song</name></author><author><name sortKey="Tousignant, J D" sort="Tousignant, J D" uniqKey="Tousignant J" first="J D" last="Tousignant">J D Tousignant</name></author><author><name sortKey="Przybylska, M" sort="Przybylska, M" uniqKey="Przybylska M" first="M" last="Przybylska">M. 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(immunologie)</term><term>Interleukine-12 (antagonistes et inhibiteurs)</term><term>Interleukine-12 (biosynthèse)</term><term>Lipides</term><term>Liquide de lavage bronchoalvéolaire (immunologie)</term><term>Mutagenèse dirigée</term><term>Mépacrine (immunologie)</term><term>Mépacrine (pharmacologie)</term><term>Plasmides</term><term>Poumon (métabolisme)</term><term>Rate (métabolisme)</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Techniques de transfert de gènes</term><term>Vecteurs génétiques (génétique)</term><term>Vecteurs génétiques (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Cytokines</term><term>Interleukin-12</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Cytokines</term><term>Interleukin-12</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>DNA, 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Site-Directed</term><term>Plasmids</term><term>Sequence Deletion</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Administration par voie nasale</term><term>Animaux</term><term>Délétion de séquence</term><term>Ilots CpG</term><term>Lipides</term><term>Mutagenèse dirigée</term><term>Plasmides</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Techniques de transfert de gènes</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">An inflammatory response is invariably associated with administration of gene transfer complexes composed of cationic lipids and plasmid DNA (pDNA). In the lung, an influx of neutrophils and elevated levels of several proinflammatory cytokines such as TNF-alpha, IFN-gamma, IL-6, and IL-12 characterize this dose-dependent response. The induction of these cytokines was shown previously to be due in part to the presence of unmethylated CpG dinucleotides in the bacterially derived pDNA. We have eliminated 270 of 526 CpG dinucleotides in a reporter plasmid (pCFA-CAT) and tested the inflammatory response to cationic lipid:pDNA complexes containing the modified vector (pGZA-CAT) after intravenous (i.v.) or intranasal (i.n.) delivery into BALB/c mice. Compared to the unmodified vector, the CpG-reduced pGZA-CAT was found to be significantly less immunostimulatory, as the levels of IL-12, IFN-gamma, and IL-6 in the serum 24 h after i.v. delivery were reduced by 40 to 75%. Similar reductions in cytokine levels were also observed in the bronchoalveolar lavage fluids (BALF) after i.n. administration, while the levels of reporter gene expression were not affected by the modifications. We have also investigated known inhibitors of the CpG signaling pathways in order to decrease the inflammatory response. Two such inhibitors, chloroquine and quinacrine, greatly reduced the induction of IL-12 from mouse spleen cells in vitro and inhibited cytokine production in the lung by approximately 50% without affecting gene expression. These results illustrate that use of a less immunostimulatory pDNA vector or inhibitors of CpG immunostimulation can reduce significantly the toxicity associated with cationic lipid:pDNA complexes thereby increasing the therapeutic index of this synthetic gene transfer vector.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">10933941</PMID><DateCompleted><Year>2000</Year><Month>09</Month><Day>01</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1525-0016</ISSN><JournalIssue CitedMedium="Print"><Volume>1</Volume><Issue>3</Issue><PubDate><Year>2000</Year><Month>Mar</Month></PubDate></JournalIssue><Title>Molecular therapy : the journal of the American Society of Gene Therapy</Title><ISOAbbreviation>Mol. Ther.</ISOAbbreviation></Journal><ArticleTitle>Reduced inflammatory response to plasmid DNA vectors by elimination and inhibition of immunostimulatory CpG motifs.</ArticleTitle><Pagination><MedlinePgn>255-62</MedlinePgn></Pagination><Abstract><AbstractText>An inflammatory response is invariably associated with administration of gene transfer complexes composed of cationic lipids and plasmid DNA (pDNA). In the lung, an influx of neutrophils and elevated levels of several proinflammatory cytokines such as TNF-alpha, IFN-gamma, IL-6, and IL-12 characterize this dose-dependent response. The induction of these cytokines was shown previously to be due in part to the presence of unmethylated CpG dinucleotides in the bacterially derived pDNA. We have eliminated 270 of 526 CpG dinucleotides in a reporter plasmid (pCFA-CAT) and tested the inflammatory response to cationic lipid:pDNA complexes containing the modified vector (pGZA-CAT) after intravenous (i.v.) or intranasal (i.n.) delivery into BALB/c mice. Compared to the unmodified vector, the CpG-reduced pGZA-CAT was found to be significantly less immunostimulatory, as the levels of IL-12, IFN-gamma, and IL-6 in the serum 24 h after i.v. delivery were reduced by 40 to 75%. Similar reductions in cytokine levels were also observed in the bronchoalveolar lavage fluids (BALF) after i.n. administration, while the levels of reporter gene expression were not affected by the modifications. We have also investigated known inhibitors of the CpG signaling pathways in order to decrease the inflammatory response. Two such inhibitors, chloroquine and quinacrine, greatly reduced the induction of IL-12 from mouse spleen cells in vitro and inhibited cytokine production in the lung by approximately 50% without affecting gene expression. These results illustrate that use of a less immunostimulatory pDNA vector or inhibitors of CpG immunostimulation can reduce significantly the toxicity associated with cationic lipid:pDNA complexes thereby increasing the therapeutic index of this synthetic gene transfer vector.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yew</LastName><ForeName>N S</ForeName><Initials>NS</Initials><AffiliationInfo><Affiliation>Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA. nelson.yew@genzyme.com</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhao</LastName><ForeName>H</ForeName><Initials>H</Initials></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>I H</ForeName><Initials>IH</Initials></Author><Author ValidYN="Y"><LastName>Song</LastName><ForeName>A</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Tousignant</LastName><ForeName>J D</ForeName><Initials>JD</Initials></Author><Author ValidYN="Y"><LastName>Przybylska</LastName><ForeName>M</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Cheng</LastName><ForeName>S H</ForeName><Initials>SH</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mol Ther</MedlineTA><NlmUniqueID>100890581</NlmUniqueID><ISSNLinking>1525-0016</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000962">Antimalarials</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016207">Cytokines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004269">DNA, Bacterial</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008055">Lipids</NameOfSubstance></Chemical><Chemical><RegistryNumber>187348-17-0</RegistryNumber><NameOfSubstance UI="D018664">Interleukin-12</NameOfSubstance></Chemical><Chemical><RegistryNumber>886U3H6UFF</RegistryNumber><NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance></Chemical><Chemical><RegistryNumber>H0C805XYDE</RegistryNumber><NameOfSubstance UI="D011796">Quinacrine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>Mol Ther. 2000 Mar;1(3):209-10</RefSource><PMID Version="1">10933935</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000281" MajorTopicYN="N">Administration, Intranasal</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000962" MajorTopicYN="N">Antimalarials</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001992" MajorTopicYN="N">Bronchoalveolar Lavage Fluid</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018899" MajorTopicYN="Y">CpG Islands</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016207" MajorTopicYN="N">Cytokines</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000096" MajorTopicYN="N">biosynthesis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004269" MajorTopicYN="N">DNA, Bacterial</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018014" MajorTopicYN="Y">Gene Transfer Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005822" MajorTopicYN="N">Genetic Vectors</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007249" MajorTopicYN="N">Inflammation</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018664" MajorTopicYN="N">Interleukin-12</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000096" MajorTopicYN="N">biosynthesis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008055" MajorTopicYN="N">Lipids</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008168" MajorTopicYN="N">Lung</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016297" MajorTopicYN="N">Mutagenesis, Site-Directed</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010957" MajorTopicYN="N">Plasmids</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011796" MajorTopicYN="N">Quinacrine</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017384" MajorTopicYN="N">Sequence Deletion</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013154" MajorTopicYN="N">Spleen</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2000</Year><Month>8</Month><Day>10</Day><Hour>11</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2000</Year><Month>9</Month><Day>9</Day><Hour>11</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2000</Year><Month>8</Month><Day>10</Day><Hour>11</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">10933941</ArticleId><ArticleId 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