A transgenic mouse model for HLA-B57:01–linked abacavir drug tolerance and reactivity
Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, s...
Gespeichert in:
| Veröffentlicht in: | The Journal of clinical investigation 2018-07, Vol.128 (7), p.2819-2832 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2832 |
|---|---|
| container_issue | 7 |
| container_start_page | 2819 |
| container_title | The Journal of clinical investigation |
| container_volume | 128 |
| creator | Cardone, Marco Garcia, Karla Tilahun, Mulualem E Boyd, Lisa F Gebreyohannes, Sintayehu Yano, Masahide Roderiquez, Gregory Akue, Adovi D Juengst, Leslie Mattson, Elliot Ananthula, Suryatheja Natarajan, Kannan Puig, Montserrat Margulies, David H Norcross, Michael A |
| description | Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8+ T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4+ T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8+ T cells with an effector-like and skin-homing phenotype along with CD8+ infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8+ T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8+ T cells dependent on both HLA genetic risk and immunoregulatory host factors. |
| doi_str_mv | 10.1172/JCI99321. |
| format | Article |
| fullrecord | <record><control><sourceid>proquest</sourceid><recordid>TN_cdi_proquest_journals_2243317846</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2243317846</sourcerecordid><originalsourceid>FETCH-proquest_journals_22433178463</originalsourceid><addsrcrecordid>eNqNi71OwzAURi3USqQ_A29wJeYUX9shDlupWhXUEYmxcpPbyiXYYDuVuvEOvCFP0gw8QJfvDOd8jN0hnyGW4uF18VJVUuDshmVYFDrXQuoByzgXmFel1LdsFOORc1SqUBl7n0MKxsUDOVvDp-8i9dtQC3sfYL2Z589F-cTx7-e3te6DGjA7U5uTDdCE7gDJt9T_awLjGghk6mRPNp0nbLg3baTpP8fsfrV8W6zzr-C_O4ppe_RdcL3aCqGkxFKrR3lddQFbAUYg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2243317846</pqid></control><display><type>article</type><title>A transgenic mouse model for HLA-B57:01–linked abacavir drug tolerance and reactivity</title><source>Journals@Ovid Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Cardone, Marco ; Garcia, Karla ; Tilahun, Mulualem E ; Boyd, Lisa F ; Gebreyohannes, Sintayehu ; Yano, Masahide ; Roderiquez, Gregory ; Akue, Adovi D ; Juengst, Leslie ; Mattson, Elliot ; Ananthula, Suryatheja ; Natarajan, Kannan ; Puig, Montserrat ; Margulies, David H ; Norcross, Michael A</creator><creatorcontrib>Cardone, Marco ; Garcia, Karla ; Tilahun, Mulualem E ; Boyd, Lisa F ; Gebreyohannes, Sintayehu ; Yano, Masahide ; Roderiquez, Gregory ; Akue, Adovi D ; Juengst, Leslie ; Mattson, Elliot ; Ananthula, Suryatheja ; Natarajan, Kannan ; Puig, Montserrat ; Margulies, David H ; Norcross, Michael A</creatorcontrib><description>Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8+ T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4+ T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8+ T cells with an effector-like and skin-homing phenotype along with CD8+ infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8+ T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8+ T cells dependent on both HLA genetic risk and immunoregulatory host factors.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI99321.</identifier><language>eng</language><publisher>Ann Arbor: American Society for Clinical Investigation</publisher><subject>Abacavir ; Anergy ; Antigens ; Antiretroviral drugs ; B7 antigen ; Biomedical research ; CD4 antigen ; CD8 antigen ; Cell activation ; Dendritic cells ; Drug development ; Drug tolerance ; Effector cells ; Histocompatibility antigen HLA ; HIV ; Human immunodeficiency virus ; Hypersensitivity ; Immunological tolerance ; Immunoregulation ; Infections ; Inflammation ; Lymphocytes ; Lymphocytes T ; Peptides ; Phenotypes ; RNA-directed DNA polymerase ; Skin ; T cell receptors ; Transgenic animals ; Transgenic mice ; Viral infections</subject><ispartof>The Journal of clinical investigation, 2018-07, Vol.128 (7), p.2819-2832</ispartof><rights>Copyright American Society for Clinical Investigation Jul 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Cardone, Marco</creatorcontrib><creatorcontrib>Garcia, Karla</creatorcontrib><creatorcontrib>Tilahun, Mulualem E</creatorcontrib><creatorcontrib>Boyd, Lisa F</creatorcontrib><creatorcontrib>Gebreyohannes, Sintayehu</creatorcontrib><creatorcontrib>Yano, Masahide</creatorcontrib><creatorcontrib>Roderiquez, Gregory</creatorcontrib><creatorcontrib>Akue, Adovi D</creatorcontrib><creatorcontrib>Juengst, Leslie</creatorcontrib><creatorcontrib>Mattson, Elliot</creatorcontrib><creatorcontrib>Ananthula, Suryatheja</creatorcontrib><creatorcontrib>Natarajan, Kannan</creatorcontrib><creatorcontrib>Puig, Montserrat</creatorcontrib><creatorcontrib>Margulies, David H</creatorcontrib><creatorcontrib>Norcross, Michael A</creatorcontrib><title>A transgenic mouse model for HLA-B57:01–linked abacavir drug tolerance and reactivity</title><title>The Journal of clinical investigation</title><description>Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8+ T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4+ T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8+ T cells with an effector-like and skin-homing phenotype along with CD8+ infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8+ T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8+ T cells dependent on both HLA genetic risk and immunoregulatory host factors.</description><subject>Abacavir</subject><subject>Anergy</subject><subject>Antigens</subject><subject>Antiretroviral drugs</subject><subject>B7 antigen</subject><subject>Biomedical research</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell activation</subject><subject>Dendritic cells</subject><subject>Drug development</subject><subject>Drug tolerance</subject><subject>Effector cells</subject><subject>Histocompatibility antigen HLA</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Hypersensitivity</subject><subject>Immunological tolerance</subject><subject>Immunoregulation</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Peptides</subject><subject>Phenotypes</subject><subject>RNA-directed DNA polymerase</subject><subject>Skin</subject><subject>T cell receptors</subject><subject>Transgenic animals</subject><subject>Transgenic mice</subject><subject>Viral infections</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNi71OwzAURi3USqQ_A29wJeYUX9shDlupWhXUEYmxcpPbyiXYYDuVuvEOvCFP0gw8QJfvDOd8jN0hnyGW4uF18VJVUuDshmVYFDrXQuoByzgXmFel1LdsFOORc1SqUBl7n0MKxsUDOVvDp-8i9dtQC3sfYL2Z589F-cTx7-e3te6DGjA7U5uTDdCE7gDJt9T_awLjGghk6mRPNp0nbLg3baTpP8fsfrV8W6zzr-C_O4ppe_RdcL3aCqGkxFKrR3lddQFbAUYg</recordid><startdate>20180701</startdate><enddate>20180701</enddate><creator>Cardone, Marco</creator><creator>Garcia, Karla</creator><creator>Tilahun, Mulualem E</creator><creator>Boyd, Lisa F</creator><creator>Gebreyohannes, Sintayehu</creator><creator>Yano, Masahide</creator><creator>Roderiquez, Gregory</creator><creator>Akue, Adovi D</creator><creator>Juengst, Leslie</creator><creator>Mattson, Elliot</creator><creator>Ananthula, Suryatheja</creator><creator>Natarajan, Kannan</creator><creator>Puig, Montserrat</creator><creator>Margulies, David H</creator><creator>Norcross, Michael A</creator><general>American Society for Clinical Investigation</general><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope></search><sort><creationdate>20180701</creationdate><title>A transgenic mouse model for HLA-B57:01–linked abacavir drug tolerance and reactivity</title><author>Cardone, Marco ; Garcia, Karla ; Tilahun, Mulualem E ; Boyd, Lisa F ; Gebreyohannes, Sintayehu ; Yano, Masahide ; Roderiquez, Gregory ; Akue, Adovi D ; Juengst, Leslie ; Mattson, Elliot ; Ananthula, Suryatheja ; Natarajan, Kannan ; Puig, Montserrat ; Margulies, David H ; Norcross, Michael A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_22433178463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Abacavir</topic><topic>Anergy</topic><topic>Antigens</topic><topic>Antiretroviral drugs</topic><topic>B7 antigen</topic><topic>Biomedical research</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cell activation</topic><topic>Dendritic cells</topic><topic>Drug development</topic><topic>Drug tolerance</topic><topic>Effector cells</topic><topic>Histocompatibility antigen HLA</topic><topic>HIV</topic><topic>Human immunodeficiency virus</topic><topic>Hypersensitivity</topic><topic>Immunological tolerance</topic><topic>Immunoregulation</topic><topic>Infections</topic><topic>Inflammation</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Peptides</topic><topic>Phenotypes</topic><topic>RNA-directed DNA polymerase</topic><topic>Skin</topic><topic>T cell receptors</topic><topic>Transgenic animals</topic><topic>Transgenic mice</topic><topic>Viral infections</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cardone, Marco</creatorcontrib><creatorcontrib>Garcia, Karla</creatorcontrib><creatorcontrib>Tilahun, Mulualem E</creatorcontrib><creatorcontrib>Boyd, Lisa F</creatorcontrib><creatorcontrib>Gebreyohannes, Sintayehu</creatorcontrib><creatorcontrib>Yano, Masahide</creatorcontrib><creatorcontrib>Roderiquez, Gregory</creatorcontrib><creatorcontrib>Akue, Adovi D</creatorcontrib><creatorcontrib>Juengst, Leslie</creatorcontrib><creatorcontrib>Mattson, Elliot</creatorcontrib><creatorcontrib>Ananthula, Suryatheja</creatorcontrib><creatorcontrib>Natarajan, Kannan</creatorcontrib><creatorcontrib>Puig, Montserrat</creatorcontrib><creatorcontrib>Margulies, David H</creatorcontrib><creatorcontrib>Norcross, Michael A</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cardone, Marco</au><au>Garcia, Karla</au><au>Tilahun, Mulualem E</au><au>Boyd, Lisa F</au><au>Gebreyohannes, Sintayehu</au><au>Yano, Masahide</au><au>Roderiquez, Gregory</au><au>Akue, Adovi D</au><au>Juengst, Leslie</au><au>Mattson, Elliot</au><au>Ananthula, Suryatheja</au><au>Natarajan, Kannan</au><au>Puig, Montserrat</au><au>Margulies, David H</au><au>Norcross, Michael A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A transgenic mouse model for HLA-B57:01–linked abacavir drug tolerance and reactivity</atitle><jtitle>The Journal of clinical investigation</jtitle><date>2018-07-01</date><risdate>2018</risdate><volume>128</volume><issue>7</issue><spage>2819</spage><epage>2832</epage><pages>2819-2832</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8+ T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4+ T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8+ T cells with an effector-like and skin-homing phenotype along with CD8+ infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8+ T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8+ T cells dependent on both HLA genetic risk and immunoregulatory host factors.</abstract><cop>Ann Arbor</cop><pub>American Society for Clinical Investigation</pub><doi>10.1172/JCI99321.</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2018-07, Vol.128 (7), p.2819-2832 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_proquest_journals_2243317846 |
| source | Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Abacavir Anergy Antigens Antiretroviral drugs B7 antigen Biomedical research CD4 antigen CD8 antigen Cell activation Dendritic cells Drug development Drug tolerance Effector cells Histocompatibility antigen HLA HIV Human immunodeficiency virus Hypersensitivity Immunological tolerance Immunoregulation Infections Inflammation Lymphocytes Lymphocytes T Peptides Phenotypes RNA-directed DNA polymerase Skin T cell receptors Transgenic animals Transgenic mice Viral infections |
| title | A transgenic mouse model for HLA-B57:01–linked abacavir drug tolerance and reactivity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-19T18%3A10%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20transgenic%20mouse%20model%20for%20HLA-B57:01%E2%80%93linked%20abacavir%20drug%20tolerance%20and%20reactivity&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Cardone,%20Marco&rft.date=2018-07-01&rft.volume=128&rft.issue=7&rft.spage=2819&rft.epage=2832&rft.pages=2819-2832&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI99321.&rft_dat=%3Cproquest%3E2243317846%3C/proquest%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2243317846&rft_id=info:pmid/&rfr_iscdi=true |