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Robust Identification of Suitable T-Cell Subsets for Personalized CMV-Specific T-Cell Immunotherapy Using CD45RA and CD62L Microbeads
Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (T ) are mainly responsible for GvHD,...
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Published in: | International journal of molecular sciences 2019-03, Vol.20 (6), p.1415 |
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description | Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (T
) are mainly responsible for GvHD, methods were developed to generate naive T-cell-depleted products while preserving immune memory against viral infections. We compared two major strategies to deplete potentially alloreactive T cells: CD45RA and CD62L depletion and analyzed phenotype and functionality of the resulting CD45RA
/CD62L
naive T-cell-depleted as well as CD45RA⁺/CD62L⁺ naive T-cell-enriched fractions in the CMV pp65 and IE1 antigen model. CD45RA depletion resulted in loss of terminally differentiated effector memory T cells re-expressing CD45RA (T
), and CD62L depletion in loss of central memory T cells (T
). Based on these differences in target cell-dependent and target cell-independent assays, antigen-specific T-cell responses in CD62L-depleted fraction were consistently 3⁻5 fold higher than those in CD45RA-depleted fraction. Interestingly, we also observed high donor variability in the CD45RA-depleted fraction, resulting in a substantial loss of immune memory. Accordingly, we identified donors with expected response (DER) and unexpected response (DUR). Taken together, our results showed that a naive T-cell depletion method should be chosen individually, based on the immunophenotypic composition of the T-cell populations present. |
doi_str_mv | 10.3390/ijms20061415 |
format | article |
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) are mainly responsible for GvHD, methods were developed to generate naive T-cell-depleted products while preserving immune memory against viral infections. We compared two major strategies to deplete potentially alloreactive T cells: CD45RA and CD62L depletion and analyzed phenotype and functionality of the resulting CD45RA
/CD62L
naive T-cell-depleted as well as CD45RA⁺/CD62L⁺ naive T-cell-enriched fractions in the CMV pp65 and IE1 antigen model. CD45RA depletion resulted in loss of terminally differentiated effector memory T cells re-expressing CD45RA (T
), and CD62L depletion in loss of central memory T cells (T
). Based on these differences in target cell-dependent and target cell-independent assays, antigen-specific T-cell responses in CD62L-depleted fraction were consistently 3⁻5 fold higher than those in CD45RA-depleted fraction. Interestingly, we also observed high donor variability in the CD45RA-depleted fraction, resulting in a substantial loss of immune memory. Accordingly, we identified donors with expected response (DER) and unexpected response (DUR). Taken together, our results showed that a naive T-cell depletion method should be chosen individually, based on the immunophenotypic composition of the T-cell populations present.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms20061415</identifier><identifier>PMID: 30897843</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Activation ; Adenoviruses ; Antigens ; CCR7 protein ; CD27 antigen ; CD28 antigen ; CD45RA antigen ; CD8 antigen ; Cytokines ; Cytomegalovirus ; cytomegalovirus (CMV) ; Cytotoxicity ; Depletion ; donor lymphocyte infusions (DLIs) ; Genotype & phenotype ; Good Manufacturing Practice ; graft versus host disease (GvHD) ; Graft-versus-host reaction ; Hepatitis C ; Immunocompromised hosts ; Immunological memory ; Immunosuppression ; Immunotherapy ; Infections ; L-selectin ; Latent infection ; Lymphocytes ; Lymphocytes T ; Memory cells ; Microspheres ; Mortality ; naive T-cell depletion ; Opportunist infection ; Pathogens ; Phenotypes ; Transplants & implants ; Viral infections ; Viruses</subject><ispartof>International journal of molecular sciences, 2019-03, Vol.20 (6), p.1415</ispartof><rights>2019. This work is licensed under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-4536aa2f54e5e026ce2d0069c51497411d638316facf4f349f1458760838c7453</citedby><cites>FETCH-LOGICAL-c478t-4536aa2f54e5e026ce2d0069c51497411d638316facf4f349f1458760838c7453</cites><orcidid>0000-0002-5228-7627</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2332198888/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2332198888?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30897843$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mangare, Caroline</creatorcontrib><creatorcontrib>Tischer-Zimmermann, Sabine</creatorcontrib><creatorcontrib>Riese, Sebastian B</creatorcontrib><creatorcontrib>Dragon, Anna C</creatorcontrib><creatorcontrib>Prinz, Immo</creatorcontrib><creatorcontrib>Blasczyk, Rainer</creatorcontrib><creatorcontrib>Maecker-Kolhoff, Britta</creatorcontrib><creatorcontrib>Eiz-Vesper, Britta</creatorcontrib><title>Robust Identification of Suitable T-Cell Subsets for Personalized CMV-Specific T-Cell Immunotherapy Using CD45RA and CD62L Microbeads</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (T
) are mainly responsible for GvHD, methods were developed to generate naive T-cell-depleted products while preserving immune memory against viral infections. We compared two major strategies to deplete potentially alloreactive T cells: CD45RA and CD62L depletion and analyzed phenotype and functionality of the resulting CD45RA
/CD62L
naive T-cell-depleted as well as CD45RA⁺/CD62L⁺ naive T-cell-enriched fractions in the CMV pp65 and IE1 antigen model. CD45RA depletion resulted in loss of terminally differentiated effector memory T cells re-expressing CD45RA (T
), and CD62L depletion in loss of central memory T cells (T
). Based on these differences in target cell-dependent and target cell-independent assays, antigen-specific T-cell responses in CD62L-depleted fraction were consistently 3⁻5 fold higher than those in CD45RA-depleted fraction. Interestingly, we also observed high donor variability in the CD45RA-depleted fraction, resulting in a substantial loss of immune memory. Accordingly, we identified donors with expected response (DER) and unexpected response (DUR). Taken together, our results showed that a naive T-cell depletion method should be chosen individually, based on the immunophenotypic composition of the T-cell populations present.</description><subject>Activation</subject><subject>Adenoviruses</subject><subject>Antigens</subject><subject>CCR7 protein</subject><subject>CD27 antigen</subject><subject>CD28 antigen</subject><subject>CD45RA antigen</subject><subject>CD8 antigen</subject><subject>Cytokines</subject><subject>Cytomegalovirus</subject><subject>cytomegalovirus (CMV)</subject><subject>Cytotoxicity</subject><subject>Depletion</subject><subject>donor lymphocyte infusions (DLIs)</subject><subject>Genotype & phenotype</subject><subject>Good Manufacturing Practice</subject><subject>graft versus host disease (GvHD)</subject><subject>Graft-versus-host reaction</subject><subject>Hepatitis C</subject><subject>Immunocompromised hosts</subject><subject>Immunological memory</subject><subject>Immunosuppression</subject><subject>Immunotherapy</subject><subject>Infections</subject><subject>L-selectin</subject><subject>Latent infection</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Memory cells</subject><subject>Microspheres</subject><subject>Mortality</subject><subject>naive T-cell depletion</subject><subject>Opportunist infection</subject><subject>Pathogens</subject><subject>Phenotypes</subject><subject>Transplants & implants</subject><subject>Viral infections</subject><subject>Viruses</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNpdkstv1DAQxiMEog-4cUaWuHAg4GccX5CqlMdKW4H64GpNHHvrVRJv7QSpvfN_42Xbaosv9ti_79PMeIriDcEfGVP4k18PiWJcEU7Es-KQcErLHMrne-eD4iilNcaUUaFeFgcM10rWnB0Wf85DO6cJLTo7Tt55A5MPIwoOXcx-gra36LJsbN_nuE12SsiFiH7amMIIvb-zHWrOfpUXG2u26gd4MQzzGKZrG2Fzi66SH1eoOeXi_ATBmCWnFV2iM29iaC106VXxwkGf7Ov7_bi4-vrlsvleLn98WzQny9JwWU8lF6wCoE5wKyymlbG0y-UpIwhXkhPSVaxmpHJgHHeMK0e4qGWFa1YbmdXHxWLn2wVY6030A8RbHcDrfxchrjTEyZveaocBt9gpJYnlQEzbKaCcMN7VEgTg7PV557WZ28F2JvcvQv_E9OnL6K_1KvzWFZdEVjIbvL83iOFmtmnSg08mdw9GG-akKVGVoEyJbd7v_kPXYY75AzLFWAbrvDL1YUfltqYUrXtMhmC9nRW9PysZf7tfwCP8MBzsL56CuMM</recordid><startdate>20190320</startdate><enddate>20190320</enddate><creator>Mangare, Caroline</creator><creator>Tischer-Zimmermann, Sabine</creator><creator>Riese, Sebastian B</creator><creator>Dragon, Anna C</creator><creator>Prinz, Immo</creator><creator>Blasczyk, Rainer</creator><creator>Maecker-Kolhoff, Britta</creator><creator>Eiz-Vesper, Britta</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-5228-7627</orcidid></search><sort><creationdate>20190320</creationdate><title>Robust Identification of Suitable T-Cell Subsets for Personalized CMV-Specific T-Cell Immunotherapy Using CD45RA and CD62L Microbeads</title><author>Mangare, Caroline ; Tischer-Zimmermann, Sabine ; Riese, Sebastian B ; Dragon, Anna C ; Prinz, Immo ; Blasczyk, Rainer ; Maecker-Kolhoff, Britta ; Eiz-Vesper, Britta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-4536aa2f54e5e026ce2d0069c51497411d638316facf4f349f1458760838c7453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Activation</topic><topic>Adenoviruses</topic><topic>Antigens</topic><topic>CCR7 protein</topic><topic>CD27 antigen</topic><topic>CD28 antigen</topic><topic>CD45RA antigen</topic><topic>CD8 antigen</topic><topic>Cytokines</topic><topic>Cytomegalovirus</topic><topic>cytomegalovirus (CMV)</topic><topic>Cytotoxicity</topic><topic>Depletion</topic><topic>donor lymphocyte infusions (DLIs)</topic><topic>Genotype & phenotype</topic><topic>Good Manufacturing Practice</topic><topic>graft versus host disease (GvHD)</topic><topic>Graft-versus-host reaction</topic><topic>Hepatitis C</topic><topic>Immunocompromised hosts</topic><topic>Immunological memory</topic><topic>Immunosuppression</topic><topic>Immunotherapy</topic><topic>Infections</topic><topic>L-selectin</topic><topic>Latent infection</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Memory cells</topic><topic>Microspheres</topic><topic>Mortality</topic><topic>naive T-cell depletion</topic><topic>Opportunist infection</topic><topic>Pathogens</topic><topic>Phenotypes</topic><topic>Transplants & implants</topic><topic>Viral infections</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mangare, Caroline</creatorcontrib><creatorcontrib>Tischer-Zimmermann, Sabine</creatorcontrib><creatorcontrib>Riese, Sebastian B</creatorcontrib><creatorcontrib>Dragon, Anna C</creatorcontrib><creatorcontrib>Prinz, Immo</creatorcontrib><creatorcontrib>Blasczyk, Rainer</creatorcontrib><creatorcontrib>Maecker-Kolhoff, Britta</creatorcontrib><creatorcontrib>Eiz-Vesper, Britta</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mangare, Caroline</au><au>Tischer-Zimmermann, Sabine</au><au>Riese, Sebastian B</au><au>Dragon, Anna C</au><au>Prinz, Immo</au><au>Blasczyk, Rainer</au><au>Maecker-Kolhoff, Britta</au><au>Eiz-Vesper, Britta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Robust Identification of Suitable T-Cell Subsets for Personalized CMV-Specific T-Cell Immunotherapy Using CD45RA and CD62L Microbeads</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2019-03-20</date><risdate>2019</risdate><volume>20</volume><issue>6</issue><spage>1415</spage><pages>1415-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (T
) are mainly responsible for GvHD, methods were developed to generate naive T-cell-depleted products while preserving immune memory against viral infections. We compared two major strategies to deplete potentially alloreactive T cells: CD45RA and CD62L depletion and analyzed phenotype and functionality of the resulting CD45RA
/CD62L
naive T-cell-depleted as well as CD45RA⁺/CD62L⁺ naive T-cell-enriched fractions in the CMV pp65 and IE1 antigen model. CD45RA depletion resulted in loss of terminally differentiated effector memory T cells re-expressing CD45RA (T
), and CD62L depletion in loss of central memory T cells (T
). Based on these differences in target cell-dependent and target cell-independent assays, antigen-specific T-cell responses in CD62L-depleted fraction were consistently 3⁻5 fold higher than those in CD45RA-depleted fraction. Interestingly, we also observed high donor variability in the CD45RA-depleted fraction, resulting in a substantial loss of immune memory. Accordingly, we identified donors with expected response (DER) and unexpected response (DUR). Taken together, our results showed that a naive T-cell depletion method should be chosen individually, based on the immunophenotypic composition of the T-cell populations present.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>30897843</pmid><doi>10.3390/ijms20061415</doi><orcidid>https://orcid.org/0000-0002-5228-7627</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Activation Adenoviruses Antigens CCR7 protein CD27 antigen CD28 antigen CD45RA antigen CD8 antigen Cytokines Cytomegalovirus cytomegalovirus (CMV) Cytotoxicity Depletion donor lymphocyte infusions (DLIs) Genotype & phenotype Good Manufacturing Practice graft versus host disease (GvHD) Graft-versus-host reaction Hepatitis C Immunocompromised hosts Immunological memory Immunosuppression Immunotherapy Infections L-selectin Latent infection Lymphocytes Lymphocytes T Memory cells Microspheres Mortality naive T-cell depletion Opportunist infection Pathogens Phenotypes Transplants & implants Viral infections Viruses |
title | Robust Identification of Suitable T-Cell Subsets for Personalized CMV-Specific T-Cell Immunotherapy Using CD45RA and CD62L Microbeads |
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