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Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells: A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade
Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinicall...
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| Published in: | Cell transplantation 2018-11, Vol.27 (11), p.1692-1704 |
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| creator | Watanabe, M. Kumagai-Braesch, Makiko Yao, M. Thunberg, S. Berglund, D. Sellberg, F. Jorns, C. Enoksson, S. Lind Henriksson, J. Lundgren, T. Uhlin, M. Berglund, E. Ericzon, B.-G. |
| description | Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 × 106 cells) with irradiated donor PBMCs (20 × 106 cells) from eight human leukocyte antigen-mismatched responder–donor pairs in the presence of either 2D10.4/IT2.2 (3 μg/106 cells) or belatacept (40 μg/106 cells). After 14 days of coculture, the frequencies of CD4+ T cells, CD8+ T cells, and natural killer cells as well as interferon gamma (IFN-γ) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19+ B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4+CD25+CD127lowFOXP3+ T cells increased from 4.1±1.0% (preculture) to 7.1±2.6% and 7.3±2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p |
| doi_str_mv | 10.1177/0963689718794642 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_485304</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sage_id>10.1177_0963689718794642</sage_id><sourcerecordid>2114696694</sourcerecordid><originalsourceid>FETCH-LOGICAL-c420t-ef022048d91fdec20c7828db9e5feef7f5bd778db5c9b867e74ba4bdd4b907f43</originalsourceid><addsrcrecordid>eNp1kc1P3DAQxa2qqGyh956qHHtowHb8EV-QVgsFJCQOLVwtxxlvDYm9tRNa_vsm2gVBJU625v3mzWgeQp8JPiJEymOsRCVqJUktFROMvkMLwjkvq1rR92gxy-Ws76OPOd9hjGVF-Qe0X2EqiORkgVZnf4tb_xCLcwiQzOBjKKIrTmOIqViGwa8hlD82YL3ztrjs-zHEPrZjZ4aYHosVdF0-RHvOdBk-7d4DdPP97Ofqory6Pr9cLa9KyygeSnCYUszqVhHXgqXYyprWbaOAOwAnHW9aKacCt6qphQTJGsOatmWNwtKx6gCVW9_8BzZjozfJ9yY96mi83pXupx9oVvMKz_y3N_lTf7vUMa31OOpKEoarCT_Z4hPbQ2shDMl0r7peK8H_0uv4oAVViig5GXzdGaT4e4Q86N5nO13IBIhj1pQQJpQQal4Nb1GbYs4J3PMYgvUcrf4_2qnly8v1nhuesnxxHrMGfRfHFKY03jb8B9nYrhI</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2114696694</pqid></control><display><type>article</type><title>Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells: A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade</title><source>Publicly Available Content Database</source><source>Sage Journals GOLD Open Access 2024</source><source>PubMed Central</source><creator>Watanabe, M. ; Kumagai-Braesch, Makiko ; Yao, M. ; Thunberg, S. ; Berglund, D. ; Sellberg, F. ; Jorns, C. ; Enoksson, S. Lind ; Henriksson, J. ; Lundgren, T. ; Uhlin, M. ; Berglund, E. ; Ericzon, B.-G.</creator><creatorcontrib>Watanabe, M. ; Kumagai-Braesch, Makiko ; Yao, M. ; Thunberg, S. ; Berglund, D. ; Sellberg, F. ; Jorns, C. ; Enoksson, S. Lind ; Henriksson, J. ; Lundgren, T. ; Uhlin, M. ; Berglund, E. ; Ericzon, B.-G.</creatorcontrib><description>Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 × 106 cells) with irradiated donor PBMCs (20 × 106 cells) from eight human leukocyte antigen-mismatched responder–donor pairs in the presence of either 2D10.4/IT2.2 (3 μg/106 cells) or belatacept (40 μg/106 cells). After 14 days of coculture, the frequencies of CD4+ T cells, CD8+ T cells, and natural killer cells as well as interferon gamma (IFN-γ) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19+ B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4+CD25+CD127lowFOXP3+ T cells increased from 4.1±1.0% (preculture) to 7.1±2.6% and 7.3±2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p<0.05). Concurrently, delta-2 FOXP3 mRNA expression increased significantly. Compared with cells derived from the no-antibody treated control group, cells generated from both the 2D10.4/IT2.2- and belatacept-treated groups produced lower IFN-γ and higher interleukin-10 levels in response to donor-antigens, as detected by enzyme-linked immunospot. Most importantly, 2D10.4/IT2.2- and belatacept-generated cells effectively impeded the proliferative responses of freshly isolated responder PBMCs against donor-antigens. Our results indicate that belatacept-generated donor-specific immunomodulatory cells possess comparable phenotypes and immunomodulatory efficacies to those generated with 2D10.4/IT2.2. We suggest that belatacept could be used for ex vivo generation of clinical grade alloantigen-specific immunomodulatory cells for tolerance induction after transplantation.</description><identifier>ISSN: 0963-6897</identifier><identifier>ISSN: 1555-3892</identifier><identifier>EISSN: 1555-3892</identifier><identifier>DOI: 10.1177/0963689718794642</identifier><identifier>PMID: 30261751</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>anti-CD80/86 antibodies ; CTLA4-Ig ; donor antigen specificity ; ex vivo generation ; FOXP3 ; Immunomodulatory cells ; Original</subject><ispartof>Cell transplantation, 2018-11, Vol.27 (11), p.1692-1704</ispartof><rights>The Author(s) 2018</rights><rights>The Author(s) 2018 2018 SAGE Publications Inc, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c420t-ef022048d91fdec20c7828db9e5feef7f5bd778db5c9b867e74ba4bdd4b907f43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299197/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299197/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,21946,27832,27903,27904,36992,44924,45312,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30261751$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-371403$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:139634344$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Watanabe, M.</creatorcontrib><creatorcontrib>Kumagai-Braesch, Makiko</creatorcontrib><creatorcontrib>Yao, M.</creatorcontrib><creatorcontrib>Thunberg, S.</creatorcontrib><creatorcontrib>Berglund, D.</creatorcontrib><creatorcontrib>Sellberg, F.</creatorcontrib><creatorcontrib>Jorns, C.</creatorcontrib><creatorcontrib>Enoksson, S. Lind</creatorcontrib><creatorcontrib>Henriksson, J.</creatorcontrib><creatorcontrib>Lundgren, T.</creatorcontrib><creatorcontrib>Uhlin, M.</creatorcontrib><creatorcontrib>Berglund, E.</creatorcontrib><creatorcontrib>Ericzon, B.-G.</creatorcontrib><title>Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells: A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade</title><title>Cell transplantation</title><addtitle>Cell Transplant</addtitle><description>Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 × 106 cells) with irradiated donor PBMCs (20 × 106 cells) from eight human leukocyte antigen-mismatched responder–donor pairs in the presence of either 2D10.4/IT2.2 (3 μg/106 cells) or belatacept (40 μg/106 cells). After 14 days of coculture, the frequencies of CD4+ T cells, CD8+ T cells, and natural killer cells as well as interferon gamma (IFN-γ) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19+ B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4+CD25+CD127lowFOXP3+ T cells increased from 4.1±1.0% (preculture) to 7.1±2.6% and 7.3±2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p<0.05). Concurrently, delta-2 FOXP3 mRNA expression increased significantly. Compared with cells derived from the no-antibody treated control group, cells generated from both the 2D10.4/IT2.2- and belatacept-treated groups produced lower IFN-γ and higher interleukin-10 levels in response to donor-antigens, as detected by enzyme-linked immunospot. Most importantly, 2D10.4/IT2.2- and belatacept-generated cells effectively impeded the proliferative responses of freshly isolated responder PBMCs against donor-antigens. Our results indicate that belatacept-generated donor-specific immunomodulatory cells possess comparable phenotypes and immunomodulatory efficacies to those generated with 2D10.4/IT2.2. We suggest that belatacept could be used for ex vivo generation of clinical grade alloantigen-specific immunomodulatory cells for tolerance induction after transplantation.</description><subject>anti-CD80/86 antibodies</subject><subject>CTLA4-Ig</subject><subject>donor antigen specificity</subject><subject>ex vivo generation</subject><subject>FOXP3</subject><subject>Immunomodulatory cells</subject><subject>Original</subject><issn>0963-6897</issn><issn>1555-3892</issn><issn>1555-3892</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>AFRWT</sourceid><recordid>eNp1kc1P3DAQxa2qqGyh956qHHtowHb8EV-QVgsFJCQOLVwtxxlvDYm9tRNa_vsm2gVBJU625v3mzWgeQp8JPiJEymOsRCVqJUktFROMvkMLwjkvq1rR92gxy-Ws76OPOd9hjGVF-Qe0X2EqiORkgVZnf4tb_xCLcwiQzOBjKKIrTmOIqViGwa8hlD82YL3ztrjs-zHEPrZjZ4aYHosVdF0-RHvOdBk-7d4DdPP97Ofqory6Pr9cLa9KyygeSnCYUszqVhHXgqXYyprWbaOAOwAnHW9aKacCt6qphQTJGsOatmWNwtKx6gCVW9_8BzZjozfJ9yY96mi83pXupx9oVvMKz_y3N_lTf7vUMa31OOpKEoarCT_Z4hPbQ2shDMl0r7peK8H_0uv4oAVViig5GXzdGaT4e4Q86N5nO13IBIhj1pQQJpQQal4Nb1GbYs4J3PMYgvUcrf4_2qnly8v1nhuesnxxHrMGfRfHFKY03jb8B9nYrhI</recordid><startdate>20181101</startdate><enddate>20181101</enddate><creator>Watanabe, M.</creator><creator>Kumagai-Braesch, Makiko</creator><creator>Yao, M.</creator><creator>Thunberg, S.</creator><creator>Berglund, D.</creator><creator>Sellberg, F.</creator><creator>Jorns, C.</creator><creator>Enoksson, S. Lind</creator><creator>Henriksson, J.</creator><creator>Lundgren, T.</creator><creator>Uhlin, M.</creator><creator>Berglund, E.</creator><creator>Ericzon, B.-G.</creator><general>SAGE Publications</general><scope>AFRWT</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><scope>ACNBI</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>DF2</scope><scope>ZZAVC</scope></search><sort><creationdate>20181101</creationdate><title>Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells</title><author>Watanabe, M. ; Kumagai-Braesch, Makiko ; Yao, M. ; Thunberg, S. ; Berglund, D. ; Sellberg, F. ; Jorns, C. ; Enoksson, S. 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Lind</creatorcontrib><creatorcontrib>Henriksson, J.</creatorcontrib><creatorcontrib>Lundgren, T.</creatorcontrib><creatorcontrib>Uhlin, M.</creatorcontrib><creatorcontrib>Berglund, E.</creatorcontrib><creatorcontrib>Ericzon, B.-G.</creatorcontrib><collection>Sage Journals GOLD Open Access 2024</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SWEPUB Uppsala universitet full text</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Uppsala universitet</collection><collection>SwePub Articles full text</collection><jtitle>Cell transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Watanabe, M.</au><au>Kumagai-Braesch, Makiko</au><au>Yao, M.</au><au>Thunberg, S.</au><au>Berglund, D.</au><au>Sellberg, F.</au><au>Jorns, C.</au><au>Enoksson, S. Lind</au><au>Henriksson, J.</au><au>Lundgren, T.</au><au>Uhlin, M.</au><au>Berglund, E.</au><au>Ericzon, B.-G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells: A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade</atitle><jtitle>Cell transplantation</jtitle><addtitle>Cell Transplant</addtitle><date>2018-11-01</date><risdate>2018</risdate><volume>27</volume><issue>11</issue><spage>1692</spage><epage>1704</epage><pages>1692-1704</pages><issn>0963-6897</issn><issn>1555-3892</issn><eissn>1555-3892</eissn><abstract>Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 × 106 cells) with irradiated donor PBMCs (20 × 106 cells) from eight human leukocyte antigen-mismatched responder–donor pairs in the presence of either 2D10.4/IT2.2 (3 μg/106 cells) or belatacept (40 μg/106 cells). After 14 days of coculture, the frequencies of CD4+ T cells, CD8+ T cells, and natural killer cells as well as interferon gamma (IFN-γ) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19+ B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4+CD25+CD127lowFOXP3+ T cells increased from 4.1±1.0% (preculture) to 7.1±2.6% and 7.3±2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p<0.05). Concurrently, delta-2 FOXP3 mRNA expression increased significantly. Compared with cells derived from the no-antibody treated control group, cells generated from both the 2D10.4/IT2.2- and belatacept-treated groups produced lower IFN-γ and higher interleukin-10 levels in response to donor-antigens, as detected by enzyme-linked immunospot. Most importantly, 2D10.4/IT2.2- and belatacept-generated cells effectively impeded the proliferative responses of freshly isolated responder PBMCs against donor-antigens. Our results indicate that belatacept-generated donor-specific immunomodulatory cells possess comparable phenotypes and immunomodulatory efficacies to those generated with 2D10.4/IT2.2. We suggest that belatacept could be used for ex vivo generation of clinical grade alloantigen-specific immunomodulatory cells for tolerance induction after transplantation.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>30261751</pmid><doi>10.1177/0963689718794642</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | anti-CD80/86 antibodies CTLA4-Ig donor antigen specificity ex vivo generation FOXP3 Immunomodulatory cells Original |
| title | Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells: A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade |
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