Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients
We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19...
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| Veröffentlicht in: | Journal of the American Society of Nephrology 2023-01, Vol.34 (1), p.160-174 |
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| creator | Morath, Christian Schaier, Matthias Ibrahim, Eman Wang, Lei Kleist, Christian Opelz, Gerhard Süsal, Caner Ponath, Gerald Aly, Mostafa Alvarez, Cristiam M Kälble, Florian Speer, Claudius Benning, Louise Nusshag, Christian Pego da Silva, Luiza Sommerer, Claudia Hückelhoven-Krauss, Angela Czock, David Mehrabi, Arianeb Schwab, Constantin Waldherr, Rüdiger Schnitzler, Paul Merle, Uta Tran, Thuong Hien Scherer, Sabine Böhmig, Georg A Müller-Tidow, Carsten Reiser, Jochen Zeier, Martin Schmitt, Michael Terness, Peter Schmitt, Anita Daniel, Volker |
| description | We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls.
Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080.
Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P |
| doi_str_mv | 10.1681/ASN.2022020210 |
| format | Article |
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Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080.
Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P <0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness.
These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants.
MIC Cell Therapy for Individualized Immunosuppression in Living Donor Kidney Transplant Recipients (TOL-1), NCT02560220.</description><identifier>ISSN: 1046-6673</identifier><identifier>EISSN: 1533-3450</identifier><identifier>DOI: 10.1681/ASN.2022020210</identifier><identifier>PMID: 36137752</identifier><language>eng</language><publisher>United States: American Society of Nephrology</publisher><subject>B-Lymphocytes, Regulatory ; Clinical Research ; Humans ; Immune Tolerance ; Immunosuppression Therapy ; Immunosuppressive Agents - therapeutic use ; Kidney Transplantation ; Transplant Recipients ; Transplantation</subject><ispartof>Journal of the American Society of Nephrology, 2023-01, Vol.34 (1), p.160-174</ispartof><rights>Copyright © 2022 by the American Society of Nephrology.</rights><rights>Copyright © 2022 by the American Society of Nephrology 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-8da0f14af077ec059ac08cd11361e2619e9677fbbe48fd4ecdc0957b3442ea293</citedby><cites>FETCH-LOGICAL-c391t-8da0f14af077ec059ac08cd11361e2619e9677fbbe48fd4ecdc0957b3442ea293</cites><orcidid>0000-0001-8345-1031 ; 0000-0002-8366-2100</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10101591/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10101591/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36137752$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morath, Christian</creatorcontrib><creatorcontrib>Schaier, Matthias</creatorcontrib><creatorcontrib>Ibrahim, Eman</creatorcontrib><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Kleist, Christian</creatorcontrib><creatorcontrib>Opelz, Gerhard</creatorcontrib><creatorcontrib>Süsal, Caner</creatorcontrib><creatorcontrib>Ponath, Gerald</creatorcontrib><creatorcontrib>Aly, Mostafa</creatorcontrib><creatorcontrib>Alvarez, Cristiam M</creatorcontrib><creatorcontrib>Kälble, Florian</creatorcontrib><creatorcontrib>Speer, Claudius</creatorcontrib><creatorcontrib>Benning, Louise</creatorcontrib><creatorcontrib>Nusshag, Christian</creatorcontrib><creatorcontrib>Pego da Silva, Luiza</creatorcontrib><creatorcontrib>Sommerer, Claudia</creatorcontrib><creatorcontrib>Hückelhoven-Krauss, Angela</creatorcontrib><creatorcontrib>Czock, David</creatorcontrib><creatorcontrib>Mehrabi, Arianeb</creatorcontrib><creatorcontrib>Schwab, Constantin</creatorcontrib><creatorcontrib>Waldherr, Rüdiger</creatorcontrib><creatorcontrib>Schnitzler, Paul</creatorcontrib><creatorcontrib>Merle, Uta</creatorcontrib><creatorcontrib>Tran, Thuong Hien</creatorcontrib><creatorcontrib>Scherer, Sabine</creatorcontrib><creatorcontrib>Böhmig, Georg A</creatorcontrib><creatorcontrib>Müller-Tidow, Carsten</creatorcontrib><creatorcontrib>Reiser, Jochen</creatorcontrib><creatorcontrib>Zeier, Martin</creatorcontrib><creatorcontrib>Schmitt, Michael</creatorcontrib><creatorcontrib>Terness, Peter</creatorcontrib><creatorcontrib>Schmitt, Anita</creatorcontrib><creatorcontrib>Daniel, Volker</creatorcontrib><title>Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients</title><title>Journal of the American Society of Nephrology</title><addtitle>J Am Soc Nephrol</addtitle><description>We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls.
Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080.
Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P <0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness.
These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants.
MIC Cell Therapy for Individualized Immunosuppression in Living Donor Kidney Transplant Recipients (TOL-1), NCT02560220.</description><subject>B-Lymphocytes, Regulatory</subject><subject>Clinical Research</subject><subject>Humans</subject><subject>Immune Tolerance</subject><subject>Immunosuppression Therapy</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Kidney Transplantation</subject><subject>Transplant Recipients</subject><subject>Transplantation</subject><issn>1046-6673</issn><issn>1533-3450</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1r3DAQFaElX-01x6BjLt7qw5bsU0mWJF3ittCmZyFL441SW3IsO-B_H5VsPsoMzMC8eW-Gh9AJJSsqSvrl_PePFSMsJWGU7KFDWnCe8bwgH1JPcpEJIfkBOorxnhBaMCn30QEXlEtZsEP0d-PtbCYXPA4troPfZrWOk_Nb_Au2c6enMC74AtdLP9wFs0wQcbPg78G61oHFm76fPeA1dF3EzuMbZz0s-HbUPg6d9lOiMW5w4Kf4CX1sdRfh864eoz9Xl7frb1n983qzPq8zwys6ZaXVpKW5bomUYEhRaUNKYylNVwMTtIJKSNk2DeRla3Mw1pCqkA3PcwaaVfwYfX3mHeamB2uS9qg7NYyu1-Oignbq_4l3d2obHhUlKYqKJoazHcMYHmaIk-pdNOlH7SHMUTFJpSgZ4SJBV89QM4YYR2hfdShR_yxSySL1ZlFaOH1_3Sv8xRP-BE2Fjis</recordid><startdate>20230101</startdate><enddate>20230101</enddate><creator>Morath, Christian</creator><creator>Schaier, Matthias</creator><creator>Ibrahim, Eman</creator><creator>Wang, Lei</creator><creator>Kleist, Christian</creator><creator>Opelz, Gerhard</creator><creator>Süsal, Caner</creator><creator>Ponath, Gerald</creator><creator>Aly, Mostafa</creator><creator>Alvarez, Cristiam M</creator><creator>Kälble, Florian</creator><creator>Speer, Claudius</creator><creator>Benning, Louise</creator><creator>Nusshag, Christian</creator><creator>Pego da Silva, Luiza</creator><creator>Sommerer, Claudia</creator><creator>Hückelhoven-Krauss, Angela</creator><creator>Czock, David</creator><creator>Mehrabi, Arianeb</creator><creator>Schwab, Constantin</creator><creator>Waldherr, Rüdiger</creator><creator>Schnitzler, Paul</creator><creator>Merle, Uta</creator><creator>Tran, Thuong Hien</creator><creator>Scherer, Sabine</creator><creator>Böhmig, Georg A</creator><creator>Müller-Tidow, Carsten</creator><creator>Reiser, Jochen</creator><creator>Zeier, Martin</creator><creator>Schmitt, Michael</creator><creator>Terness, Peter</creator><creator>Schmitt, Anita</creator><creator>Daniel, Volker</creator><general>American Society of Nephrology</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8345-1031</orcidid><orcidid>https://orcid.org/0000-0002-8366-2100</orcidid></search><sort><creationdate>20230101</creationdate><title>Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients</title><author>Morath, Christian ; Schaier, Matthias ; Ibrahim, Eman ; Wang, Lei ; Kleist, Christian ; Opelz, Gerhard ; Süsal, Caner ; Ponath, Gerald ; Aly, Mostafa ; Alvarez, Cristiam M ; Kälble, Florian ; Speer, Claudius ; Benning, Louise ; Nusshag, Christian ; Pego da Silva, Luiza ; Sommerer, Claudia ; Hückelhoven-Krauss, Angela ; Czock, David ; Mehrabi, Arianeb ; Schwab, Constantin ; Waldherr, Rüdiger ; Schnitzler, Paul ; Merle, Uta ; Tran, Thuong Hien ; Scherer, Sabine ; Böhmig, Georg A ; Müller-Tidow, Carsten ; Reiser, Jochen ; Zeier, Martin ; Schmitt, Michael ; Terness, Peter ; Schmitt, Anita ; Daniel, Volker</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-8da0f14af077ec059ac08cd11361e2619e9677fbbe48fd4ecdc0957b3442ea293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>B-Lymphocytes, Regulatory</topic><topic>Clinical Research</topic><topic>Humans</topic><topic>Immune Tolerance</topic><topic>Immunosuppression Therapy</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Kidney Transplantation</topic><topic>Transplant Recipients</topic><topic>Transplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morath, Christian</creatorcontrib><creatorcontrib>Schaier, Matthias</creatorcontrib><creatorcontrib>Ibrahim, Eman</creatorcontrib><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Kleist, Christian</creatorcontrib><creatorcontrib>Opelz, Gerhard</creatorcontrib><creatorcontrib>Süsal, Caner</creatorcontrib><creatorcontrib>Ponath, Gerald</creatorcontrib><creatorcontrib>Aly, Mostafa</creatorcontrib><creatorcontrib>Alvarez, Cristiam M</creatorcontrib><creatorcontrib>Kälble, Florian</creatorcontrib><creatorcontrib>Speer, Claudius</creatorcontrib><creatorcontrib>Benning, Louise</creatorcontrib><creatorcontrib>Nusshag, Christian</creatorcontrib><creatorcontrib>Pego da Silva, Luiza</creatorcontrib><creatorcontrib>Sommerer, Claudia</creatorcontrib><creatorcontrib>Hückelhoven-Krauss, Angela</creatorcontrib><creatorcontrib>Czock, David</creatorcontrib><creatorcontrib>Mehrabi, Arianeb</creatorcontrib><creatorcontrib>Schwab, Constantin</creatorcontrib><creatorcontrib>Waldherr, Rüdiger</creatorcontrib><creatorcontrib>Schnitzler, Paul</creatorcontrib><creatorcontrib>Merle, Uta</creatorcontrib><creatorcontrib>Tran, Thuong Hien</creatorcontrib><creatorcontrib>Scherer, Sabine</creatorcontrib><creatorcontrib>Böhmig, Georg A</creatorcontrib><creatorcontrib>Müller-Tidow, Carsten</creatorcontrib><creatorcontrib>Reiser, Jochen</creatorcontrib><creatorcontrib>Zeier, Martin</creatorcontrib><creatorcontrib>Schmitt, Michael</creatorcontrib><creatorcontrib>Terness, Peter</creatorcontrib><creatorcontrib>Schmitt, Anita</creatorcontrib><creatorcontrib>Daniel, Volker</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American Society of Nephrology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morath, Christian</au><au>Schaier, Matthias</au><au>Ibrahim, Eman</au><au>Wang, Lei</au><au>Kleist, Christian</au><au>Opelz, Gerhard</au><au>Süsal, Caner</au><au>Ponath, Gerald</au><au>Aly, Mostafa</au><au>Alvarez, Cristiam M</au><au>Kälble, Florian</au><au>Speer, Claudius</au><au>Benning, Louise</au><au>Nusshag, Christian</au><au>Pego da Silva, Luiza</au><au>Sommerer, Claudia</au><au>Hückelhoven-Krauss, Angela</au><au>Czock, David</au><au>Mehrabi, Arianeb</au><au>Schwab, Constantin</au><au>Waldherr, Rüdiger</au><au>Schnitzler, Paul</au><au>Merle, Uta</au><au>Tran, Thuong Hien</au><au>Scherer, Sabine</au><au>Böhmig, Georg A</au><au>Müller-Tidow, Carsten</au><au>Reiser, Jochen</au><au>Zeier, Martin</au><au>Schmitt, Michael</au><au>Terness, Peter</au><au>Schmitt, Anita</au><au>Daniel, Volker</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients</atitle><jtitle>Journal of the American Society of Nephrology</jtitle><addtitle>J Am Soc Nephrol</addtitle><date>2023-01-01</date><risdate>2023</risdate><volume>34</volume><issue>1</issue><spage>160</spage><epage>174</epage><pages>160-174</pages><issn>1046-6673</issn><eissn>1533-3450</eissn><abstract>We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls.
Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080.
Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P <0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness.
These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants.
MIC Cell Therapy for Individualized Immunosuppression in Living Donor Kidney Transplant Recipients (TOL-1), NCT02560220.</abstract><cop>United States</cop><pub>American Society of Nephrology</pub><pmid>36137752</pmid><doi>10.1681/ASN.2022020210</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-8345-1031</orcidid><orcidid>https://orcid.org/0000-0002-8366-2100</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of the American Society of Nephrology, 2023-01, Vol.34 (1), p.160-174 |
| issn | 1046-6673 1533-3450 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | B-Lymphocytes, Regulatory Clinical Research Humans Immune Tolerance Immunosuppression Therapy Immunosuppressive Agents - therapeutic use Kidney Transplantation Transplant Recipients Transplantation |
| title | Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients |
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