Desensitization and Prevention of Antibody-Mediated Rejection in Vascularized Composite Allotransplantation by Syngeneic Hematopoietic Stem Cell Transplantation
BACKGROUNDCandidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the...
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| Veröffentlicht in: | Transplantation 2018-04, Vol.102 (4), p.593-600 |
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| creator | Wang, Howard D Fidder, Samuel A.J Miller, Devin T Furtmüller, Georg J Ahmadi, Ali R Nägele, Felix Lopez, Joseph Quan, Amy Budihardjo, Joshua Lough, Denver M Akpinarli, Burcu Etra, Joanna W Vasilic, Dalibor Raimondi, Giorgio Lee, W.P Andrew Montgomery, Robert A Sun, Zhaoli Brandacher, Gerald |
| description | BACKGROUNDCandidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA.
METHODSSkin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry.
RESULTSSensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6).
CONCLUSIONSIn summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats. |
| doi_str_mv | 10.1097/TP.0000000000002070 |
| format | Article |
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METHODSSkin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry.
RESULTSSensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6).
CONCLUSIONSIn summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.</description><identifier>ISSN: 0041-1337</identifier><identifier>EISSN: 1534-6080</identifier><identifier>DOI: 10.1097/TP.0000000000002070</identifier><identifier>PMID: 29298238</identifier><language>eng</language><publisher>United States: Copyright Wolters Kluwer Health, Inc. All rights reserved</publisher><subject><![CDATA[Animals ; Complement C4b - immunology ; Composite Tissue Allografts - blood supply ; Composite Tissue Allografts - transplantation ; Desensitization, Immunologic - adverse effects ; Desensitization, Immunologic - methods ; Graft Rejection - blood ; Graft Rejection - immunology ; Graft Rejection - prevention & control ; Graft Survival ; Hematopoietic Stem Cell Transplantation - adverse effects ; Hematopoietic Stem Cell Transplantation - methods ; Hindlimb - blood supply ; Hindlimb - transplantation ; Immunosuppressive Agents - administration & dosage ; Isoantibodies - blood ; Isoantibodies - immunology ; Male ; Models, Animal ; Myeloablative Agonists - administration & dosage ; Peptide Fragments - immunology ; Rats, Inbred Lew ; Skin Transplantation - adverse effects ; Skin Transplantation - methods ; Tacrolimus - administration & dosage ; Time Factors ; Transplantation, Isogeneic ; Vascularized Composite Allotransplantation - adverse effects ; Vascularized Composite Allotransplantation - methods ; Vidarabine - administration & dosage ; Vidarabine - analogs & derivatives]]></subject><ispartof>Transplantation, 2018-04, Vol.102 (4), p.593-600</ispartof><rights>Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3530-c4a2d4177c669ae528ccfe5d82acccbd220bbe2c2d2c3d1f45c11240a9958c3f3</citedby><cites>FETCH-LOGICAL-c3530-c4a2d4177c669ae528ccfe5d82acccbd220bbe2c2d2c3d1f45c11240a9958c3f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29298238$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Howard D</creatorcontrib><creatorcontrib>Fidder, Samuel A.J</creatorcontrib><creatorcontrib>Miller, Devin T</creatorcontrib><creatorcontrib>Furtmüller, Georg J</creatorcontrib><creatorcontrib>Ahmadi, Ali R</creatorcontrib><creatorcontrib>Nägele, Felix</creatorcontrib><creatorcontrib>Lopez, Joseph</creatorcontrib><creatorcontrib>Quan, Amy</creatorcontrib><creatorcontrib>Budihardjo, Joshua</creatorcontrib><creatorcontrib>Lough, Denver M</creatorcontrib><creatorcontrib>Akpinarli, Burcu</creatorcontrib><creatorcontrib>Etra, Joanna W</creatorcontrib><creatorcontrib>Vasilic, Dalibor</creatorcontrib><creatorcontrib>Raimondi, Giorgio</creatorcontrib><creatorcontrib>Lee, W.P Andrew</creatorcontrib><creatorcontrib>Montgomery, Robert A</creatorcontrib><creatorcontrib>Sun, Zhaoli</creatorcontrib><creatorcontrib>Brandacher, Gerald</creatorcontrib><title>Desensitization and Prevention of Antibody-Mediated Rejection in Vascularized Composite Allotransplantation by Syngeneic Hematopoietic Stem Cell Transplantation</title><title>Transplantation</title><addtitle>Transplantation</addtitle><description>BACKGROUNDCandidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA.
METHODSSkin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry.
RESULTSSensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6).
CONCLUSIONSIn summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.</description><subject>Animals</subject><subject>Complement C4b - immunology</subject><subject>Composite Tissue Allografts - blood supply</subject><subject>Composite Tissue Allografts - transplantation</subject><subject>Desensitization, Immunologic - adverse effects</subject><subject>Desensitization, Immunologic - methods</subject><subject>Graft Rejection - blood</subject><subject>Graft Rejection - immunology</subject><subject>Graft Rejection - prevention & control</subject><subject>Graft Survival</subject><subject>Hematopoietic Stem Cell Transplantation - adverse effects</subject><subject>Hematopoietic Stem Cell Transplantation - methods</subject><subject>Hindlimb - blood supply</subject><subject>Hindlimb - transplantation</subject><subject>Immunosuppressive Agents - administration & dosage</subject><subject>Isoantibodies - blood</subject><subject>Isoantibodies - immunology</subject><subject>Male</subject><subject>Models, Animal</subject><subject>Myeloablative Agonists - administration & dosage</subject><subject>Peptide Fragments - immunology</subject><subject>Rats, Inbred Lew</subject><subject>Skin Transplantation - adverse effects</subject><subject>Skin Transplantation - methods</subject><subject>Tacrolimus - administration & dosage</subject><subject>Time Factors</subject><subject>Transplantation, Isogeneic</subject><subject>Vascularized Composite Allotransplantation - adverse effects</subject><subject>Vascularized Composite Allotransplantation - methods</subject><subject>Vidarabine - administration & dosage</subject><subject>Vidarabine - analogs & derivatives</subject><issn>0041-1337</issn><issn>1534-6080</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd1u1DAQhS1ERbeFJ0BCvuQmrX_idXK5Wn6KVNQVXbiNHHtCXRw72A7V9mn6qLjdgoAL5sYzmu-csXQQeknJCSWtPN1uTsgfxYgkT9CCCl5XS9KQp2hBSE0ryrk8REcpXRdIcCmfoUPWsrZhvFmguzeQwCeb7a3KNnisvMGbCD_AP4xhwKvS9cHsqo9grMpg8Ce4Bv2wth5_UUnPTkV7WzbrME6huAFeORdyVD5NTvm89-53-HLnv4IHq_EZjCqHKVjIZbrMMOI1OIe3f4ueo4NBuQQvHt9j9Pnd2-36rDq_eP9hvTqvNBecVLpWzNRUSr1ctgoEa7QeQJiGKa11bxgjfQ9MM8M0N3SohaaU1US1rWg0H_gxer33nWL4PkPK3WiTLh9SHsKcOto2tRSMMVFQvkd1DClFGLop2lHFXUdJdx9Nt910_0ZTVK8eD8z9COa35lcWBZB74Ca4DDF9c_MNxO4KlMtX_7X-CcQUn0A</recordid><startdate>201804</startdate><enddate>201804</enddate><creator>Wang, Howard D</creator><creator>Fidder, Samuel A.J</creator><creator>Miller, Devin T</creator><creator>Furtmüller, Georg J</creator><creator>Ahmadi, Ali R</creator><creator>Nägele, Felix</creator><creator>Lopez, Joseph</creator><creator>Quan, Amy</creator><creator>Budihardjo, Joshua</creator><creator>Lough, Denver M</creator><creator>Akpinarli, Burcu</creator><creator>Etra, Joanna W</creator><creator>Vasilic, Dalibor</creator><creator>Raimondi, Giorgio</creator><creator>Lee, W.P Andrew</creator><creator>Montgomery, Robert A</creator><creator>Sun, Zhaoli</creator><creator>Brandacher, Gerald</creator><general>Copyright Wolters Kluwer Health, Inc. All rights reserved</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></search><sort><creationdate>201804</creationdate><title>Desensitization and Prevention of Antibody-Mediated Rejection in Vascularized Composite Allotransplantation by Syngeneic Hematopoietic Stem Cell Transplantation</title><author>Wang, Howard D ; Fidder, Samuel A.J ; Miller, Devin T ; Furtmüller, Georg J ; Ahmadi, Ali R ; Nägele, Felix ; Lopez, Joseph ; Quan, Amy ; Budihardjo, Joshua ; Lough, Denver M ; Akpinarli, Burcu ; Etra, Joanna W ; Vasilic, Dalibor ; Raimondi, Giorgio ; Lee, W.P Andrew ; Montgomery, Robert A ; Sun, Zhaoli ; Brandacher, Gerald</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3530-c4a2d4177c669ae528ccfe5d82acccbd220bbe2c2d2c3d1f45c11240a9958c3f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Complement C4b - immunology</topic><topic>Composite Tissue Allografts - blood supply</topic><topic>Composite Tissue Allografts - transplantation</topic><topic>Desensitization, Immunologic - adverse effects</topic><topic>Desensitization, Immunologic - methods</topic><topic>Graft Rejection - blood</topic><topic>Graft Rejection - immunology</topic><topic>Graft Rejection - prevention & control</topic><topic>Graft Survival</topic><topic>Hematopoietic Stem Cell Transplantation - adverse effects</topic><topic>Hematopoietic Stem Cell Transplantation - methods</topic><topic>Hindlimb - blood supply</topic><topic>Hindlimb - transplantation</topic><topic>Immunosuppressive Agents - administration & dosage</topic><topic>Isoantibodies - blood</topic><topic>Isoantibodies - immunology</topic><topic>Male</topic><topic>Models, Animal</topic><topic>Myeloablative Agonists - administration & dosage</topic><topic>Peptide Fragments - immunology</topic><topic>Rats, Inbred Lew</topic><topic>Skin Transplantation - adverse effects</topic><topic>Skin Transplantation - methods</topic><topic>Tacrolimus - administration & dosage</topic><topic>Time Factors</topic><topic>Transplantation, Isogeneic</topic><topic>Vascularized Composite Allotransplantation - adverse effects</topic><topic>Vascularized Composite Allotransplantation - methods</topic><topic>Vidarabine - administration & dosage</topic><topic>Vidarabine - analogs & derivatives</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Howard D</creatorcontrib><creatorcontrib>Fidder, Samuel A.J</creatorcontrib><creatorcontrib>Miller, Devin T</creatorcontrib><creatorcontrib>Furtmüller, Georg J</creatorcontrib><creatorcontrib>Ahmadi, Ali R</creatorcontrib><creatorcontrib>Nägele, Felix</creatorcontrib><creatorcontrib>Lopez, Joseph</creatorcontrib><creatorcontrib>Quan, Amy</creatorcontrib><creatorcontrib>Budihardjo, Joshua</creatorcontrib><creatorcontrib>Lough, Denver M</creatorcontrib><creatorcontrib>Akpinarli, Burcu</creatorcontrib><creatorcontrib>Etra, Joanna W</creatorcontrib><creatorcontrib>Vasilic, Dalibor</creatorcontrib><creatorcontrib>Raimondi, Giorgio</creatorcontrib><creatorcontrib>Lee, W.P Andrew</creatorcontrib><creatorcontrib>Montgomery, Robert A</creatorcontrib><creatorcontrib>Sun, Zhaoli</creatorcontrib><creatorcontrib>Brandacher, Gerald</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><jtitle>Transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Howard D</au><au>Fidder, Samuel A.J</au><au>Miller, Devin T</au><au>Furtmüller, Georg J</au><au>Ahmadi, Ali R</au><au>Nägele, Felix</au><au>Lopez, Joseph</au><au>Quan, Amy</au><au>Budihardjo, Joshua</au><au>Lough, Denver M</au><au>Akpinarli, Burcu</au><au>Etra, Joanna W</au><au>Vasilic, Dalibor</au><au>Raimondi, Giorgio</au><au>Lee, W.P Andrew</au><au>Montgomery, Robert A</au><au>Sun, Zhaoli</au><au>Brandacher, Gerald</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Desensitization and Prevention of Antibody-Mediated Rejection in Vascularized Composite Allotransplantation by Syngeneic Hematopoietic Stem Cell Transplantation</atitle><jtitle>Transplantation</jtitle><addtitle>Transplantation</addtitle><date>2018-04</date><risdate>2018</risdate><volume>102</volume><issue>4</issue><spage>593</spage><epage>600</epage><pages>593-600</pages><issn>0041-1337</issn><eissn>1534-6080</eissn><abstract>BACKGROUNDCandidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA.
METHODSSkin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry.
RESULTSSensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6).
CONCLUSIONSIn summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.</abstract><cop>United States</cop><pub>Copyright Wolters Kluwer Health, Inc. All rights reserved</pub><pmid>29298238</pmid><doi>10.1097/TP.0000000000002070</doi><tpages>8</tpages></addata></record> |
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| subjects | Animals Complement C4b - immunology Composite Tissue Allografts - blood supply Composite Tissue Allografts - transplantation Desensitization, Immunologic - adverse effects Desensitization, Immunologic - methods Graft Rejection - blood Graft Rejection - immunology Graft Rejection - prevention & control Graft Survival Hematopoietic Stem Cell Transplantation - adverse effects Hematopoietic Stem Cell Transplantation - methods Hindlimb - blood supply Hindlimb - transplantation Immunosuppressive Agents - administration & dosage Isoantibodies - blood Isoantibodies - immunology Male Models, Animal Myeloablative Agonists - administration & dosage Peptide Fragments - immunology Rats, Inbred Lew Skin Transplantation - adverse effects Skin Transplantation - methods Tacrolimus - administration & dosage Time Factors Transplantation, Isogeneic Vascularized Composite Allotransplantation - adverse effects Vascularized Composite Allotransplantation - methods Vidarabine - administration & dosage Vidarabine - analogs & derivatives |
| title | Desensitization and Prevention of Antibody-Mediated Rejection in Vascularized Composite Allotransplantation by Syngeneic Hematopoietic Stem Cell Transplantation |
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