In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries
IntroductionDonor brain death (BD) is an unavoidable component of vascularized composite allograft (VCA) transplantation and a key contributor to ischemia-reperfusion injury (IRI). Complement is activated and deposited within solid organ grafts as a consequence of BD and has been shown to exacerbate...
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.630581/full |
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| author | Biao Lei M. Mahdi Sleiman Qi Cheng Qi Cheng Zhenxiao Tu Zhenxiao Tu Peng Zhu Peng Zhu Martin Goddard Paulo N. Martins Logan Langerude Satish Nadig Satish Nadig Stephen Tomlinson Stephen Tomlinson Stephen Tomlinson Carl Atkinson Carl Atkinson Carl Atkinson |
| author_facet | Biao Lei M. Mahdi Sleiman Qi Cheng Qi Cheng Zhenxiao Tu Zhenxiao Tu Peng Zhu Peng Zhu Martin Goddard Paulo N. Martins Logan Langerude Satish Nadig Satish Nadig Stephen Tomlinson Stephen Tomlinson Stephen Tomlinson Carl Atkinson Carl Atkinson Carl Atkinson |
| author_sort | Biao Lei |
| collection | DOAJ |
| description | IntroductionDonor brain death (BD) is an unavoidable component of vascularized composite allograft (VCA) transplantation and a key contributor to ischemia-reperfusion injury (IRI). Complement is activated and deposited within solid organ grafts as a consequence of BD and has been shown to exacerbate IRI, although the role of BD and complement in VCA and the role it plays in IRI and VCA rejection has not been studied.MethodsBD was induced in Balb/c donors, and the VCA perfused prior to graft procurement with UW solution supplemented with or without CR2-Crry, a C3 convertase complement inhibitor that binds at sites of complement activation, such as that induced on the endothelium by induction of BD. Following perfusion, donor VCAs were cold stored for 6 hours before transplantation into C57BL/6 recipients. Donor VCAs from living donors (LD) were also procured and stored. Analyses included CR2-Crry graft binding, complement activation, toxicity, injury/inflammation, graft gene expression and survival.ResultsCompared to LD VCAs, BD donor VCAs had exacerbated IRI and rejected earlier. Following pretransplant in-situ perfusion of the donor graft, CR2-Crry bound within the graft and was retained post-transplantation. CR2-Crry treatment significantly reduced complement deposition, inflammation and IRI as compared to vehicle-treated BD donors. Treatment of BD donor VCAs with CR2-Crry led to an injury profile not dissimilar to that seen in recipients of LD VCAs.ConclusionPre-coating a VCA with CR2-Crry in a clinically relevant treatment paradigm provides localized, and therefore minimally immunosuppressive, protection from the complement-mediated effects of BD induced exacerbated IRI. |
| first_indexed | 2024-12-17T12:29:01Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T12:29:01Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-425393ad8d704183a5a0339c9e8355f92022-12-21T21:48:41ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.630581630581In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced InjuriesBiao Lei0M. Mahdi Sleiman1Qi Cheng2Qi Cheng3Zhenxiao Tu4Zhenxiao Tu5Peng Zhu6Peng Zhu7Martin Goddard8Paulo N. Martins9Logan Langerude10Satish Nadig11Satish Nadig12Stephen Tomlinson13Stephen Tomlinson14Stephen Tomlinson15Carl Atkinson16Carl Atkinson17Carl Atkinson18Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Institute of Organ Transplantation, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Surgery, Hepatic and Vascular Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Surgery, Hepatic and Vascular Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaPathology Department, Papworth Hospital NHS Trust, Cambridge, United KingdomUMass Memorial Medical Center, Department of Surgery, Transplant Division, University of Massachusetts, Worcester, MA, United StatesDivision of Pulmonary Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, SC, United StatesDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesDepartment of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, SC, United StatesRalph H. Johnson VA Medical Center, Charleston, SC, United StatesDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United StatesDivision of Pulmonary Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, SC, United StatesIntroductionDonor brain death (BD) is an unavoidable component of vascularized composite allograft (VCA) transplantation and a key contributor to ischemia-reperfusion injury (IRI). Complement is activated and deposited within solid organ grafts as a consequence of BD and has been shown to exacerbate IRI, although the role of BD and complement in VCA and the role it plays in IRI and VCA rejection has not been studied.MethodsBD was induced in Balb/c donors, and the VCA perfused prior to graft procurement with UW solution supplemented with or without CR2-Crry, a C3 convertase complement inhibitor that binds at sites of complement activation, such as that induced on the endothelium by induction of BD. Following perfusion, donor VCAs were cold stored for 6 hours before transplantation into C57BL/6 recipients. Donor VCAs from living donors (LD) were also procured and stored. Analyses included CR2-Crry graft binding, complement activation, toxicity, injury/inflammation, graft gene expression and survival.ResultsCompared to LD VCAs, BD donor VCAs had exacerbated IRI and rejected earlier. Following pretransplant in-situ perfusion of the donor graft, CR2-Crry bound within the graft and was retained post-transplantation. CR2-Crry treatment significantly reduced complement deposition, inflammation and IRI as compared to vehicle-treated BD donors. Treatment of BD donor VCAs with CR2-Crry led to an injury profile not dissimilar to that seen in recipients of LD VCAs.ConclusionPre-coating a VCA with CR2-Crry in a clinically relevant treatment paradigm provides localized, and therefore minimally immunosuppressive, protection from the complement-mediated effects of BD induced exacerbated IRI.https://www.frontiersin.org/articles/10.3389/fimmu.2021.630581/fullvascularized composite allotransplantationgraft treatmenttransplantationcomplement inhibitionbrain deathischemia reperfusion injury |
| spellingShingle | Biao Lei M. Mahdi Sleiman Qi Cheng Qi Cheng Zhenxiao Tu Zhenxiao Tu Peng Zhu Peng Zhu Martin Goddard Paulo N. Martins Logan Langerude Satish Nadig Satish Nadig Stephen Tomlinson Stephen Tomlinson Stephen Tomlinson Carl Atkinson Carl Atkinson Carl Atkinson In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries Frontiers in Immunology vascularized composite allotransplantation graft treatment transplantation complement inhibition brain death ischemia reperfusion injury |
| title | In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries |
| title_full | In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries |
| title_fullStr | In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries |
| title_full_unstemmed | In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries |
| title_short | In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries |
| title_sort | in situ pre treatment of vascularized composite allografts with a targeted complement inhibitor protects against brain death and ischemia reperfusion induced injuries |
| topic | vascularized composite allotransplantation graft treatment transplantation complement inhibition brain death ischemia reperfusion injury |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.630581/full |
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