Department of Surgery, Transplant Division
Immunology and Infectious Disease | Medical Immunology | Surgery | Surgical Procedures, Operative
Introduction: Donor 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.
Methods: BD 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.
Results: Compared 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.
Conclusion: Pre-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.
brain death, complement inhibition, graft treatment, immunogenicity, ischemia reperfusion injury, preservation, transplantation, vascularized composite allotransplantation
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Copyright © 2021 Lei, Sleiman, Cheng, Tu, Zhu, Goddard, Martins, Langerude, Nadig, Tomlinson and Atkinson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
Lei B, Sleiman MM, Cheng Q, Tu Z, Zhu P, Goddard M, Martins PN, Langerude L, Nadig S, Tomlinson S, Atkinson C. In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries. Front Immunol. 2021 Jul 29;12:630581. doi: 10.3389/fimmu.2021.630581. PMID: 34394069; PMCID: PMC8358649. Link to article on publisher's site
Frontiers in immunology
Lei B, Sleiman MM, Cheng Q, Tu Z, Zhu P, Goddard M, Martins PN, Langerude L, Nadig S, Tomlinson S, Atkinson C. (2021). In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries. Open Access Publications by UMass Chan Authors. https://doi.org/10.3389/fimmu.2021.630581. Retrieved from https://escholarship.umassmed.edu/oapubs/4835
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