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Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation

BACKGROUND: Ischemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms. STUDY DESIGN: We investigated the benefits of pre-reperfusion treatment with recombinant human C1INH (rhC1INH), inhibit...

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Autores principales: Delpech, Pierre-Olivier, Thuillier, Raphael, SaintYves, Thibault, Danion, Jerome, Le Pape, Sylvain, van Amersfoort, Edwin S., Oortwijn, Beatrijs, Blancho, Gilles, Hauet, Thierry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035455/
https://www.ncbi.nlm.nih.gov/pubmed/27663514
http://dx.doi.org/10.1186/s12967-016-1013-7
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author Delpech, Pierre-Olivier
Thuillier, Raphael
SaintYves, Thibault
Danion, Jerome
Le Pape, Sylvain
van Amersfoort, Edwin S.
Oortwijn, Beatrijs
Blancho, Gilles
Hauet, Thierry
author_facet Delpech, Pierre-Olivier
Thuillier, Raphael
SaintYves, Thibault
Danion, Jerome
Le Pape, Sylvain
van Amersfoort, Edwin S.
Oortwijn, Beatrijs
Blancho, Gilles
Hauet, Thierry
author_sort Delpech, Pierre-Olivier
collection PubMed
description BACKGROUND: Ischemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms. STUDY DESIGN: We investigated the benefits of pre-reperfusion treatment with recombinant human C1INH (rhC1INH), inhibitor of both complement and contact activation, in a pig model of kidney autotransplantation, subjecting the organ to 60 min warm ischemia prior to 24 h static preservation to maximize damage. RESULTS: Serum creatinine measurement showed that treated animals recovered glomerular function quicker than the Vehicle group. However, no difference was observed in tubular function recovery, and elevated level of urinary NGal (Neutrophil gelatinase-associated lipocalin) and plasma AST (Aspartate Aminotransferase) were detected, indicating that treatment did not influence IRI-mediated tubular cell necrosis. Regarding chronic graft outcome, rhC1INH significantly prevented fibrosis development and improved function. Immunohistochemistry and western blot showed decreased invasion by macrophages and T lymphocytes, and reduction of epithelial to mesenchymal transition. We determined the effect of treatment on complement activation with immunofluorescence analyses at 30 min post reperfusion, showing an inhibition of C4d deposition and MBL staining in treated animals. CONCLUSIONS: In this model, the inhibition of complement activation by rhC1INH at reperfusion, while not completely counteracting IRI, limited immune system activation, significantly improving graft outcome on the short and long term. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-016-1013-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-50354552016-09-29 Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation Delpech, Pierre-Olivier Thuillier, Raphael SaintYves, Thibault Danion, Jerome Le Pape, Sylvain van Amersfoort, Edwin S. Oortwijn, Beatrijs Blancho, Gilles Hauet, Thierry J Transl Med Research BACKGROUND: Ischemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms. STUDY DESIGN: We investigated the benefits of pre-reperfusion treatment with recombinant human C1INH (rhC1INH), inhibitor of both complement and contact activation, in a pig model of kidney autotransplantation, subjecting the organ to 60 min warm ischemia prior to 24 h static preservation to maximize damage. RESULTS: Serum creatinine measurement showed that treated animals recovered glomerular function quicker than the Vehicle group. However, no difference was observed in tubular function recovery, and elevated level of urinary NGal (Neutrophil gelatinase-associated lipocalin) and plasma AST (Aspartate Aminotransferase) were detected, indicating that treatment did not influence IRI-mediated tubular cell necrosis. Regarding chronic graft outcome, rhC1INH significantly prevented fibrosis development and improved function. Immunohistochemistry and western blot showed decreased invasion by macrophages and T lymphocytes, and reduction of epithelial to mesenchymal transition. We determined the effect of treatment on complement activation with immunofluorescence analyses at 30 min post reperfusion, showing an inhibition of C4d deposition and MBL staining in treated animals. CONCLUSIONS: In this model, the inhibition of complement activation by rhC1INH at reperfusion, while not completely counteracting IRI, limited immune system activation, significantly improving graft outcome on the short and long term. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-016-1013-7) contains supplementary material, which is available to authorized users. BioMed Central 2016-09-23 /pmc/articles/PMC5035455/ /pubmed/27663514 http://dx.doi.org/10.1186/s12967-016-1013-7 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Delpech, Pierre-Olivier
Thuillier, Raphael
SaintYves, Thibault
Danion, Jerome
Le Pape, Sylvain
van Amersfoort, Edwin S.
Oortwijn, Beatrijs
Blancho, Gilles
Hauet, Thierry
Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation
title Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation
title_full Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation
title_fullStr Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation
title_full_unstemmed Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation
title_short Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation
title_sort inhibition of complement improves graft outcome in a pig model of kidney autotransplantation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035455/
https://www.ncbi.nlm.nih.gov/pubmed/27663514
http://dx.doi.org/10.1186/s12967-016-1013-7
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