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Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys

Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non-human primates. Here we demonstrate that inhibition of the archetypal...

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Autores principales: Dehnadi, Abbas, Benedict Cosimi, A., Neal Smith, Rex, Li, Xiangen, Alonso, José L., Means, Terry K., Arnaout, M. Amin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234083/
https://www.ncbi.nlm.nih.gov/pubmed/28071653
http://dx.doi.org/10.1038/ncomms13899
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author Dehnadi, Abbas
Benedict Cosimi, A.
Neal Smith, Rex
Li, Xiangen
Alonso, José L.
Means, Terry K.
Arnaout, M. Amin
author_facet Dehnadi, Abbas
Benedict Cosimi, A.
Neal Smith, Rex
Li, Xiangen
Alonso, José L.
Means, Terry K.
Arnaout, M. Amin
author_sort Dehnadi, Abbas
collection PubMed
description Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non-human primates. Here we demonstrate that inhibition of the archetypal innate immune receptor CD11b/CD18 prevents progression of AKI to CKD in cynomolgus monkeys. Severe ischaemia-reperfusion injury of the right kidney, with subsequent periods of the left ureter ligation, causes irreversible right kidney failure 3, 6 or 9 months after AKI. Moreover, prophylactic inactivation of CD11b/CD18, using the orthosteric CD11b/CD18 inhibitor mAb107, improves microvascular perfusion and histopathology, reduces intrarenal pro-inflammatory mediators and salvages kidney function long term. These studies reveal an important early role of CD11b(+) leukocytes in post-ischaemic kidney fibrosis and failure, and suggest a potential early therapeutic intervention to mitigate progression of ischaemic AKI to CKD in humans.
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spelling pubmed-52340832017-01-24 Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys Dehnadi, Abbas Benedict Cosimi, A. Neal Smith, Rex Li, Xiangen Alonso, José L. Means, Terry K. Arnaout, M. Amin Nat Commun Article Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non-human primates. Here we demonstrate that inhibition of the archetypal innate immune receptor CD11b/CD18 prevents progression of AKI to CKD in cynomolgus monkeys. Severe ischaemia-reperfusion injury of the right kidney, with subsequent periods of the left ureter ligation, causes irreversible right kidney failure 3, 6 or 9 months after AKI. Moreover, prophylactic inactivation of CD11b/CD18, using the orthosteric CD11b/CD18 inhibitor mAb107, improves microvascular perfusion and histopathology, reduces intrarenal pro-inflammatory mediators and salvages kidney function long term. These studies reveal an important early role of CD11b(+) leukocytes in post-ischaemic kidney fibrosis and failure, and suggest a potential early therapeutic intervention to mitigate progression of ischaemic AKI to CKD in humans. Nature Publishing Group 2017-01-10 /pmc/articles/PMC5234083/ /pubmed/28071653 http://dx.doi.org/10.1038/ncomms13899 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Dehnadi, Abbas
Benedict Cosimi, A.
Neal Smith, Rex
Li, Xiangen
Alonso, José L.
Means, Terry K.
Arnaout, M. Amin
Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
title Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
title_full Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
title_fullStr Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
title_full_unstemmed Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
title_short Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
title_sort prophylactic orthosteric inhibition of leukocyte integrin cd11b/cd18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234083/
https://www.ncbi.nlm.nih.gov/pubmed/28071653
http://dx.doi.org/10.1038/ncomms13899
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