title: Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys.
abstract: 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.
authors.affiliation: Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehnadi
authors.affiliation: Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: A
authors.initials: A
authors.lastname: Benedict Cosimi
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Rex
authors.initials: R
authors.lastname: Neal Smith
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, USA.|Leukocyte Biology and Inflammation Program, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Xiangen
authors.initials: X
authors.lastname: Li
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, USA.|Leukocyte Biology and Inflammation Program, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: José L
authors.initials: JL
authors.lastname: Alonso
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Rheumatology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, USA.|Leukocyte Biology and Inflammation Program, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Center For Regenerative Medicine, Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: M Amin
authors.initials: MA
authors.lastname: Arnaout
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D039481:CD11b Antigen / Q000037:antagonists & inhibitors*; D018821:CD18 Antigens / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D007677:Kidney Function Tests; D008252:Macaca fascicularis; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D015427:Reperfusion Injury / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D039481:CD11b Antigen; D018821:CD18 Antigens; D018836:Inflammation Mediators