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

Author

Listed:
  • Abbas Dehnadi

    (Massachusetts General Hospital)

  • A. Benedict Cosimi

    (Massachusetts General Hospital
    Harvard Medical School)

  • Rex Neal Smith

    (Harvard Medical School
    Massachusetts General Hospital)

  • Xiangen Li

    (Harvard Medical School
    Leukocyte Biology and Inflammation Program, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Massachusetts General Hospital)

  • José L. Alonso

    (Harvard Medical School
    Leukocyte Biology and Inflammation Program, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Massachusetts General Hospital)

  • Terry K. Means

    (Harvard Medical School
    Massachusetts General Hospital)

  • M. Amin Arnaout

    (Harvard Medical School
    Leukocyte Biology and Inflammation Program, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Massachusetts General Hospital
    Center For Regenerative Medicine, Medical Services, Massachusetts General Hospital)

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.

Suggested Citation

  • Abbas Dehnadi & A. Benedict Cosimi & Rex Neal Smith & Xiangen Li & José L. Alonso & Terry K. Means & M. Amin Arnaout, 2017. "Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys," Nature Communications, Nature, vol. 8(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms13899
    DOI: 10.1038/ncomms13899
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