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Stimulation of the PD-1/PDL-1 T-cell co-inhibitory pathway is effective in treatment of experimental autoimmune glomerulonephritis

  • John Reynolds
    ,
  • Gregg S. Sando
    ,
  • Olivia B. Marsh
    ,
  • Alan D. Salama
    ,
  • David J. Evans
    ,
  • H. Terence Cook
  • Imperial College London
Research Output: Contribution to journal Article Peer-review

Sustainable Development Goals

  • SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well

Abstract

Background. Experimental autoimmune glomerulonephritis (EAG) can be induced in Wistar–Kyoto (WKY) rats by immunization with the recombinant NC1 domain of the alpha 3 chain of type IV collagen [α3(IV)NC1]. EAG is characterized by circulating and deposited anti-α3(IV)NC1 antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. Programmed death-1 (PD-1) receptor is preferentially expressed on activated T cells and binds two known ligands present on antigen presenting cells, PDL-1 and PDL-2. Engagement of PD-1 by its ligands results in a negative regulatory effect, with inhibition of downstream cellular signalling events and diminished cellular proliferation. Methods. In order to investigate the role of the PD-1/PDL-1 co-inhibitory pathway in development of EAG, the in vivo effects of a stimulating PDL-1/Fc fusion protein were examined after the onset of disease. Results. Stimulation of PD-1 led to a significant reduction in albuminuria, serum urea, serum creatinine, crescent formation and tubular damage compared with controls. There was also a reduction in numbers of glomerular macrophages, CD4+ T cells, CD8+ T cells and PD1+ cells compared with controls. No reduction was observed in levels of circulating or deposited antibodies. Conclusions. These results demonstrate that PDL-1/Fc fusion protein is effective in treatment of glomerulonephritis and confirm the importance of the PD-1/PDL-1 T-cell co-inhibitory pathway in development of EAG. Strategies designed to stimulate this pathway may provide a novel approach to treatment of human glomerulonephritis.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 1343-1350

Journal (Volume, Issue Number)

Nephrology Dialysis Transplantation (Volume 27, Issue 4)

Publication milestones

  • Published - 01/01/2012

Publication status

Published - 01/01/2012

ISSN

0931-0509

Publication IDs

  • handle.net: 10547/229031
  • Scopus: 84859327145

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