Journal Article

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 and Charles D. Pusey

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 27, issue 4, pages 1343-1350
Published in print April 2012 | ISSN: 0931-0509
Published online September 2011 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfr529
Stimulation of the PD-1/PDL-1 T-cell co-inhibitory pathway is effective in treatment of experimental autoimmune glomerulonephritis

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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.

Keywords: alpha 3 chain of type IV collagen; co-stimulatory molecules; experimental autoimmune glomerulonephritis; glomerular basement membrane; WKY rat

Journal Article.  4394 words.  Illustrated.

Subjects: Nephrology

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