title: Stimulation of the PD-1/PDL-1 T-cell co-inhibitory pathway is effective in treatment of experimental autoimmune glomerulonephritis.
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.
authors.affiliation: Department of Medicine, Imperial College London, UK. john.reynolds@imperial.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.forename: Gregg S
authors.initials: GS
authors.lastname: Sando
authors.forename: Olivia B
authors.initials: OB
authors.lastname: Marsh
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: David J
authors.initials: DJ
authors.lastname: Evans
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
mesh_terms: D000419:Albuminuria / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D024141:Collagen Type IV / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D007114:Immunization; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000276:immunology; D008213:Lymphocyte Activation; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D060890:B7-H1 Antigen; D024141:Collagen Type IV; D007074:Immunoglobulin G; D061026:Programmed Cell Death 1 Receptor; D011993:Recombinant Fusion Proteins; C057112:type IV collagen alpha3 chain