Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes.
BACKGROUND
Anti-glomerular basement membrane (anti-GBM) disease often results in end-stage renal failure despite therapy with plasma exchange and immunosuppressive drugs. The newly discovered streptococcal enzymes IgG-degrading enzyme of S.pyogenes (IdeS) and endoglycosidase S (EndoS) act with remarkable specificity on circulating IgG. In this study, we investigate their ability in vivo to prevent damage mediated by kidney-bound antibodies in a mouse model of anti-GBM disease.


METHODS
Anti-GBM disease was induced in mice by injection of subnephritogenic doses of rabbit anti-mouse GBM, followed a week later by injection of monoclonal mouse anti-rabbit IgG antibodies. By administrating IdeS or EndoS as fusion partners with GST between these antibody injections, we tested their ability to prevent damage by acting on kidney-bound rabbit anti-GBM. Control animals received placebo injections.


RESULTS
All animals in the positive control groups developed severe albuminuria immediately after the second antibody injection (mean, 2.51 mg/24 h; range, 0.13-8.20). This was significantly diminished by EndoS (1.3 +/- 1.3 mg/24 h) and completely prevented by IdeS (0.017 +/- 0.014 mg/24 h). Immunofluorescence studies showed that IdeS treatment effectively removed the Fc fragments of the rabbit IgG. This was accompanied by a significant reduction of the deposition of the complement components C3 and C1q, and this diminished the recruitment of leukocytes to the glomeruli.


CONCLUSIONS
IdeS degrades IgG bound to the GBM in vivo, thereby preventing renal damage in this animal model. Most likely, IdeS would degrade both circulating and kidney-bound anti-GBM in patients with Goodpasture's disease. Whether this would lead to a halt in disease progression and a better prognosis remains to be determined.
Yang
Rui
R
Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
Otten
Marielle A
MA
Hellmark
Thomas
T
Collin
Mattias
M
Björck
Lars
L
Zhao
Ming-Hui
MH
Daha
Mohamed R
MR
Segelmark
Mårten
M
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D001323:Autoantibodies / Q000009:adverse effects; D001426:Bacterial Proteins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006026:Glycoside Hydrolases / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000097:blood; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome
D001323:Autoantibodies; D001426:Bacterial Proteins; D007074:Immunoglobulin G; C442815:Mac-1-like protein, Streptococcus; C051951:antiglomerular basement membrane antibody; D006026:Glycoside Hydrolases; C431325:NDOS protein, Streptococcus pyogenes