Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes

Abstract

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.

Conclusion: 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.