C5a receptor (CD88) blockade protects against MPO-ANCA GN

Hong Xiao, Daniel J. Dairaghi, Jay P. Powers, Linda S. Ertl, Trageen Baumgart, Yu Wang, Lisa C. Seitz, Mark E.T. Penfold, Lin Gan, Peiqi Hu, Bao Lu, Norma P. Gerard, Craig Gerard, Thomas J. Schall, Juan C. Jaen, Ronald J. Falk, J. Charles Jennette

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associatedwith ANCA. Themost common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.

Original languageEnglish (US)
Pages (from-to)225-231
Number of pages7
JournalJournal of the American Society of Nephrology
Volume25
Issue number2
DOIs
Publication statusPublished - Feb 1 2014
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Nephrology

Cite this

Xiao, H., Dairaghi, D. J., Powers, J. P., Ertl, L. S., Baumgart, T., Wang, Y., ... Jennette, J. C. (2014). C5a receptor (CD88) blockade protects against MPO-ANCA GN. Journal of the American Society of Nephrology, 25(2), 225-231. https://doi.org/10.1681/ASN.2013020143