C5a receptor (CD88) blockade protects against MPO-ANCA GN.
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Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, Seitz LC, Penfold ME, Gan L, Hu P, Lu B, Gerard NP, Gerard C, Schall TJ, Jaen JC, Falk RJ, Jennette JC
C5a receptor (CD88) blockade protects against MPO-ANCA GN.
J Am Soc Nephrol. 2014 Feb;25(2):225-31. doi: 10.1681/ASN.2013020143. Epub 2013 Oct 31.
- PubMed ID
- 24179165 [ View in PubMed]
- Abstract
Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Avacopan C5a anaphylatoxin chemotactic receptor 1 Protein Humans YesAntagonistDetails