title: C5a receptor (CD88) blockade protects against MPO-ANCA GN.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine and.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dairaghi
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
authors.forename: Linda S
authors.initials: LS
authors.lastname: Ertl
authors.forename: Trageen
authors.initials: T
authors.lastname: Baumgart
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Seitz
authors.forename: Mark E T
authors.initials: ME
authors.lastname: Penfold
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.forename: Peiqi
authors.initials: P
authors.lastname: Hu
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Norma P
authors.initials: NP
authors.lastname: Gerard
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
mesh_terms: D000284:Administration, Oral; D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000517:prevention & control*; D001324:Autoantigens / Q000276:immunology*; D003183:Complement C6 / Q000276:immunology; D003170:Complement Pathway, Alternative; D004305:Dose-Response Relationship, Drug; D055879:Gene Knock-In Techniques; D005921:Glomerulonephritis / Q000150:complications / Q000276:immunology / Q000517:prevention & control*; D006417:Hematuria / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007116:Immunization, Passive; D007962:Leukocytes; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000172:deficiency / Q000276:immunology*; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins; D014556:Urine / Q000166:cytology
chemical_list: D001324:Autoantigens; C488033:C5AR1 protein, human; C000594938:C5ar2 protein, mouse; D003183:Complement C6; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; D009195:Peroxidase