title: The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice.
abstract: OBJECTIVE
  Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (ICs) and apoptotic cells and its role in inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. The aim of this study was to investigate the effect of a new targeted inhibitor of the alternative pathway, CR2-fH, on lupus-like renal disease in MRL/lpr mice.
  
  
  METHODS
  Mice were treated with either saline, CR2-fH, CR2-Crry (which inhibits all complement pathways), or soluble CR2 (sCR2; C3d-binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs, and C3. Urinary excretion of albumin was also determined, and kidneys were collected at 23 weeks for histologic evaluation.
  
  
  RESULTS
  Treatment with CR2-fH or CR2-Crry improved survival and significantly reduced proteinuria, glomerular C3 deposition, and the level of circulating ICs. CR2-fH, but not CR2-Crry, also significantly reduced glomerulonephritis, expression of serum anti-double-stranded DNA (anti-dsDNA) antibodies, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced the levels of anti-dsDNA antibodies and circulating ICs and reduced glomerular deposition of IgG, C1q, and C3, although there was no significant reduction in glomerulonephritis, proteinuria, or mortality.
  
  
  CONCLUSIONS
  Targeted and selective inhibition of the alternative complement pathway is an effective treatment of murine lupus and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact and indicate distinct roles for the classical and alternative pathways of complement in disease progression. The sCR2-targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity.
authors: Medical University of South Carolina, Charleston, SC, USA.
authors: Hideharu
authors: H
authors: Sekine
authors: Ting Ting Hsieh
authors: TT
authors: Kinser
authors: Fei
authors: F
authors: Qiao
authors: Efrain
authors: E
authors: Martinez
authors: Emily
authors: E
authors: Paulling
authors: Phillip
authors: P
authors: Ruiz
authors: Gary S
authors: GS
authors: Gilkeson
authors: Stephen
authors: S
authors: Tomlinson
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D000936:Antigen-Antibody Complex / Q000097:blood; D015551:Autoimmunity / Q000187:drug effects* / Q000502:physiology; D015922:Complement C1q / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D051056:Complement Inactivating Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D003170:Complement Pathway, Alternative / Q000187:drug effects* / Q000502:physiology; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000936:Antigen-Antibody Complex; C527099:CR2-Crry fusion protein, mouse; D003176:Complement C3; D051056:Complement Inactivating Agents; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D015922:Complement C1q; D004247:DNA