title: Selective therapeutic control of C5a and the terminal complement complex by anti-C5 single-chain Fv in an experimental model of antigen-induced arthritis in rats.
abstract: OBJECTIVE
  To determine the role of the terminal complement complex (TCC) in the development of experimental antigen-induced arthritis (AIA) and the therapeutic effects of human anti-C5 single-chain Fv (scFv).
  
  
  METHODS
  Two different anti-C5 scFv, one that inhibits both release of C5a and assembly of the TCC (TS-A 12/22) and another that selectively blocks formation of the TCC (TS-A 8), were injected at the onset of AIA. The effects of these scFv on disease severity were evaluated for up to 21 days and compared with the effects of injection of an unrelated scFv. AIA was also established in C6-deficient and C6-sufficient PVG rats to obtain further information on the role of the TCC in this model.
  
  
  RESULTS
  TS-A 12/22 and TS-A 8 proved to be equally effective in reducing joint swelling, cell counts and tumor necrosis factor alpha levels in synovial lavage fluids, and the degree of histomorphologic changes compared with the effects of the unrelated scFv. TS-A 12/22 and TS-A 8 prevented the deposition of C9 but not that of C3, confirming the ability of the 2 scFv to neutralize C5. Administration of the 2 anti-C5 scFv after AIA onset also reduced disease severity. In C6-deficient rats with AIA, disease activity was reduced markedly compared with that in C6-sufficient rats.
  
  
  CONCLUSIONS
  These 2 human anti-C5 scFv could represent potential therapeutic reagents to be used in patients with rheumatoid arthritis. In addition, the finding that TS-A 8 was as effective as TS-A 12/22 in reducing disease severity suggests that the TCC is mainly responsible for the joint inflammation and damage observed in AIA.
authors: Department of Physiology and Pathology, University of Trieste, Trieste, Italy.
authors: Fabio
authors: F
authors: Fischetti
authors: Paolo
authors: P
authors: Durigutto
authors: Paolo
authors: P
authors: Macor
authors: Roberto
authors: R
authors: Marzari
authors: Renzo
authors: R
authors: Carretta
authors: Francesco
authors: F
authors: Tedesco
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015936:Complement C5a / Q000276:immunology* / Q000378:metabolism; D003183:Complement C6 / Q000172:deficiency / Q000235:genetics; D003169:Complement Inactivator Proteins / Q000627:therapeutic use*; D020868:Gene Silencing; D006801:Humans; D007128:Immunoglobulin Fragments / Q000627:therapeutic use*; D007270:Injections, Intra-Articular; D008297:Male; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D013264:Stifle / Q000187:drug effects / Q000473:pathology; D013582:Synovial Fluid / Q000737:chemistry / Q000378:metabolism; D013585:Synovitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D003183:Complement C6; D003169:Complement Inactivator Proteins; D007128:Immunoglobulin Fragments; D014409:Tumor Necrosis Factor-alpha; C055966:immunoglobulin Fv; D015936:Complement C5a