title: Inhibition of synovitis and joint destruction by a new single domain antibody specific for cyclophilin A in two different mouse models of rheumatoid arthritis.
abstract: BACKGROUND
  Cyclophilin A (CypA) is implicated in rheumatoid arthritis (RA) pathogenesis. We studied whether a novel anti-CypA single domain antibody (sdAb) treatment would modulate the severity of the disease in two different animal models of RA.
  
  
  METHODS
  A novel sdAb, named sdAbA1, was screened from an immunized camel sdAb library and found to have a high binding affinity (KD = 6.9 × 10-9 M) for CypA. The SCID-HuRAg model and the collagen-induced arthritis (CIA) in mice were used to evaluate the effects of sdAbA1 treatment on inflammation and joint destruction. For in vitro analysis, monocytes/macrophages were purified from synovial fluid and peripheral blood of patients with RA and were tested for the effect of anti-CypA sdAb on metalloproteinase (MMP) production. Human monocyte cell line THP-1 cells were selected and western blot analyses were performed to examine the potential signaling pathways.
  
  
  RESULTS
  In the CIA model of RA, the sdAbA1 treatment resulted in a significant decrease in clinical symptoms as well as of joint damage (P <0.05). In the SCID-HuRAg model, treatment with anti-CypA antibody sdAbA1 significantly reduced cartilage erosion, inflammatory cell numbers and MMP-9 production in the implanted tissues (P <0.05). It also significantly reduced the levels of human inflammatory cytokines IL-6 and IL-8 in mouse serum (P <0.05). No toxic effects were observed in the two animal models. In vitro results showed that sdAbA1 could counteract CypA-dependent MMP-9 secretion and IL-8 production by interfering with the ERK-NF-κB pathway.
  
  
  CONCLUSIONS
  Blockade of CypA significantly inhibited synovitis and cartilage/bone erosion in the two tested animal models of RA. Our findings provide evidence that sdAbA1 may be a potential therapeutic agent for RA.
authors: Li
authors: L
authors: Wang
authors: Junfeng
authors: J
authors: Jia
authors: Conghua
authors: C
authors: Wang
authors: Xiaokui
authors: X
authors: Ma
authors: Chenggong
authors: C
authors: Liao
authors: Zhiguang
authors: Z
authors: Fu
authors: Bin
authors: B
authors: Wang
authors: Xiangmin
authors: X
authors: Yang
authors: Ping
authors: P
authors: Zhu
authors: Yu
authors: Y
authors: Li
authors: Zhinan
authors: Z
authors: Chen
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000473:pathology; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D015153:Blotting, Western; D002460:Cell Line; D021984:Cyclophilin A / Q000037:antagonists & inhibitors* / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology; D015398:Signal Transduction; D061905:Single-Domain Antibodies / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D013585:Synovitis / Q000276:immunology* / Q000473:pathology
chemical_list: D061905:Single-Domain Antibodies; D021984:Cyclophilin A