title: Monitoring the effects of dexamethasone treatment by MRI using in vivo iron oxide nanoparticle-labeled macrophages.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is a chronic disease causing recurring inflammatory joint attacks. These attacks are characterized by macrophage infiltration contributing to joint destruction. Studies have shown that RA treatment efficacy is correlated to synovial macrophage number. The aim of this study was to experimentally validate the use of in vivo superparamagnetic iron oxide nanoparticle (SPION) labeled macrophages to evaluate RA treatment by MRI.
  
  
  METHODS
  The evolution of macrophages was monitored with and without dexamethasone (Dexa) treatment in rats. Two doses of 3 and 1 mg/kg Dexa were administered two and five days following induction of antigen induced arthritis. SPIONs (7 mg Fe/rat) were injected intravenously and the knees were imaged in vivo on days 6, 10 and 13. The MR images were scored for three parameters: SPION signal intensity, SPION distribution pattern and synovial oedema. Using 3D semi-automated software, the MR SPION signal was quantified. The efficacy of SPIONs and gadolinium chelate (Gd), an MR contrast agent, in illustrating treatment effects were compared. Those results were confirmed through histological measurements of number and area of macrophages and nanoparticle clusters using CD68 immunostaining and Prussian blue staining respectively.
  
  
  RESULTS
  Results show that the pattern and the intensity of SPION-labeled macrophages on MRI were altered by Dexa treatment. While the Dexa group had a uniform elliptical line surrounding an oedema pocket, the untreated group showed a diffused SPION distribution on day 6 post-induction. Dexa reduced the intensity of SPION signal 50-60% on days 10 and 13 compared to controls (P = 0.00008 and 0.002 respectively). Similar results were found when the signal was measured by the 3D tool. On day 13, the persisting low grade arthritis progression could not be demonstrated by Gd. Analysis of knee samples by Prussian blue and CD68 immunostaining confirmed in vivo SPION uptake by macrophages. Furthermore, CD68 immunostaining revealed that Dexa treatment significantly decreased the area and number of synovial macrophages. Prussian blue quantification corresponded to the macrophage measurements and both were in agreement with the MRI findings.
  
  
  CONCLUSIONS
  We have demonstrated the feasibility of MRI tracking of in vivo SPION-labeled macrophages to assess RA treatment effects.
authors: Azza
authors: A
authors: Gramoun
authors: Lindsey A
authors: LA
authors: Crowe
authors: Lionel
authors: L
authors: Maurizi
authors: Wolfgang
authors: W
authors: Wirth
authors: Frank
authors: F
authors: Tobalem
authors: Kerstin
authors: K
authors: Grosdemange
authors: Geraldine
authors: G
authors: Coullerez
authors: Felix
authors: F
authors: Eckstein
authors: Marije I
authors: MI
authors: Koenders
authors: Wim B
authors: WB
authors: Van den Berg
authors: Heinrich
authors: H
authors: Hofmann
authors: Jean-Paul
authors: JP
authors: Vallée
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D003287:Contrast Media; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D004487:Edema / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005295:Ferrocyanides / Q000737:chemistry; D019786:Gadolinium DTPA; D007150:Immunohistochemistry; D007719:Knee Joint / Q000737:chemistry / Q000000981:diagnostic imaging / Q000187:drug effects; D008264:Macrophages / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000187:drug effects*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D011859:Radiography; D011917:Rats, Inbred Lew; D015203:Reproducibility of Results; D013194:Staining and Labeling / Q000379:methods; D013583:Synovial Membrane / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D000097382:CD68 Molecule
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003287:Contrast Media; D003907:Dexamethasone; D005295:Ferrocyanides; D019786:Gadolinium DTPA; D058185:Magnetite Nanoparticles; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000170:ferric ferrocyanide