title: Whole orbital tissue culture identifies imatinib mesylate and adalimumab as potential therapeutics for Graves' ophthalmopathy.
abstract: OBJECTIVE
  Biologicals and small inhibitory molecules are used to treat inflammatory diseases, but their efficacy varies upon clinical application. Using a whole orbital tissue culture system, we tested the potential efficacy of imatinib mesylate (a tyrosine kinase inhibitor that blocks platelet-derived growth factor (PDGF)-receptor, c-Abl and c-Kit activity) and adalimumab (an anti-TNF-α antibody) for the treatment of Graves' ophthalmopathy (GO).
  
  
  METHODS
  Orbital fat tissue from GO patients (n=10) was cultured with or without imatinib mesylate or adalimumab. PDGF-B and tumour necrosis factor (TNF)-α mRNA expression levels were determined in the primary orbital tissue, and interleukin (IL)-6 and hyaluronan were measured in tissue-culture supernatants.
  
  
  RESULTS
  Imatinib mesylate significantly (p=0.005) reduced IL-6 and hyaluronan production. The inhibition of hyaluronan production correlated positively and significantly (p<0.05) with the PDGF-B mRNA level in the primary tissue. Adalimumab also significantly (p=0.005) reduced IL-6 production. The amount of IL-6 inhibition correlated positively with the TNF-α mRNA level in the primary tissue, but this was not significant.
  
  
  CONCLUSIONS
  Imatinib mesylate can be expected to reduce inflammation and tissue remodelling in GO, while adalimumab can be mainly expected to reduce inflammation. This in vitro tissue-culture model may, in future, prove valuable to test novel therapeutics for their presumed effect in GO as well as in other inflammatory diseases.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Leendert
authors.initials: L
authors.lastname: van Steensel
authors.forename: P Martin
authors.initials: PM
authors.lastname: van Hagen
authors.forename: Dion
authors.initials: D
authors.lastname: Paridaens
authors.forename: Robert W A M
authors.initials: RW
authors.lastname: Kuijpers
authors.forename: Willem A
authors.initials: WA
authors.lastname: van den Bosch
authors.forename: Hemmo A
authors.initials: HA
authors.lastname: Drexhage
authors.forename: Herbert
authors.initials: H
authors.lastname: Hooijkaas
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D049970:Graves Ophthalmopathy / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D000068877:Imatinib Mesylate; D015850:Interleukin-6 / Q000096:biosynthesis*; D008297:Male; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis; D046509:Tissue Culture Techniques / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D015850:Interleukin-6; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000068877:Imatinib Mesylate; D006820:Hyaluronic Acid; D000068879:Adalimumab