title: Oral administration of retinoic acid receptor-alpha/beta-specific ligand Am80 suppresses experimental autoimmune uveoretinitis.
abstract: OBJECTIVE
  To determine whether synthetic retinoic acid receptor (RAR)-α/β-specific agonist Am80 reduces inflammation in experimental autoimmune uveoretinitis (EAU).
  
  
  METHODS
  Naive CD4(+) T cells were activated with anti-CD3, anti-CD28, and transforming growth factor (TGF)-β, in the presence or absence of Am80. Intracellular expression of forkhead box p3 (Foxp3) and interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. For induction of EAU, C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein (IRBP) peptide 1 to 20 (IRBP(1-20)). Am80 was administered orally every other day (3 mg/kg/time point) from day 0 to day 21. In vivo primed draining lymph node cells from vehicle-treated or Am80-treated mice were stimulated with IRBP(1-20), and culture supernatant was harvested for assay of interferon (IFN)-γ, IL-6, IL-10, and IL-17. The expression of Foxp3 and IL-6 receptor α in CD4(+) T cells of draining lymph node cells was assessed by a flow cytometer.
  
  
  RESULTS
  Am80 synergized with TGF-β to induce Foxp3(+) T regulatory cells (Treg) and reciprocally inhibited development of IL-17-producing T helper cells (Th17) induced by TGF-β and IL-6. Am80 treatment reduced the severity of EAU clinically, and IFN-γ and IL-17 production was significantly reduced in Am80-treated mice. In addition, the expression of IL-6 receptor α on CD4(+) T cells was downregulated in Am80-treated mice.
  
  
  CONCLUSIONS
  These findings demonstrate that Am80 treatment ameliorates severity of EAU and reduces the Th1/Th17 responses. The synthetic retinoid Am80 appears to be a promising agent for preventing autoimmune uveoretinal inflammation.
authors.affiliation: Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan. keino@eye-center.org
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Keino
authors.forename: Takayo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sato
authors.forename: Annabelle A
authors.initials: AA
authors.lastname: Okada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D001565:Benzoates / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005136:Eye Proteins; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D020381:Interleukin-17 / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D012173:Retinitis / Q000188:drug therapy* / Q000276:immunology; D000072482:Retinoic Acid Receptor alpha; D012177:Retinol-Binding Proteins; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*; D014605:Uveitis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D001565:Benzoates; D005136:Eye Proteins; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D008024:Ligands; D019947:Receptors, Interleukin-6; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012177:Retinol-Binding Proteins; D013764:Tetrahydronaphthalenes; D000099214:Retinol-Binding Proteins, Interstitial; C498833:Foxp3 protein, mouse; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C082925:retinoic acid receptor beta; C061133:tamibarotene