Oral administration of retinoic acid receptor-alpha/beta-specific ligand Am80 suppresses experimental autoimmune uveoretinitis.

Abstract

PURPOSE:

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: Hiroshi Keino, Takayo Watanabe, Yasuhiko Sato, Annabelle A Okada
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 52 Issue 3 Pg. 1548-56 (Mar 01 2011) ISSN: 1552-5783 [Electronic] United States
• PMID: 20861477 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Eye Proteins
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-17
• Ligands
• RARA protein, human
• Rara protein, mouse
• Receptors, Interleukin-6
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• Retinol-Binding Proteins
• Tetrahydronaphthalenes
• interstitial retinol-binding protein
• retinoic acid receptor beta
• tamibarotene

Topics

• Administration, Oral
• Animals
• Autoimmune Diseases (drug therapy, genetics, immunology)
• Benzoates (administration & dosage)
• CD4-Positive T-Lymphocytes (immunology)
• Disease Models, Animal
• Eye Proteins
• Female
• Flow Cytometry
• Forkhead Transcription Factors (metabolism)
• Gene Expression
• Interleukin-17 (metabolism)
• Ligands
• Lymph Nodes (metabolism)
• Lymphocyte Activation
• Mice
• Mice, Inbred C57BL
• Nucleic Acid Hybridization
• Oligonucleotide Array Sequence Analysis
• Receptors, Interleukin-6 (metabolism)
• Receptors, Retinoic Acid (agonists)
• Retinitis (drug therapy, immunology)
• Retinoic Acid Receptor alpha
• Retinol-Binding Proteins
• Tetrahydronaphthalenes (administration & dosage)
• Uveitis (drug therapy, genetics, immunology)