Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis.

Abstract

Recent evidence suggests that interleukin-17-producing CD4(+) T cells (Th17 cells) are the dominant pathogenic cellular component in autoimmune inflammatory diseases, including multiple sclerosis. It has recently been demonstrated that all-trans retinoic acid can suppress Th17 differentiation and promote the generation of Foxp3(+) regulatory T cells via retinoic acid receptor signals. Here, we investigated the effects of AM80, a synthetic retinoid with enhanced biological properties to all-trans retinoic acid, on Th17 differentiation and function and evaluated its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. AM80 treatment was more effective than all-trans retinoic acid in inhibiting Th17 differentiation in vitro. Oral administration of AM80 was protective for the early development of EAE and the down-modulation of Th17 differentiation and effector functions in vivo. Moreover, AM80 inhibited interleukin-17 production by splenic memory T cells, in vitro-differentiated Th17 cells, and central nervous system-infiltrating effector T cells. Accordingly, AM80 was effective when administered therapeutically after the onset of EAE. Continuous AM80 treatment, however, was ineffective at inhibiting late EAE symptoms despite the maintained suppression of RORgammat and interleukin-17 expression levels by central nervous system-infiltrating T cells. We reveal that continuous AM80 treatment also led to the suppression of interleukin-10 production by a distinct T cell subset that expressed both Foxp3 and RORgammat. These findings suggest that retinoid signaling regulates both inflammatory Th17 cells and Th17-like regulatory cells.

• Authors: Christian Klemann, Benjamin J E Raveney, Anna K Klemann, Tomoko Ozawa, Stephan von Hörsten, Koichi Shudo, Shinji Oki, Takashi Yamamura
• Journal: The American journal of pathology (Am J Pathol) Vol. 174 Issue 6 Pg. 2234-45 (Jun 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19389933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Cytokines
• Interleukin-17
• Neuroprotective Agents
• Retinoids
• Tetrahydronaphthalenes
• tamibarotene
• Tretinoin

Topics

• Animals
• Benzoates (pharmacology)
• Cell Differentiation (drug effects)
• Cytokines (biosynthesis, drug effects)
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology, pathology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Interleukin-17 (immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (pharmacology)
• Retinoids (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocyte Subsets (cytology, drug effects)
• T-Lymphocytes, Regulatory (cytology, drug effects, immunology)
• Tetrahydronaphthalenes (pharmacology)
• Tretinoin (pharmacology)