Therapeutic effect of the potent IL-12/IL-23 inhibitor STA-5326 on experimental autoimmune uveoretinitis.

Abstract

INTRODUCTION:

The purpose of this study was to determine if oral administration of the interleukin (IL) 12/IL-23 inhibitor, STA-5326, is effective in experimental autoimmune uveoretinitis (EAU).

METHODS:

C57BL/6J mice were immunised with human interphotoreceptor retinoid binding protein peptide (IRBP 1-20). STA-5326 at a dose of either 5 mg/kg or 20 mg/kg, or vehicle alone, was orally administered once a day for six days a week from day 0 to day 14. Fundus examination was performed on day 14 and day 18 after immunisation. Mice were euthanased on day 18 and the eyes were enucleated for histopathological examination. In vivo-primed draining lymph node cells were stimulated with IRBP 1-20 and culture supernatant was harvested for assay of interferon (IFN)-gamma and IL-17 by ELISA. Intracellular expression of IFN-gamma and IL-17 in CD4+ T cells of cultured draining lymph node cells was assessed by flow cytometry. The level of IL-12 p40 in serum was examined in STA-5326-treated or vehicle-treated mice receiving immunisation.

RESULTS:

The level of IL-12 p40 in serum was decreased in mice treated with STA-5326. Oral administration of either 5 mg/kg or 20 mg/kg STA-5326 reduced the severity of EAU on day 14 and 18. In addition, mice treated with 20 mg/kg STA-5326 showed significantly decreased severity of EAU by histopathological analysis. Although IFN-gamma production of draining lymph node cells was increased in STA-5326-treated mice by ELISA analysis, the proportion of IFN-gamma-producing cells was not significantly altered. However, IL-17 production and the proportion of IL-17-producing cells were significantly reduced in STA-5326-treated mice. Furthermore, oral administration of STA-5326 during the effector phase reduced the severity of EAU.

CONCLUSIONS:

These results indicate that oral administration of the IL-12/IL-23 inhibitor STA-5326 is effective in suppressing inflammation in the EAU model, and reduces the expansion of IL-17-producing cells. STA-5326 may represent a new therapeutic modality for human refractory uveitis.

• Authors: Hiroshi Keino, Takayo Watanabe, Yasuhiko Sato, Mamoru Niikura, Yumiko Wada, Annabelle A Okada
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 10 Issue 5 Pg. R122 ( 2008) ISSN: 1478-6362 [Electronic] England
• PMID: 18847496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Eye Proteins
• Hydrazones
• Interleukin-12 Subunit p40
• Interleukin-17
• Interleukin-23
• Morpholines
• Pyrimidines
• Retinol-Binding Proteins
• Triazines
• interstitial retinol-binding protein
• Interferon-gamma
• apilimod

Topics

• Animals
• Autoimmune Diseases (drug therapy, immunology, pathology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Eye Proteins (immunology)
• Female
• Flow Cytometry
• Humans
• Hydrazones
• Interferon-gamma (biosynthesis)
• Interleukin-12 Subunit p40 (antagonists & inhibitors, blood, drug effects)
• Interleukin-17 (biosynthesis, immunology, metabolism)
• Interleukin-23 (antagonists & inhibitors, drug effects)
• Mice
• Mice, Inbred C57BL
• Morpholines (therapeutic use)
• Pyrimidines
• Retinol-Binding Proteins (immunology)
• Triazines (therapeutic use)
• Uveitis (drug therapy, immunology, pathology)