Therapeutic effect of the potent IL-12/IL-23 inhibitor STA-5326 on experimental autoimmune uveoretinitis.
BACKGROUND
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.
Department of Ophthalmology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611 Japan. keino@eye-center.org
Hiroshi
H
Keino
Takayo
T
Watanabe
Yasuhiko
Y
Sato
Mamoru
M
Niikura
Yumiko
Y
Wada
Annabelle A
AA
Okada
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006835:Hydrazones; D007371:Interferon-gamma / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors / Q000097:blood / Q000187:drug effects*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000627:therapeutic use*; D011743:Pyrimidines; D012177:Retinol-Binding Proteins / Q000276:immunology; D014227:Triazines / Q000627:therapeutic use*; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000099214:Retinol-Binding Proteins, Interstitial
D005136:Eye Proteins; D006835:Hydrazones; D007371:Interferon-gamma; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D009025:Morpholines; D011743:Pyrimidines; D012177:Retinol-Binding Proteins; D014227:Triazines; D000099214:Retinol-Binding Proteins, Interstitial; C504227:apilimod