Therapeutic effect of the potent IL-12/IL-23 inhibitor STA-5326 on experimental autoimmune uveoretinitis
© Keino et al.; licensee BioMed Central Ltd. 2008
Received: 08 August 2008
Accepted: 13 October 2008
Published: 13 October 2008
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).
C57BL/6J mice were immunised with human interphotoreceptor retinoid binding protein peptide (IRBP1–20). 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 IRBP1–20 and culture supernatant was harvested for assay of interferon (IFN)-γ and IL-17 by ELISA. Intracellular expression of IFN-γ 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.
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-γ production of draining lymph node cells was increased in STA-5326-treated mice by ELISA analysis, the proportion of IFN-γ-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.
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.
Interleukin (IL) 23 is a heterodimeric cytokine, sharing a p40 subunit with the Th1 cytokine IL-12, but differing from IL-12 in its unique p19 subunit [1, 2]. IL-23 is required for the generation of effector memory T cells and IL-17-producing T cells (Th17), which in turn play critical roles in inflammatory responses [3, 4]. Thus, IL-12/IL-23 has become an attractive clinical target in a number of studies. Investigation into regulation of the p40 and IL-23 specific p19 subunits has demonstrated a critical role of IL-12/IL-23 in the pathogenesis of autoimmune disease [5–9]. Recent studies have demonstrated that monoclonal antibodies to the IL-12/IL-23 p40 subunit are effective in human clinical trials for Crohn's disease and psoriasis [10–12].
Experimental autoimmune uveoretinitis (EAU) is an animal model that shares many clinical and histological features with human uveitic disorders such as Behcet's disease [13–15]. Therefore, much information is gained by using the model to analyse the immunopharmacology of various immunosuppressive agents in uveitis. EAU is induced by immunization with a retinal antigen (S-antigen or interphotoreceptor-retinoid binding protein (IRBP)) or by adoptive transfer of retinal antigen-specific CD4+ T cells [16–18]. Recent studies have demonstrated that a Th1/Th17 response to the retinal antigen is dominant in EAU in mice [19–24]. Although previous reports have stated that IL-12 is required for the induction of EAU [25, 26], new research has clearly indicated that it is IL-23, rather than IL-12, that is necessary for EAU induction .
The nuclear factor (NF) κB is a popular target for effective blockade of activation of the promoter for genes encoding proinflammatory cytokines in cells involved in innate and adaptive immunity. The NF-κB family includes the p65, RelB, c-Rel, p50 and p52 proteins. Although p50/p65 is the most common form of NF-κB to activate the promoters of many genes, including those for tumour necrosis factor (TNF)-α and IL-6, the c-Rel-containing form is essential for activation of the p40 gene in macrophages . Furthermore, a recent study of the p19 gene promoter showed that c-Rel binds to the κB sites on this promoter and controls p19 gene expression in dendritic cells . Thus, c-Rel is a specific transcriptional regulator of both IL-12 and IL-23.
STA-5326 is a small molecule developed from a novel triazine derivative identified by high-throughout IL-12 inhibitor screening . STA-5326 inhibits the expression of genes encoding the p40 subunit present in both IL-12 and IL-23 by selective inhibition of c-Rel translocation . The protein c-Rel, a member of the Rel/NF-κB family of transcription factors, requires transport from the cytoplasm to the nucleus for activity. STA-5326 blocks the nuclear localization of c-Rel without inhibiting the nuclear import of other Rel/NF-κB family members. Oral administration of STA-5326 led to suppression of inflammation by histopathological analysis in a model of inflammatory bowel disease (IBD) . In the current study, we examined if oral administration of the potent IL-12/IL-23 inhibitor, STA-5326, would be effective in EAU.
Materials and methods
Six- to eight-week-old female C57BL/6J mice were purchased from Japan CLEA (Shizuoka, Japan). All mice were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and institutional guidelines regarding animal experimentation.
Induction and scoring of EAU
Mice were immunized subcutaneously in the neck region with 200 μg of IRBP1–20 emulsified in 0.2 ml of complete Freund's adjuvant (CFA) (Difco, Detroit, MI) containing 1 mg of the Mycobacterium tuberculosis strain H37Ra (Difco, Detroit, MI). They were also given 100 ng of pertussis toxin (Sigma, St. Louis, MO) intraperitoneally as additional adjuvant . Funduscopic examination was performed on days 14, 15 and 18 after immunization, and clinical findings were graded from 0 to 4 as previously described . Eyes were enucleated on day 18 and inflammation was assessed histopathologically by scoring on a scale of 0 to 4 in half-point increments, according to a semi-quantitative system .
Oral administration of STA-5326
In most experiments, 5 mg/kg or 20 mg/kg STA-5326 (Synta Pharmaceuticals Corporation, Lexington, MA) or vehicle only (0.5% carboxyl methyl cellulose) was orally administered once a day for six days a week from day 0 to day 14 after immunization. In the effector phase experiments, 20 mg/kg STA-5326 or vehicle was orally administered once a day, from day 9 to day 14 after immunization.
In vitroproliferation and cytokine assay
Cervical lymph node cells obtained from immunized mice on day 18 (2 × 105cells/well) were cultured in 0.2 ml RPMI 1640 (Sigma Aldrich, St. Louis, MO) containing 10 mM HEPES (Invitrogen Life Technologies, Carlsbad, CA), 0.1 mM nonessential amino acid (Invitrogen Life Technologies, Carlsbad, CA), 1 mM sodium pyruvate (Invitrogen Life Technologies, Carlsbad, CA), 100 U/ml penicillin (Invitrogen Life Technologies, Carlsbad, CA), 100 μg/ml streptomycin (Invitrogen Life Technologies, Carlsbad, CA), 1 × 10-5 M 2-mercaptoethanol (2-ME; Sigma Aldrich, St. Louis, MO), 10% FCS, and 10 μg/ml IRBP1–20. For cytokine assay, supernatants were collected after 72 hours and analysed for IFN-γ, IL-4 and IL-17 by quantitative capture ELISA using quantikine ELISA kits (R&D Systems, Minneapolis, MN) and mouse IL-17 ELISA Ready-SET-Go kits (eBioscience, San Diego, CA). Cell proliferation was evaluated using a cell proliferation assay (bromodeoxyuridine; Roche Diagnostics, Mannheim, Germany).
Intracellular cytokine flow cytometry
Cervical lymph node cells obtained from immunized mice were seeded at 1.5 × 106 cells/well in 24-well plates and stimulated with 10 μg/ml IRBP1–20 for 72 hours. The stimulated cervical lymph node cells were harvested and cultured in vitro with 5 ng/ml PMA, 500 ng/ml ionomycin and cytokine secretion blocker Gogi-stop (Brefeldin A; BD Bioscience, San Jose, CA) for four hours, then stained using fluorescein isothiocyanate-conjugated monoclonal antibodies against mouse CD4 or CD8 (BD Bioscience, San Jose, CA). The cells were washed, fixed, permeabilised with Cytofix/Cytoperm (BD Bioscience, San Jose, CA), intracellularly stained with phycoerythrin-conjugated antibodies against IFN-γ and IL-17 (BD Bioscience, San Jose, CA) and analyzed on a flow cytometer (FACSCalibur; BD Bioscience, San Jose, CA) using acquisition and analysis software (CellQuest; Becton Dickinson, Franklin Lakes, NJ).
IL-12 production in the serum of STA-5326-treated or vehicle-treated mice after immunization
Mice were immunized as described above, and 5 mg/kg or 20 mg/kg STA-5326 or vehicle alone was orally administered once a day from day 0 to day 14 after immunization. STA-5326-treated or vehicle-treated mice were euthanased on day 18 after immunization, and serum from individual mice were collected for IL-12 p40 measurement using quantikine ELISA kits (R&D systems, Minneapolis, MN).
Results of experiments were analyzed using Mann-Whitney U test and Student's t-test. Data are expressed as the mean ± standard deviation (SD). Means were considered to be significantly different for p < 0.05. All experiments were repeated at least twice, with similar results confirmed.
STA-5326 does not alter body weight in EAU mice
The level of IL-12 p40 in serum is decreased in STA-5326-treated mice
STA-5326 has been reported to inhibit the expression of genes encoding the p40 subunit present in both IL-12 and IL-23 . To determine if oral administration of STA-5326 changes the level of IL-12p40 in vivo, we examined the level of IL-12 p40 in serum. STA-5326 at a dose of 5 mg/kg or 20 mg/kg or vehicle only was orally administered from day 0 to day 14 after immunization. Serum from individual mice was collected on day 18 after immunization, and IL-12 p40 was assayed by ELISA. The level of IL-12 p40 was reduced in STA-5326-treated mice, particularly in the high-dose group, compared with vehicle-treated mice (Figure 1b). These data indicate that oral administration of STA-5326 is capable of reducing the level of IL-12 p40 in vivo.
Oral administration of STA-5326 reduces the severity of EAU by clinical and pathological analysis
IL-17 production and the proportion of IL-17-producing cells of draining lymph nodes are significantly reduced in STA-5326-treated mice
Oral administration of STA-5326 during the effector phase reduces the severity of EAU by clinical analysis
In the present study, we showed that oral administration of the potent IL-12/IL-23 inhibitor, STA-5326, reduces the severity of EAU by clinical and histopathological analysis. In STA-5326-treated mice, the serum level of IL-12 p40 was decreased. Although antigen specific IFN-γ production was not inhibited in draining lymph node cells from STA-5326-treated mice, IL-17 production and the proportion of IL-17-producing cells were significantly reduced. Furthermore, oral administration of STA-5326 significantly ameliorated the severity of EAU even after effector cells were presumably generated.
Production of the Th1 cytokine, IFN-γ, was not reduced in STA-5326-treated mice. This was not expected, because reduced IFN-γ production had been observed in an animal model of IBD treated with STA-5326 . It is possible that decreased IL-17 production may be affecting IFN-γ production during the late phase of EAU. Luger and colleagues showed that an enhanced Th1 response was observed in lymph node cells of IL-17 knockout mice, suggesting that IL-17 may have an antagonistic effect on the development of Th1 effectors . Yoshimura and colleagues also demonstrated that anti-IFN-γ and anti-IL-4 antibody treatment augmented Th17 differentiation in vivo . Therefore, IL-17 and IFN-γ may be acting in a reciprocal fashion during the late phase of EAU, resulting in an absence of down-regulation of IFN-γ due to reduced IL-17 production in STA-5326-treated mice.
Oral administration of STA-5326 during the effector phase only resulted in decreased EAU inflammation on clinical analysis. It has recently been shown that systemic neutralization of IL-23 does not reverse EAU during the effector phase in B10.RIII mice . IL-23 is required for expansion and maintenance of Th17 effectors . In addition, Tarrant and colleagues clearly demonstrated that endogenous IL-12 plays a role in pathogenesis during the expression phase of EAU, after uveitogenic effector cells have been primed . Down-regulation of the IL-12/Th1 pathway and the IL-23/Th17 pathway may be necessary for significant amelioration of EAU during the effector phase and the induction phase, respectively. This would explain why STA-5326, by blocking both IL-12 and IL-23, is efficacious in both phases.
Although the present study examined clinical and histopathological changes only on day 14 and day 18 when STA-5326 was administered during the entire course of EAU, the possibility exists that STA-5326 may be merely delaying the onset of EAU rather than decreasing the overall severity of inflammation. However, STA-5326 also decreased inflammation when administered only during the effector phase of EAU, after the presumed production of uveitogenic effector cells and migration of these cells to the eye. This suggests that STA-5326 may have a therapeutic effect on ocular inflammation in the clinical setting.
Our data are in agreement with previous reports showing that IL-12 p40 knockout and IL-23 p19 knockout mice are highly resistant to EAU and anti-IL-12 antibody treatment prevents EAU induction [24–26]. The present study showed that serum levels of IL-12 p40 were reduced in STA-5326-treated mice in a dose-dependent manner. IL-12 and IFN-γ are known to be important cytokines for host defense and immune surveillance. Recently, the IL-23/IL-17 pathway has been shown to be necessary for host defence against Klebsiella pneumoniae [32, 33]. p40 is a subunit of both IL-12 and IL-23, and decreased levels of IL-12 p40 may affect a broad range of immune responses. The present study showed that production of IFN-γ from draining lymph node cells was not decreased in mice treated with STA-5326 through the entire course of EAU. Therefore, the safety of STA-5326 administration would need to be assessed further in terms of effect on host defence mechanisms.
It has been demonstrated that STA-5326 inhibits the expression of genes encoding the p40 subunit present in both IL-12 and IL-23 by way of selective inhibition of c-Rel translocation . However, in the present study, it is not clear where SAT-5326 is having this effect. STA-5326 has been reported to inhibit IL-12 production by human monocytes, monocyte-derived dendritic cells, and the human monocyte cell line THP-1 . Serum levels of IL-12/IL-23 p40 were significantly decreased in STA-5326-treated mice in the current study, so STA-5326 may be blocking activation of the promoter for IL-12/IL-23 p40 in macrophages and dendritic cells in lymph nodes, spleen and blood. It is also likely that STA-5326 blocks c-Rel translocation in ocular tissues and infiltrating inflammatory cells, including ocular antigen presenting cells, resulting in inhibition of gene expression of IL-12/IL-23 in the uveitic lesion.
It has been reported that STA-5326 does not affect the production of inflammatory cytokines, including IL-1β, IL-2, IL-4, IL-6, IL-8 and IL-18, in an IFN-γ stimulated human monocytic cell line and in mouse spleen cells . Although the NF-κB family p50/p65 is the most common form of NF-κB to activate the promoters of many genes, including those for TNF-α and IL-6, the c-Rel-containing form is essential for activation of the p40 gene in macrophages . Furthermore, it has recently been shown that c-Rel binds to the κB sites on this promoter and controls p19 gene expression in dendritic cells . Thus, c-Rel appears to be a specific transcriptional regulator for both IL-12 and IL-23. The present study also showed that serum levels of IL-12 p40 were decreased in STA-5326-treated mice. Taken together, we believe that STA-5326 represents a potent IL-12/IL-23 inhibitor.
Compared with anti-cytokine antibodies that act by neutralization of IL-12 and IL-23 proteins that have already been produced, STA-5326 acts by selectively shutting off transcription of the p35, p40 and p19 genes  and has the added advantage of being a small-molecule that can be administered orally. Therefore, we believe that STA-5326 has great potential as a therapeutic agent. Accordingly, a biomarker study in which patients with stable psoriasis vulgaris skin plaques received oral STA-5326, showed that expression of IL-23 p19 and IL-12/IL-23 p40 was reduced , and STA-5326 is currently undergoing evaluation in a phase 2a study in rheumatoid arthritis, a disease characterized by elevated IL-12 levels.
Oral administration of STA-5326 was effective in suppressing inflammation in the EAU model, and reduced the serum level of IL-12/IL-23 p40 and the expansion of IL-17-producing cells. STA-5326 represents a new promising therapeutic modality for refractory uveitis in humans.
complete Freund's adjuvant
experimental autoimmune uveoretinitis
enzyme linked immunosorbent assay
Roswell Park Memorial Institute
Phorbol 12-Myristate 13 Acetate
fetal calf serum
inflammatory bowel disease
interphotoreceptor retinoid binding protein
tumour necrosis factor.
This work was supported by Grant-in-Aid 17791258 for Scientific Research from the Japan Society for the Promotion of Science. We thank Nobuko Takahashi for her technical assistance.
STA-5326 was provided by Synta Pharmaceuticals Corporation. (Lexington, MA).
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