Takayo Watanabe

Enhanced depth imaging optical coherence tomography of the choroid in Vogt-Koyanagi-Harada disease.

Purpose: Optical coherence tomography (OCT) using enhanced depth imaging (EDI) allows evaluation of choroidal thickness. Our objective was to analyze subfoveal choroidal thickness by EDI-OCT before and after the initiation of high-dose corticosteroid treatment in 8 patients (16 eyes) with new-onset acute Vogt–Koyanagi–Harada (VKH) disease. Methods: Retrospective review of clinical records. Results: The outer border of the choroid was not evident by EDI-OCT in any patients at presentation. Subfoveal choroidal thickness was measurable by 1 week after the initiation of treatment (mean, 578 &mgr;m) and decreased thereafter (mean at 1 month, 397 &mgr;m; 3 months, 392 &mgr;m; 6 months, 384 &mgr;m; 12 months, 332 &mgr;m). Rebound of choroidal thickening was observed in three patients (five eyes) during corticosteroid tapering in the absence of other evidence of increased inflammation. Peripapillary atrophy was present at 12 months in 6 of 6 eyes that had a choroidal thickness >550 &mgr;m at 1 week after initiating treatment, in contrast to none of the 8 eyes with a choroidal thickness ⩽550 &mgr;m (P = 0.0003). Conclusion: Enhanced depth imaging–optical coherence tomography revealed decreasing choroidal thickness with high-dose corticosteroid treatment in our patients. Choroidal thickness as measured by EDI-OCT may serve as a marker for degree of choroidal inflammation in acute VKH disease.

Decreased ocular inflammatory attacks and background retinal and disc vascular leakage in patients with Behçet's disease on infliximab therapy

Aim To evaluate the efficacy of infliximab treatment in patients with refractory uveoretinitis associated with Behçets disease. Methods Clinical records of 14 patients were retrospectively reviewed. Patients received infliximab infusions (5 mg/kg) at weeks 0, 2 and 6, and every 8 weeks thereafter. The main outcome measures were frequency of clinically observable ocular inflammatory attacks, background retinal and disc vascular leakage as assessed by fluorescein angiography during periods of clinical quiescence, visual acuity and adverse effects. Results The median follow-up after initiating infliximab therapy was 19 months (range 12–29 months). At 12 months, eight of 14 patients (57%) had experienced no inflammatory attacks, and the frequency of attacks was significantly reduced when compared with the 6-month period just prior to infliximab use. Background retinal and disc vascular leakage assessed at 12 months improved in 11 of 14 patients (79%). Visual acuity improved or remained unchanged at 12 months in 26 of 28 eyes (93%). Infliximab therapy was terminated in two patients owing to infusion reactions. However, no serious adverse effects were observed. Conclusion Infliximab over the first year of treatment appeared effective in reducing ocular inflammatory attacks, as well as background retinal and disc vascular leakage, in patients with refractory uveoretinitis associated with Behçets disease.

Frequency and clinical features of intraocular inflammation in Tokyo

Background:  To investigate frequencies and clinical features of intraocular inflammation (uveitis) in Tokyo, Japan.

DHMEQ, a new NF-κB inhibitor, induces apoptosis and enhances fludarabine effects on chronic lymphocytic leukemia cells

Chronic lymphocytic leukemia (CLL) is a low-grade lymphoid malignancy incurable with conventional modalities of chemotherapy. Strong and constitutive nuclear factor kappa B (NF-κB) activation is a characteristic of CLL cells. We examined the effects of a new NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on CLL cells. Dehydroxymethylepoxyquinomicin completely abrogated constitutive NF-κB activity and induced apoptosis of CLL cells. Apoptosis induced by DHMEQ was accompanied by downregulation of NF-κB-dependent antiapoptotic genes: c-IAP, Bfl-1, Bcl-XL and c-FLIP. Dehydroxymethylepoxyquinomicin also inhibited NF-κB induced by CD40 and enhanced fludarabine-mediated apoptosis of CLL cells. Results of this study suggest that inhibition of constitutive and inducible NF-κB by DHMEQ in combination with fludarabine is a promising strategy for the treatment of CLL.

Anti-inflammatory effect of retinoic acid on experimental autoimmune uveoretinitis

Aims To determine whether an active metabolite of vitamin A, all-trans retinoic acid (ATRA), 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 ATRA. Intracellular expression of transcription factor forkhead box P3 (Foxp3) and interleukin (IL)-17 in the activated CD4+ T cells was assessed by flow cytometry. C57BL/6 mice were immunised with human interphotoreceptor retinoid binding protein peptide 1–20 (IRBP1–20). ATRA was administered intraperitoneally every other day (0.2 mg/mouse per day) from day 0 to day 21. In vivo-primed draining lymph node cells from vehicle-treated or ATRA-treated mice were stimulated with IRBP1–20 and the culture supernatant fraction was harvested for assay of interferon (IFN)-γ and IL-17 by ELISA. Results ATRA synergised 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. ATRA treatment reduced the severity of EAU clinically, and IFN-γ and IL-17 production were significantly reduced in ATRA-treated mice. Conclusion These findings demonstrate that ATRA treatment ameliorates severity of EAU and reduces the Th1/Th17 responses. ATRA may represent a new therapeutic modality for human refractory uveitis.

Effect of infliximab on gene expression profiling in Behcet's disease.

PURPOSE Recent studies have demonstrated that a new anti-tumor necrosis factor (TNF)-α antibody, infliximab, is effective in controlling ocular inflammatory attacks in Behçets disease. In this study, the effect of infliximab on gene expression patterns in peripheral blood mononuclear cells of Behçets disease patients was investigated before and after initiation of infliximab treatment. METHODS A human whole-genome microarray of 54,359 genes was used to analyze mRNA expression profiles of peripheral blood mononuclear cells obtained from four patients (three women, one man, 21-64 years at age) at baseline and at 22 weeks after initiation of infliximab. Quantitative polymerase chain reaction (PCR) analysis was performed for selected up- or downregulated genes, to confirm the microarray results. RESULTS Anti-TNF-α therapy reduced the frequency of ocular episodes in three of four patients. Among inflammatory cytokine-related genes, TNF blockade reduced expression of interleukin (IL)-1 receptor type 2, interferon-γ receptors, IL6, IL6 receptor, gp130, and IL17 receptors. Furthermore, gene expression of Toll-like receptor 2 (TLR2), receptor for mycobacterial glycolipid (C-type lectin domain family 4, member E: CLEC4E), and complexin 2 (CPLX2) was downregulated in all patients. CONCLUSIONS Several up- or downregulated genes identified in this study may be candidates for further investigation in identifying the molecular mechanism of infliximab in the treatment of Behçets disease with refractory uveoretinitis.

High Mobility Group Box Protein-1 in Experimental Autoimmune Uveoretinitis

PURPOSE To investigate whether high mobility group box protein (HMGB)-1, acting as a novel proinflammatory cytokine, is involved in experimental autoimmune uveoretinitis (EAU). METHODS HMGB-1 concentration was measured in aqueous humor, and serum was obtained from Lewis rats immunized with interphotoreceptor retinoid binding protein (IRBP) peptide (R14) and complete Freund adjuvant (CFA), rats immunized with CFA, and nontreated rats on day 14 after immunization. Immunofluorescence histochemistry was performed to examine the localization of HMGB-1 and the receptor for advanced glycation end products (RAGEs) in eyes obtained from nontreated rats or EAU-induced rats. Coexpression of CD68 (marker for macrophages) was investigated by double-immunofluorescence labeling. RESULTS The level of HMGB-1 in aqueous humor was significantly elevated in eyes with EAU, and HMGB-1 and tumor necrosis factor (TNF)-alpha levels correlated with active ocular inflammation. HMGB-1 was expressed in the iris, ciliary body, and retina of eyes from nontreated rats and EAU-induced rats. Furthermore, HMGB-1 and RAGE were found in inflammatory cells infiltrating the anterior chamber, vitreous cavity, and subretinal space in EAU-induced rats. Some HMGB-1- or RAGE-positive cells in eyes with EAU were CD68(+). Cultured macrophages expressing RAGE released TNF-alpha on stimulation with native HMGB-1. CONCLUSIONS HMGB-1 was elevated in the aqueous humor of eyes with EAU. Inflammatory cells infiltrating ocular tissue expressed HMGB-1 and RAGE. HMGB-1 has the capacity to stimulate TNF-alpha production in bone marrow-derived macrophages. These results support the possibility that extracellularly released HMGB-1 acts as a novel proinflammatory cytokine to promote and amplify ocular inflammation in autoimmune uveoretinitis.

Clinical features and visual outcomes of Japanese patients with scleritis

Purpose To analyse clinical features, systemic associations, treatment and visual outcomes in Japanese patients with scleritis. Methods Clinical records of 83 patients with scleritis who presented between 1998 and 2008 to the Ocular Inflammation Service of the Kyorin Eye Center, Tokyo, were reviewed. Results Of the 83 patients, 57 (69%) had diffuse anterior scleritis, 9 (11%) had nodular anterior scleritis, 8 (10%) had necrotising anterior scleritis and 9 (11%) had posterior scleritis. There was a slight predominance of women (55%) and unilateral disease (53%). Mean age at presentation was 51 years (range 12–82 years). Secondary ocular complications were observed in 78% of patients, including anterior uveitis in 25% and increased intraocular pressure in 40%. Investigation revealed a systemic disease association in 24 patients (29%), including six patients (7.2%) with tuberculosis and 18 patients (22%) with rheumatologic disease. Thirty-five patients (42%) received systemic corticosteroid treatment and 19 patients (23%) received immunosuppressive agents. All 17 patients with necrotising anterior scleritis or posterior scleritis were treated with oral corticosteroids and/or immunosuppressive drugs. Visual outcomes were generally good; however, poorer outcomes were observed in eyes with necrotising scleritis, mostly due to corneal ulceration or corneal opacification. Conclusions A systemic disease association was identified in 29% of Japanese patients with scleritis. Roughly one-half of patients received oral corticosteroids and/or immunosuppressive drugs to control inflammation, with generally good visual outcomes.

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

IntroductionThe 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).MethodsC57BL/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.ResultsThe 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.ConclusionsThese 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.

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

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.