Hiroshi Keino

Sunset glow fundus in Vogt-Koyanagi-Harada disease with or without chronic ocular inflammation.

Abstract Background. Sunset glow fundus is considered an important ocular finding for diagnosing and understanding the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. In this study, we investigated the association between the incidence of chronic ocular inflammation in VKH disease and the appearance of sunset glow fundus. Methods. The study was a retrospective noncomparative interventional case series. Eighty patients with VKH disease treated with high-dose corticosteroid therapy from initial onset were included in the study. We compared the incidence of sunset glow fundus between patients with VKH disease with chronic ocular inflammation lasting more than 6 months and those without chronic ocular inflammation. Results. Chronic ocular inflammation was seen in 14 of 80 patients (17.5%). The presence of severe anterior uveitis were significantly more frequent in the chronic group. Forty-one patients (62%) without chronic ocular inflammation showed sunset glow fundus, while 13 patients (93%) with chronic ocular inflammation developed sunset glow fundus. Duration from disease onset to appearance of sunset glow fundus was significantly shorter in patients with than in patients without chronic inflammation. Conclusions. There is a significant association between the incidence of chronic ocular inflammation lasting more than 6 months and the appearance of sunset glow fundus. In addition, more severe disease at onset might be associated with chronic ocular inflammation in VKH disease.

Surgical Denervation of Ocular Sympathetic Afferents Decreases Local Transforming Growth Factor-β and Abolishes Immune Privilege

Mounting evidence points to a role for the sympathetic nervous system in suppressing inflammation. This role might be of specific relevance for immune privilege in the eye, where, sporadically, patients with denervated sympathetic fibers develop chronic inflammation. The present study used mice to investigate whether the robust innervation of intraocular structures by the sympathetic system plays a role in maintaining ocular immune privilege. We first performed surgical removal of the superior cervical ganglion, which supplies sympathetic fibers to the eye, and studied the immune response generated against soluble antigens or allogeneic tumor cells injected into the ocular anterior chamber under these conditions. Our results show that in the absence of functional sympathetic fibers, the eye loses its ability to prevent either the immune rejection of intraocular allogeneic tumor cells or the suppression of delayed type hypersensitivity responses against soluble antigens injected in the anterior chamber. This loss of immune privilege is accompanied by a decrease in the concentration of transforming growth factor-beta in the aqueous humor. These results suggest that immune privilege is lost in the absence of a functional sympathetic innervation of the eye, allowing intraocular immune responses to become exaggerated. We conclude that ocular sympathetic nerves are critical for the generation and maintenance of immune privilege in the eye through the facilitation of local transforming growth factor-beta production.

Creating an Immune-Privileged Site Using Retinal Progenitor Cells and Biodegradable Polymers

We describe the creation of local immune privilege (IP) using retinal progenitor cells (RPCs) and biodegradable polymers. Murine RPCs were seeded on poly(lactic‐coglycolic acid) polymers to generate composite grafts. Composites or RPCs alone were transplanted into allogeneic kidney capsules. Grafts survived at all time points, differentiating into neurons and astrocytes. Upon treatment with interferon γ (IFNγ), major histocompatibility complex antigens were upregulated. Although 10% of IFNγ‐treated RPC grafts survived 14 days, 66% of the IFNγ‐treated composites survived in part by producing immune suppressive factors transforming growth factor‐β2, Fas ligand, and indoleamine 2,3‐dioxygenase. The composites were assayed for delayed‐type hypersensitivity (DTH) by seeding composites with antigen‐presenting cells incubated with ovalbumin. This resulted in suppression of ovalbumin‐specific DTH, indicating that composite grafts consisting of biodegradable polymers and central nervous system progenitor cells can be used to generate local IP. This technology may be used to promote the survival of nonprivileged grafts (e.g., pancreas, liver, or skin).

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.

Peritoneal Exudate Cells Treated with Calcitonin Gene-Related Peptide Suppress Murine Experimental Autoimmune Uveoretinitis via IL-10

Immunization with retinal Ag induces experimental autoimmune uveoretinitis (EAU) in mice. We investigated the suppression of murine EAU by peritoneal exudate cells (PEC) cultured with calcitonin gene-related peptide (CGRP). PEC derived from mice were treated with CGRP and residues 1–20 of human interphotoreceptor retinoid-binding protein (hIRBP 1–20). The hIRBP 1–20-immunized mice were injected i.v. with PEC treated with CGRP and hIRBP 1–20. After immunization, Ag-specific delayed hypersensitivity (DH) was measured and EAU was assessed histopathologically. Both EAU- and Ag-specific DH were suppressed by injection of PEC treated with CGRP (100 ng/ml) and hIRBP 1–20. However, hIRBP 1–20-mediated EAU was not suppressed by injection of PEC treated with CGRP and BSA. Both EAU- and Ag-specific DH were not suppressed by injection of PEC treated with CGRP and hIRBP 1–20 into splenectomized mice. In mice adoptively transferred spleen cells from hIRBP 1–20-immunized mice, EAU was also suppressed by injection of CGRP-treated PEC. EAU was markedly inhibited in hIRBP 1–20-immunized mice adoptively transferred T cells obtained from mice injected with hIRBP 1–20-pulsed, CGRP-treated PEC. Furthermore, EAU- and Ag-specific DH were not suppressed by injection of PEC treated with CGRP and hIRBP 1–20 when the recipient mice were given anti-IL-10 Ab i.p., or when the PEC were derived from IL-10 knockout mice. The present results indicate that PEC treated with CGRP suppress murine EAU in an Ag-specific manner, even in the efferent phase, and IL-10 secreted from PEC might play an important role in the CGRP-mediated suppression of murine EAU.

Circulating neutrophils in Behçet disease is resistant for apoptotic cell death in the remission phase of uveitis

BackgroundBehçet disease (BD) is manifested by recurrent acute iridocyclitis with hypopyon in the active phase, which regresses spontaneously. Hypopyon consists of inflammatory cells infiltrating the eye, with polymorphonuclear cells (PMNs) as the main component. The present study was conducted to investigate the apoptosis property of PMNs in BD patients with uveitis.MethodsPMNs were purified from peripheral blood cells of BD patients with uveitis in the active or remission phase and were cultured for 12 hours. In some cultures, lipopolysaccharide (LPS), antagonistic anti-TNFα antibody, agonistic anti-Fas antibody, or Fas:Fc fusion protein was added. At the end of cultures, apoptotic cells were evaluated by Annexin V expression using flow cytometry.ResultsSpontaneous apoptosis of PMNs showed lower levels in the remission phase of BD-related uveitis compared with the active phase or healthy controls. The lower level of PMN apoptosis in the remission phase of uveitis in BD remained even by stimulation with LPS, anti-TNFα antibody, or Fas:Fc fusion protein, which was abolished in the presence of agonistic anti-Fas antibody.ConclusionsIn BD patients, the apoptosis of PMNs was reduced in the remission phase of uveitis and restored in the active phase, which arose from the apoptotic cell death in part via Fas-Fas ligand interaction.

Association between HLA-A2 in Japanese psoriasis arthritis and susceptibility to uveitis

Psoriasis is a skin disease caused by hyperproliferation of the epidermis with resultant scaling. Although the exact cause of psoriasis is unknown, a genetic background has been implicated in its etiology. Uveitis occurs predominantly in patients who develop arthropathy [3, 6]. The uveitis predominantly involves the anterior segment of the eye and is similar to human leukocytes antigens (HLA)-B27-associated disease [1]. The highly polymorphic HLA confer genetic susceptibility to several autoimmune diseases. Uveitis with psoriasis is very rare in the Japanese population, but is more commonly found in Caucasian populations. To our knowledge, only 15 Japanese cases have been reported [2, 7, 8, 9]. In only 11 of these 15 cases, HLA (HLA-A, B, C ) was typed serologically. In this report, we present a case of a Japanese male with psoriatic arthritis (PsA) and acute anterior uveitis (AAU) in whom we examined HLA typing. In addition, to investigate a possible link between uveitis with psoriasis and HLA type in Japanese people, we analyzed the published data of HLA typing of 11 patients with psoriasis and uveitis and obtained evidence that there is a strong association between HLA-A2 in Japanese psoriasis patients and susceptibility to uveitis. Graefe’s Arch Clin Exp Ophthalmol (2003) 241:777–778

Correlation between cerebrospinal fluid cell count and cerebrospinal fluid level of chemokine, monokine induced by interferon‐γ in Vogt–Koyanagi–Harada disease

Editor, V ogt–Koyanagi–Harada (VKH) disease is a systemic autoimmune disease against melanocytes, formed mostly in the uvea, meninges, labyrinthus and skin (Moorthy et al. 1995). Pleocytosis in the cerebrospinal fluid (CSF) is observed frequently in VKH patients during the acute phase (Moorthy et al. 1995). Recently, it has been found that chemokines play a pivotal role in recruiting leukocytes to sites of inflammation (Viola et al. 2006). To investigate the role of chemokines in the CSF of patients with VKH disease at initial onset, eight CSF samples from patients with VKH disease stored at )80 C, were assayed for five chemokines [interferon inducible protein-10 (IP-10), monokine induced by interferon-c (MIG), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and Regulated on Activation, Normal T Exprosed and Secreted [RANTES] in cytometric bead array (CBA) kits by BD Pharmingen (San Diego, California, USA). Controls consisted of three CSF samples from patients with other types of uveitis. This study adhered to the tenets of the Declaration of Helsinki, and informed consent was obtained from all participating patients. Eight VKH patients (two men, six women) met the VKH committee’s diagnostic criteria (Read et al. 2001). Their mean age was 46 years (range 19–75 years). CSF was collected prior to corticosteroid therapy in seven patients, while the therapy had already been started in one patient. Controls were three patients (one man, two women) with bilateral noninfectious panuveitis with retinal vasculitis (n = 1), cystic macula oedema (n = 1) and unilateral non-infectious posterior uveitis (n = 1). Their mean age was 27 years (range 21–34 years). One of the control patients had headache as neurological symptoms; one had interstitial pneumonia; the other had no systemic symptoms. Results were presented as the CSF cell counts, mean concentration and the range of detectable samples (Table 1). The protein levels were compared between two groups with the Mann–Whitney U-test. The Pearson’s r value was calculated to analyse correlations between CSF cell counts and chemokine levels. A P-value < 0.05 was considered statistically significant. The number of inflammatory cells in the CSF was statistically higher in the VKH patients (P = 0.0317) (Table 1). The levels of MIG and IP-10 were significantly elevated in the CSF of patients with VKH (P = 0.0143) (Table 1). In addition, an elevated level of IL-8 was observed in the CSF of VKH patients (P = 0.062) (Table 1). With regard to the level of MCP-1, there was no significant difference between the two groups. RANTES were not detected in either group. Regression analysis showed a significant linear relationship between CSF cell counts and MIG concentration in VKH patients (Fig. 1). There was no significant association between CSF cell counts and IP-10 level (Pearson’s r value = 0.571; P = 0.1306). Our data showed that MIG and IP-10 were significantly higher in the CSF of patients with VKH than in controls. In addition, we demonstrated that the MIG level correlated with the CSF cell count in VKH patients. The receptor of IP-10 and MIG, CXCR3, is expressed predominantly on memory or activated T-cells, especially Th1 cells (Viola et al. 2006). It is reported that CD4 T-cells are the predominant lymphocytes in the aqueous humour and CSFs (Ohta & Yoshimura 2002). Our data suggest the possi-

Penicillium endophthalmitis in necrotizing scleritis treated with topical corticosteroid and cyclosporin A

The mean fl ap thickness for all eyes was 113.64 ± 18.97 μm: 122.50 ± 14.71 μm in the right eye, and 108.70 ± 18.73 μm in the left eye. A signifi cant difference was found between the right and left eyes (P < 0.001). Figure 1 shows the distribution of corneal fl ap thicknesses in all eyes. No signifi cant correlation was found between fl ap thickness and age (P = 0.57), preoperative spherical equivalent refraction (P = 0.48), preoperative keratometry (P = 0.17), or preoperative corneal diameter (P = 0.41). A signifi cant correlation was found between fl ap thickness and preoperative CCT (r = 0.443, P < 0.001) (Fig. 2).