Yoichi Sasamoto

Central nervous system symptoms in patients with Behçet disease receiving cyclosporine therapy

OBJECTIVE To investigate the association between the development of central nervous system (CNS) symptoms in patients with Behçet disease and medical therapy. DESIGN Retrospective cohort study. PARTICIPANTS A total of 317 patients with Behçet disease with ocular complications who visited Hokkaido University Hospital, Sapporo, Japan, between 1978 and 1994. MAIN OUTCOME MEASURES The incidence of CNS symptoms in different medical therapies. RESULTS Twenty-one (6.6%) of the 317 patients developed CNS symptoms, namely neuro-Behçet disease. Of the 21 patients, 12 were undergoing cyclosporine therapy. Of the 47 patients who underwent cyclosporine therapy, 12 (25.5%) developed CNS symptoms, whereas only 9 (3.3%) of 270 patients who did not undergo cyclosporine therapy developed CNS symptoms. CONCLUSIONS Cyclosporine in the treatment of Behçet disease appears to cause neurotoxicity or to accelerate the development of CNS symptoms. Thus, neurologic complications appear to represent a major side effect of cyclosporine in the treatment of patients with Behçet disease.

Studies on Corticosteroid Therapy in Vogt-Koyanagi-Harada Disease

We evaluated the significance of corticosteroid therapy on 47 new patients with Vogt-Koyanagi-Harada disease examined in the Uveitis Survey Clinic of the Hokkaido University Hospital. All patients were treated with topical corticosteroids, with or without systemic corticosteroids. 18 patients received systemic corticosteroid as pulse therapy, 20 patients received high-dose corticosteroid starting with prednisolone 200 mg, 2 patients received conventional-dose corticosteroid and 7 patients received no systemic corticosteroid therapy. When we evaluated the results 6 months after the initiation of treatment, anterior chamber inflammation was significantly less in patients with pulse and high-dose corticosteroid therapy than in those without systemic corticosteroid therapy. Furthermore, final visual acuity was significantly better in patients with pulse and high-dose corticosteroid than in those without them. However, there was no significant difference between patients with pulse therapy and those with high-dose corticosteroid therapy. The findings are in support of systemic corticosteroid therapy (pulse and high-dose) in the treatment of Vogt-Koyanagi-Harada disease.

Characteristics of endogenous uveitis in Hokkaido, Japan

Abstract• Background: Etiological characteristics of endogenous uveitis vary around the world. There are few epidemiological reports on the etiology of uveitis from areas within Asia. We set out to examine the statistical data on uveitis in Japan. • Methods: We reviewed all the records of patients with endogenous uveitis who visited the Uveitis Survey Clinic of Hokkaido University Hospital in 1981 and 1994 and extended the survey to include new patients with uveitis seen over the past 3 years. • Results: Behçets disease, sarcoidosis and Vogt-Koyanagi-Harada disease were the three most frequently diagnosed diseases in patients with endogenous uveitis in both 1981 and 1994. The proportion of patients with unclassified disease entities decreased (from 38% to 30%) during the 13-year period from 1981 to 1994 as a result of the new disease categories established during this interval. Notable additions included human T-lymphotropic virus type I-associated uveitis and tubulointerstitial nephritis and uveitis syndrome. Sarcoidosis is now the most frequent cause of endogenous uveitis in our clinic. • Conclusion: Not only does the etiological basis of uveitis vary with ethnicity, but advances in clinical and basic research have changed the approach to the diagnosis of uveitis, altering the etiological profile over time.

Identification of a peptide inducing experimental autoimmune uveoretinitis (EAU) in H-2Ak-carrying mice

When certain strains of mice bearing H‐2Ak are immunized with the interphotoreceptor retinoid‐binding protein (IRBP), EAU is induced. Thus far uveitogenic determinant(s) has not been determined in the H‐2Ak mouse system. In addition it is hard to prepare purified IRBP. In the present study, to circumvent these problems we attempted to identify uveitogenic peptides derived from bovine IRBP in H‐2Ak haplotype mice. Six peptides which had been selected according to the H‐2Ak binding motif (Dxxxxxxxx[A, R, T]) were synthesized. We report here that all the peptides are immunogenic but only one peptide, K2, which consisted of IRBP201–216 residues, induces EAU in various mice carrying H‐2Ak. Amino acid substitution of K2 revealed that the core region interacted with both H‐2Ak and T cell antigen receptor (TCR). The amino acid sequence of the core region derived from bovine IRBP was identical to the corresponding region of mouse IRBP. In addition, K2 appeared to be a natural peptide antigen processed from bovine IRBP. Altogether, we concluded that K2 is one of the natural autoantigens involved in induction of EAU in H‐2Ak mice.

Amelioration of Experimental Autoimmune Uveoretinitis by Pretreatment with a Pathogenic Peptide in Liposome and Anti-CD40 Ligand Monoclonal Antibody

We have defined a peptide K2 (ADKDVVVLTSSRTGGV) that corresponds to residues 201–216 of bovine interphotoreceptor retinoid-binding protein and induces experimental autoimmune uveoretinitis (EAU)4 in H-2Ak-carrying mice (H-2Ak mice). In this study, we attempted to ameliorate EAU in the H-2Ak mice without nonspecific suppression of T cell responses. Preceding s.c. administration of liposomes including K2 (liposomal K2) specifically inhibited subsequent generation of T cell response to K2. The same result was obtained with a combination of OVA323–339 peptide and the OVA-specific TCR-transgenic T cells. It was suggested that the inhibition was mainly attributed to peripheral anergy induction of T cells specific for the peptide Ag, although specific cell death might also be involved in the inhibition. Pretreatment with liposomal K2 also considerably abolished IFN-γ production but not IL-4 production. The specific inhibitory effect of the pretreatment with liposomal peptide was augmented by a simultaneous administration of anti-CD40 ligand (anti-CD40L) mAb. Moreover, it was shown that the pretreatment with liposomal K2 reduced both the incidence and severity of the subsequent K2-induced EAU, and the simultaneous administration of anti-CD40L mAb augmented this preventive effect by liposomal K2. Our findings demonstrate that the s.c. administration of liposomal pathogenic peptide and anti-CD40L mAb can be applied to preventing autoimmune diseases without detrimental nonspecific suppression of T cell responses.

Effects of bright light at lunchtime on sleep of patients in a geriatric hospital I

The effects of lunchtime bright light exposure in patients of a geriatric hospital were investigated. Ten inpatients (six women and four men; mean age ± SD: 81.2 ± 8.8 years) with sleep disturbances were studied for 9 weeks. Nurses performed daily ratings for sleep–wakefulness disturbances. Approximately 8000 lx bright light exposure was performed for 3 weeks in the light therapy room. Before and after exposure, ocular function was evaluated. Clinical ratings of sleep‐wakefulness improved in eight patients. The score of difficulty in falling asleep and drowsiness in the morning declined during the light exposure. The score of drowsiness in the afternoon decreased during the post‐light exposure. Post‐exposure ocular disturbances were not found.

Topical Application of Ciclosporin Ophthalmic Solution Containing Alpha-Cyclodextrin in Experimental Uveitis

Ciclosporin (CS) has been shown to be a potent immunosuppressive drug. However, systemic administration of CS has been limited because of its unfavourable side effects. Thus, our attention has been focused on a topical application of CS for ophthalmic diseases. In this study, we examined the influence of a topical application of CS on experimentally induced ocular inflammation. CS was prepared by a new drug delivery system, with alpha-cyclodextrin (CD) as a solvent. Topical 0.075% CD-CS reduced ocular inflammation of rabbits induced by intravitreal injection of bovine serum albumin. The magnitude of efficacy of topical 0.075% CD-CS fell within the same level as that of topical 0.02% fluorometholone. However, the topical CD-CS showed no effect on experimental autoimmune uveitis in rats which had been induced by S-antigen or interphotoreceptor retinoid-binding protein. These findings indicate that the topical CD-CS is effective on anterior uveitis.

Regulation of experimental autoimmune uveitis in rats--separation of MHC and non-MHC gene effects.

Experimental autoimmune uveitis (EAU) is an organ‐specific autoimmune disease and has served as a model of certain ocular inflammatory conditions in man. The present study was aimed at separating the effects of MHC and non‐MHC genes on the development of EAU in the rat. EAU‐susceptible LEW (RT1l) EAU‐resistant WKAH (RTIk), and WKAH.1L (RTF) MHC congenic strain of WKAH background rats were immunized with retinal soluble antigen (S‐Ag) in Freunds complete adjuvant (FCA). LEW rats showed typical EAU, while neither WKAH nor WKAH. 1L congenic rats developed EAU. However, when an additional i.v. injection of Bordetella pertussis was given, all rat strains developed EAU. Furthermore, when immunized with peptide M, an 18‐mer synthetic peptide, which corresponds to amino acid positions 303–320 of bovine S‐Ag, and given an additional i.v. injection of B. pertussis, LEW and WKAH. IL rats developed EAU, whereas WKAH did not. When ACI (RTIavl), BUF (RTIb), LEJ (RTIl), W(RTIk), F344(RTI1v1), BN (RTIq), NIG‐III (RTIq), TO (RT1I), and SDJ (RT1u) rats were immunized with peptide M or S‐Ag and then given B. pertussis, all strains developed EAU by immunization with S‐Ag plus B. pertussis, but only F344 and NIG‐III developed EAU by immunization with peptide M. These findings suggest that susceptibility to EAU in rats is controlled by both MHC and non‐MHC genes; and that in the absence of B. pertussis adjuvant, the form of disease induced by native S‐Ag in FCA is governed by non‐MHC gene(s). However, this effect of non‐MHC gene(s) could no longer be observed when the rats were also injected with B. pertussis adjuvant at sensitization.

Platelet aggregation induced by uncommon serotypes of Streptococcus sanguis isolated from patients with Behçet's disease

Uncommon serotypes were tested for their ability to induce aggregation in platelet-rich plasma. Both uncommon and common serotypes induced platelet aggregation in rabbit platelet-rich plasma, but serotonin release was higher with the uncommon serotypes. Aggregation at ATP release varied between uncommon and common serotypes. With human platelet-rich plasma, only uncommon serotypes showed aggregation. Differences in serotype selectivity and the rate of aggregation were noted among platelet donors. About half of the patients with Behçets disease and 30% of health controls showed platelet aggregation. Plasma from non-responder patients with Behçets disease inhibited aggregation of healthy responder platelets within 20 min. Thus selective binding of uncommon serotypes of Strep. sanguis to platelets might cause the vasculitis in Behçets disease.

Interphotoreceptor retinoid-binding protein derived peptide can induce experimental autoimmune uveoretinitis in various rat strains

Experimental autoimmune uveoretinitis (EAU) is an intraocular inflammatory disease model induced by retinal specific antigens such as S-antigen and interphotoreceptor retinoid-binding protein (IRBP). The present study was aimed at testing the uveitogenicity of IRBP and an IRBP-derived peptide in various strains of rats with different RT1 (major histocompatibility complex in rats) haplotypes. Immunization with IRBP induced distinct EAU in LEW (RT1l), WKAH (RT1k) W/M (RT1k), LEJ (RT1j), and BUF (RT1b) rats. IRBP also induced a low grade of EAU in SDJ (RT1u), but no disease was detected in TO rats, another strain of the RT1u haplotype. IRBP-derived peptide R16 (aa 1177-1191) induced severe EAU in LEW rats and moderate disease in the WKAH and W/M strains. Immunization with R16 also induced low levels of inflammation in eyes of 75% and 20% of LEJ and BUF rats, respectively, but this peptide did not cause any disease in SDJ and TO rats. Injection of Bordetella pertussis had minimum or no effect on the induction of EAU by peptide R16 in this study. These data thus indicate that peptide R16 can bind to various RT1 molecules in addition to RT1l. Further, our observations support the notion that certain epitopes of IRBP could be uveitogenic in humans with different HLA haplotypes.