Uveitis is one of the refractory eye diseases leading cause of severe loss of vision. It is defined as inflammation of the uvea, which has infectious or non-infectious causes. The precise immunologic mechanisms of uveitis with systemic or autoimmune diseases still remain unclear.
Our research group has shown that both Th1 and Th17 cells are responsible for the pathogenesis of uveitis using the rodent model of uveitis (Experimental Autoimmune Uveitis: EAU). (Sonoda KH et al. Acta Ophthalmol. 2011; Yoshimura T et al. Rheumatology 2009; Yoshimura T et al. Int Immunol. 2008). We recently elucidated that inflammatory cytokines (Takeda A et al. Exp Eye Res. 2014) and T cell signaling (Takeda A et al. Lab Invest. 2018) are related to the pathogenesis of uveitis. Interleukin (IL)-27 and IL-35 are inflammatory cytokines and Epstein-Barr virus-induced gene 3 (EBI3) is a component of IL-27 and IL-35. When EBI3-/- mice were induced EAU, both the clinical and histological analyses revealed that uveitis in EBI3-/- mice were diminished compared with those in control mice (Figure 1). We also showed that EBI3 controls Th1 cell and Th17 cell responses in EAU (Figure 2). In T cells, ATP, which is released by CD4+ T cells upon T cell receptor stimulation, binds to P2X7 receptor (P2RX7) to initiate T cell activation and proliferation. The severity of EAU scores in P2rx7-/- mice was reduced as compared with that in control mice. Histological analysis also showed lower inflammation in P2rx7-/- mice. The induction of IFN-γ and IL-17 in P2rx7−∕−mice was lower than that in control mice. These results suggest that ATP-P2RX7 signaling can exacerbates inflammation in uveitis. Currently, we are seeking novel morbidity marker from the aqueous humor, vitreous and serum samples of patients with uveitis.
Our group is also focusing on inflammatory pathology other than Uveitis, such as choroidal neovascularization or fibrosis in Age-related macular degeneration (AMD). Our research targets are inflammatory cells and inflammatory cytokines in those inflammatory ocular diseases. We demonstrated that IL-17, which is a major proinflammatory cytokine, had a strong potential for promoting intraocular neovascularization (Figure 3). Although Th17 is well known as the main source of IL-17, we identified infiltrated γδT cells, but not Th17 cells, were the main source of IL-17 in experimental intraocular neovascularization (Hasegawa et al. J Immunol. 2013). Also, we elucidated that metabolites of unsaturated fatty acids are responsible for regression of intraocular neovessels, which work in part by modulating the recruitment of inflammatory immune cells such as macrophages (Hasegawa et al. Proc Natl Acad Sci. 2017). We also targeted subretinal fibrosis, which is frequently observed in advanced AMD. We have established new rodent model of subretinal fibrosis (Figure 4) (Jo YJ. IOVS. 2011) and elucidated several inflammatory cytokines were involved in the pathogenesis of fibrosis (Zhang H. PLoS One. 2013, Yang Y. PLoS One. 2013). Our goal is to find novel therapeutic targets and provide novel remedy for inflammatory ocular diseases.
Intraocular proliferative diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR) are a leading cause of decreased vision and blindness in Japan. In those diseases, retinal fibro(vascular) membrane formation above and beneath the retina plays a pivotal role in the primary pathology (Figure 1).
In order to identify genes responsible for intraocular proliferation, we first determined the gene expression profiling of human retina, ERMs associated with proliferative diabetic retinopathy (PDR-ERMs), and PVR (PVR-ERMs) (Figure 2). We next determined "highly expressed genes in PDR- and in PVR-ERMs" by comparing the gene expression profiles between PDR-, PVR-ERMs and the retina. Subsequent analyses identified matricellular proteins, including periostin and tenascin C as important molecules whose expressions are enhanced specifically in proliferating ERMs compared to the retina (Ishikawa K et al. IOVS 2015).
We found increased periostin and tenascin C expression in the vitreous of patients with both PDR and PVR. Immunohistochemical analysis showed colocalization of periostin and α-SMA in PDR- and PVR-ERMs (Kobayashi Y et al. Mol Vis 2016; Ishikawa K et al. FASEB J 2014; Yoshida S et al. IOVS 2012). In vitro, both periostin and tenascin C increased proliferation, adhesion, migration and collagen production in RPE cells. Periostin blockade suppressed migration and adhesion induced by transforming growth factor-β2 (TGF-β2) and PVR vitreous. In vivo, periostin and tenascin C inhibition had the inhibitory effect on experimental retinal and choroidal fibrovascular formation, and progression of experimental PVR without affecting the viability of retinal cells (Kobayashi Y et al. Lab Invest 2016; Ishikawa K et al. FASEB J 2014). These results identified periostin and tenascin C as a pivotal molecule for fibro(vascular) formation. Thus, developing the novel antibody and/or innovative could be a potential therapeutic strategy for inhibiting the progression of intraocular proliferative diseases including DR and AMD.
In the pathogenesis of intraocular fibrosis associated with AMD and PVR, epithelial to mesenchymal transition (EMT) of RPE is one of the important steps; that is, RPE that undergo EMT acquire a fibroblast phenotype with increased capacity to proliferate and migrate and with the ability to produce ECM, which facilitate the formation of fibrotic membrane (Ishikawa K et al. Am J Pathol. 2016). Our comprehensive gene expression analyses of surgically resected human fibrous membranes associated with PDR and PVR revealed the significant EMT-related molecules (Ishikawa K et al. IOVS 2015).
We study the underlying mechanisms in EMT of RPE by investigating the expression and functions of those EMT-related molecules in human samples and/or the animal models of both pre- and subretinal fibrosis (rabbit PVR model and mouse laser-induced CNV model) by real-time PCR, ELISA, Western blot and IHC, etc (Figure 3) (Ishikawa K et al. Sci Rep. 2015; Ishikawa K et al. Exp Eye Res. 2016). Moreover, we explore the biological function and the underlying molecular pathways related to EMT in vitro and seek to establish EMT targeting therapy to prevent fibrosis associated with AMD and PVR (Figure 4).
Retinitis pigmentosa (RP) is a major cause of blindness, affecting approximately 1 in about 5,000 people pan-ethnically. RP is caused by mutations in various genes (more than 70 responsible genes), including the rhodopsin and cGMP phosphodiesterase 6 (PDE6b) genes. However, the biological processes by which these mutations lead to progressive photoreceptor death are still unclear and no effective treatment exists for RP. One of the common pathology in genetically heterogenous RP is “apoptosis” of the photoreceptor cells. We have conducted translational research to apply neuroprotective gene therapy using an original viral vector carrying pigment epithelium-derived factor (PEDF) gene to prevent photoreceptor cell apoptosis.
Previously, we demonstrated an efficient and stable retinal gene transfer mediated by the non-pathogenic simian immunodeficiency virus from African green monkeys (SIVagm)-based lentiviral vector in rodent and non-human primate retinas (et al. Gene Ther. 2003; et al. Hum Gene Ther. 2009a.), and the therapeutic outcome in animal models of retinal degeneration using recombinant SIVagm-based lentiviral vectors carrying human PEDF gene (Miyazaki M, et al. Gene Ther. 2003; Miyazaki M, et al. J Gene Med. 2008; Murakami Y, et al. Am J Pathol. 2008.). We also reported the systemic and local effects following intraocular administration of SIV-hPEDF in Macaca fascicularis, as a preclinical safety study (et al. Hum Gene Ther. 2009b.).
Based on our efficacy studies and safety studies, a clinical study (UMIN000010260) to assess the safety of subretinal administration of SIV-hPEDF has already finished. The first subject was enrolled on March 26th, 2013 and gene transfer was done in five subjects in the low titer group (2.5 x 107 transducing units [TU]/mL). No serious adverse event caused by gene transfer was detected in all subjects in the observation period (24 months). We are now going to conduct an investigator initiated clinical trial (Phase I/IIa) (UMIN000034081) aimed at establishing this strategy as the next-generation standard treatment.
Welcome to the Department of Ophthalmology, Kyushu University Hospital’s “Imaging Group” site. Here you will find information about the research being conducted by our faculty. Our group is under the leadership of Assistant Professor, Shintaro Nakao MD.,PhD.
Our Research area includes: Understanding of vitreoretinal diseases; Vascular biology; Macrophages in vitreoretinal diseases; Development of novel therapeutic agents; Retinal imaging.
Our group also provides an excellent training environment for graduate students at the University of Kyushu. Current members in our group refer to the following site.
The purpose of our group is “connect” real world in clinic and molecular world in lab with imaging. By the result of our research, we can connect the clinical disease with the basic results, molecular mechanism, and new therapeutic target.
Please explore our site to learn more about the research being performed in each laboratory. Thank you for taking the time to visit us today!
Ocular tumor is the life-threatening disease. Our department is one of the specialized institutions for the diagnosis and treatment of ocular tumors in Japan. In the Kyushu university hospital, we treat ocular tumors including orbital tumors, lacrimal gland tumors, eyelid tumors, conjunctival tumors, and intraocular tumors. The number of new cases with ocular tumors is about 250 cases per year. As well as the clinical practice, we are conducting basic research.
Recent advantages in genomic analysis expand our understandings of cancer genomes. These studies can provide us with a novel approach for the selection of the treatment drugs, and sub-classifications of the tumors based on molecular level information. Nevertheless, genomic analyses have been performed in a few tumors in the ophthalmologic field. We have started the genomic analysis of the ocular tumors by comprehensive DNA and RNA sequencing using the next-generation sequencer.
We have also launched a new project using the artificial intelligence (AI). Since the majority of the ocular tumors were rare, the diagnosis of ocular tumor is not easy for the family doctors and general ophthalmologists. Now, our department have the computational server which contains graphic processing units (GPU) in order to develop a deep learning system for the precise diagnosis of ocular tumors.
P.I.;M Yasuda , K Fujiwara
The town of Hisayama is a suburb of Fukuoka city in Japan. The population rate increase of Japan from 1960 to 2010 is similar to that of Hisayama. Age distribution was almost the same across all age categories in both 1960 and 2010, similar to that of all of Japan. Moreover, distribution of the labor population was also similar between Japan nationally and Hisayama. Therefore, we can say that Hisayama’s population is a good sample for Japan as a whole.
The Hisayama Study is an ongoing, long-term cohort study on cardiovascular disease and its risk factors in the town of Hisayama. As a part of the overall study, an epidemiologic study of eye disease among residents of the town has been under way since 1998.
The purpose of our group is to clarify the prevalence, incidence and risk factors for common ocular disease, which cause visual impairment and vision loss, in a general Japanese population.
We started a new glaucoma incidence study from 2012-2013 in partnership with Oita and Akita universities. Several systemic and environmental factors related with the incidence of glaucoma are expected to be revealed.
It is a dream of an ophthalmologist to regenerate photoreceptor cells damaged by retinal diseases such as retinal detachment and diabetic retinopathy.
In recent years retinal regenerative medicine using iPS cells has attracted much attention, but we aim to develop retinal regeneration therapy by direct reprogramming, i.e. nerve regeneration therapy not dependent on cell transplantation. The strategy of future retinal regeneration therapy that we consider is to perform radical therapy for the causative disease and retinal regeneration therapy at the same time by injection of medicine into the vitreous at the end of surgery.
We have already developed a method to change astrocytes and Müller cells into progenitor cells by stimulation with a cocktail of small molecular compounds under in vitro environment and then induce differentiation into neurons. Now we are conducting comprehensive compound screening to select the combination of cocktails that lead to more efficient differentiation into neuronal cells.
Young researchers interested in our research, please contact us at any time!