Technological innovations, such as developments in molecular biology and inspection equipment, have remarkably improved diagnostic and activity evaluation methods, including comprehensive pathogen gene analysis in the intraocular fluid using polymerase chain reaction and genomic analysis to predict disease onset and progression. Moreover, the advent of biologics represented by anti-tumor necrosis factor (TNF) -α antibodies and antivascular endothelial growth factor (VEGF) antibodies therapies has created a paradigm shift in treatment. On the back of such advancement, light perception may be restored in patients with intractable eye diseases, who have difficulty maintaining their vision due to the lack of effective treatments. However, despite these advances in diagnostic and therapeutic methods, several challenges remain. The development of technology for the comprehensive analysis of individual clinical information, such as genomics, transcriptomics, and proteomics, has recently brought us closer to the realization of individualized medicine, including effective drug selection and prediction of recurrence and prognosis.
Our research group has positioned the following conditions as pivotal clinical issues in ocular inflammatory diseases and infection diseases: (1) uveitis macular edema (UME), the leading cause of visual impairment in patients with uveitis; (2) acute retinal necrosis (ARN) and human T-cell lymphotropicvirus type 1 (HTLV-1) -associated uveitis (HAU), representative ocular diseases caused by virus; and (3) vitreoretinal lymphoma (VRL), the most life-threatening ocular disease. In this article, we will present the outcomes of our research on these three diseases, focusing on the comprehensive analysis of genes and proteins using human intraocular fluid in the basic research and the prediction of visual prognoses using statistical analyses based on clinical data in the clinical research.
I. Search for novel therapeutic targets for UME
UME initially responds to steroid therapy but becomes refractory in the long term due to resistance to steroid therapy as well as its side effects. As some patients do not respond to anti-TNF therapy, the development of novel therapeutic strategies is required. We comprehensively analyzed pro-inflammatory mediators, such as cytokines and chemokines, in the intraocular fluid of patients with uveitis and searched for novel target factors of UME. We found high levels of B-cell activating factor belonging to the TNF family (BAFF) in the vitreous fluid of patients with macular edema associated with sarcoidosis and Behçet disease. We will discuss the relevance of BAFF to UME, based on the results of the functional analysis of BAFF from the perspective of molecular biology.
II. Visual prognosis of ARN, and elucidation of pathology of HAU
ARN is a representative ocular disease with a poor visual prognosis due to its severe outcome. In the present study, we predicted visual prognosis in patients with ARN based on clinical findings at initial presentation at the Department of Ophthalmology, Kyushu University Hospital. Furthermore, we assessed an attempt to create a risk score to predict a poor visual prognosis.
Although CD4⁺ T cells play a predominant role in the pathogenesis of HAU, our investigation shows that CD8⁺ T cells may induce conditions similar to HAU.
III. Elucidation of disease control mechanism of VRL and a diagnosis based on a genetic panel
VRL, which has been on the rise in recent years, exhibits poor prognosis owing to the high rate of central nervous system (CNS) progression after onset. Although prophylactic methotrexate-based chemotherapy for CNS progression has reportedly been effective for improving prognosis, our overall survival analysis of patients with a long-term follow-up of over 4 years revealed that some patients had poor prognoses due to CNS progression in a short time, even after the chemotherapy. Based on a comprehensive analysis of proinflammatory mediators in the vitreous humor from VRL, we identified elevated concentrations of interleukin-35, a cytokine associated with regulatory T-cell (Treg) differentiation and proliferation, in patients who died early. We further report on our attempts to use a genetic panel of intraocular fluid to diagnose VRL and present candidate drugs to patients with VRL.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 128: 216-233, 2024.