New Insights Into Immunological Therapy for Retinal Disorders

Abstract

In the twentieth century, a conspicuous lack of effective treatment strategies existed for managing several retinal disorders, including age-related macular degeneration; diabetic retinopathy (DR); retinopathy of prematurity (ROP); retinitis pigmentosa (RP); uveitis, including Behçet's disease; and vitreoretinal lymphoma (VRL). However, in the first decade of this century, advances in biomedicine have provided new treatment strategies in the field of ophthalmology, particularly biologics that target vascular endothelial growth factor or tumor necrosis factor (TNF)-α. Furthermore, clinical trials on gene therapy specifically for patients with autosomal recessive or X-linked RP have commenced. The overall survival rates of patients with VRL have improved, owing to earlier diagnoses and better treatment strategies. However, some unresolved problems remain such as primary or secondary non-response to biologics or chemotherapy, and the lack of adequate strategies for treating most RP patients. In this review, we provide an overview of the immunological mechanisms of the eye under normal conditions and in several retinal disorders, including uveitis, DR, ROP, RP, and VRL. In addition, we discuss recent studies that describe the inflammatory responses that occur during the course of these retinal disorders to provide new insights into their diagnosis and treatment.

Keywords: diabetic retinopathy; immune privilege; non-infectious uveitis; retinitis pigmentosa; retinopathy of prematurity; vitreoretinal lymphoma.

Figure 1

The effects of ω-3 long chain polyunsaturated fatty acids in experimental autoimmune uveitis model mice. (A) Hematoxylin-eosin staining of retinal sections at 17 days after disease induction in experimental autoimmune uveitis (EAU) mice maintained on a diet enriched with ω-3 or ω-6 long-chain polyunsaturated fatty acids (LCPUFAs). A red arrowhead indicate inflammatory cells in the retina. A yellow arrow indicates a retinal fold. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer. Scale bars, 200 μm. (B–D) The proliferation of T cells, as assessed by the measurement of [³H]thymidine incorporation (B), and by the production of interferon-γ (C), and interleukin-17 (D) in co-cultures of CD4⁺ T cells from EAU mice and the indicated antigen presenting cell fractions from mice fed with ω-3 or ω-6 LCPUFAs. Data are expressed as the means + the standard error of the mean (SEM). ^*P < 0.05, ^***P < 0.001; NS, not significant vs. the corresponding value for the ω-6 LCPUFA diet (i.e., Sidak's multiple comparison test). The figure is reproduced from (77) with permission.

Figure 2

Summary of our hypothesis on the formation of proliferative diabetic retinopathy and antivascular endothelial growth factor resistant diabetic macular edema. Diabetic macular edema (DME) animal models such as Akimba mouse models have been developed. The details of the involvement of inflammation in the pathogenesis of DME are expected to be identified in the future.

Figure 3

Oxidative stress modulates cone cell survival and neuroinflammation in retinitis pigmentosa. The remaining cones in retinitis pigmentosa (RP) are exposed to a high level of oxygen and the resultant reactive oxygen species (ROS). ROS have a direct harmful effect on cone cells and affects the activation of microglia and monocyte-derived macrophages. Activated microglia/macrophage have a bidirectional function to protect or promote cone cell death. Which environmental factors (e.g., ROS, molecules released from dead cells) and cellular factors (e.g., microglia vs. macrophage) are critical to determine the homeostatic vs. neurotoxic function of microglia/macrophage in RP is unclear.