Cellular Immunotherapy for Pathological Retinal Neovascularization

视网膜相关性黄斑变性（AMD）是发达国家50岁以上老年人最常见的致盲原因。脉络膜新生血管（choroidal neovascularization，CNV）是AMD的并发症，新生血管通过Bruch膜侵入视网膜下腔，形成含有血管内皮细胞、成纤维细胞、视网膜色素上皮（retinal pigment epithelial，RPE）细胞和各种炎性细胞的纤维血管增生组织。我们最近的报告表明，CD 8+细胞毒性T细胞（CTL）介导的生理和病理视网膜新生血管的抑制。在肿瘤模型中，靶向在内皮细胞中高度表达的VEGFR 2的特异性免疫被报道抑制肿瘤生长和血管生成。因此，我们假设通过诱导靶向VEGFR 2的CTL应答来治疗CNV，VEGFR 2是在CNV相关内皮细胞中高度表达的特异性分子。因此，我们研究了实验CNV是否被抑制诱导特异性细胞免疫对VEGFR 2通过接种树突状细胞（DC），专业的抗原呈递cells.In的文件已经提交，我们表明，第一次，我们的知识，诱导肽特异性细胞免疫靶向内皮细胞抑制CNV的产生。用表位肽VEGFR 2400 -408脉冲的DC疫苗引发对所述肽的特异性CTL应答。此外，CD 8 T细胞显示为免疫治疗中的主要效应物。这些数据提示了CTL介导的CNV特异性免疫治疗的新概念。

Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly people over the age of 50 in the developed countries. AMD is complicated by choroidal neovascularization (CNV), during which the choroidal new vessels invade the subretinal space through Bruch's membrane to form the fibrovascular proliferative tissue containing vascular endothelial cells, fibroblasts, retinal pigment epithelial (RPE) cells and various inflammatory cells. Our recent reports demonstrated CD8+ cytotoxic T cell (CTL)-mediated suppression of physiologic and pathologic retinal new vessels. In tumor models, specific immunization targeting VEGFR2, which are highly expressed in endothelial cells, was reported to inhibit tumor growth and angiogenesis. Accordingly, we hypothesized a possible immunological therapy for CNV by inducing CTL responses targeting VEGFR2, which is a specific molecule highly expressed in CNV-associated endothelial cells. Thus, we examined whether experimental CNV is suppressed by inducing specific cellular immunity against VEGFR2 via vaccination with dendritic cells (DCs), professional antigen-presenting cells.In the paper already submitted, we showed, for the first time to our knowledge, that the induction of peptide-specific cellular immunity targeting endothelial cells inhibits CNV generation. Vaccination of DCs pulsed with the epitope peptide VEGFR2400-408 elicited the CTL responses specific for the peptide. Additionally, CD8 T cells were shown as the major effectors in the immunological treatment. These data indicate the new concept of CTL-mediated specific immunotherapy for CNV.