PATHOGENESIS OF CMV RETINITIS

巨细胞病毒视网膜炎的发病机制

• 批准号: 7024183
• 负责人: Richard D Dix
• 金额: $ 4.71万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024183
• 关键词: CD8 molecule; acquired immunodeficiency; cellular pathology; cytokine; cytomegalovirus retinitis; disease /disorder classification; disease /disorder model; enzyme linked immunosorbent assay; eye pharmacology; flow cytometry; histopathology; immunomodulators; immunosuppression; immunotherapy; laboratory mouse; lymphokine activated killer cell; murine AIDSs; natural killer cells; opportunistic infections; pathologic process; polymerase chain reaction; virus infection mechanism; western blottings

Cytomegalovirus (CMV) retinitis is the most frequent ophthalmic opportunistic infection in patients with AIDS. Although the clinical and histopathologic features of AIDS-related CMV retinitis have been extensively described, the pathogenesis of this disease is poorly understood. Our proposal explores the pathogenesis of CMV retinitis is terms of a new mouse model of the disease developed in our laboratory. We hypothesize that murine CMV (MCMV) retinitis with features similar to AIDS-related CMV retinitis will develop in adult C57BL/6 mice suffering from murine acquired immune deficiency syndrome (MAIDS), an immunosuppressive disorder produced by a mixture of murine retroviruses that parallels HIV-l-induced AIDS in humans. We predict that this animal model of CMV retinitis can be used to address several fundamental, clinically-relevant questions that relate to the pathogenesis and treatment of CMV retinitis in a setting of retrovirus-induced immunosuppression. We will evaluate this hypothesis and prediction by first performing a series of experiments designed to characterize the evolution of disease. Specifically, we will explore the histopathologic and virologic features of retinitis at various stages of MAIDS, examine the nature of the retinal inflammation associated with the disease, and identify the cell(s) of the retina that are susceptible to MCMV infection. Additional studies will focus on the effect of immunomodulators on the tempo and severity of retinitis. These will include MAIDS-induced immunosuppression, depletion of specific immune cell subsets and adoptive transfer of virus-specific effectors, and the effect of antiretrovirus drugs that are known to induce bone marrow toxicity in humans. Finally, we will investigate the effect of ganciclovir on MCMV retinitis and identify the cell(s) of the retina that serve as reservoirs for virus during treatment with this antiviral. The long term goal of this research project is to define the pathogenetic events that occur during the evolution of CMV retinitis in persons immunosuppressed by retrovirus infection, so that more innovative therapeutic approaches can be developed for improved treatment of this devastating sight-threatening disease.

巨细胞病毒（CMV）视网膜炎是最常见的眼科疾病 艾滋病患者的机会性感染。尽管临床和 艾滋病相关巨细胞病毒视网膜炎的组织病理学特征 对该病的发病机制进行了广泛的描述，但知之甚少 明白了。我们的提案探讨了 CMV 视网膜炎的发病机制是 这是我们实验室开发的一种新的小鼠疾病模型。我们 假设小鼠巨细胞病毒 (MCMV) 视网膜炎的特征与 患有艾滋病的成年 C57BL/6 小鼠将出现与艾滋病相关的巨细胞病毒视网膜炎 来自小鼠获得性免疫缺陷综合症（MAIDS） 由鼠逆转录病毒混合物产生的免疫抑制疾病 这与 HIV-1 引起的人类艾滋病相似。我们预测这种动物 CMV 视网膜炎模型可用于解决几个基本问​​题， 与发病机制相关的临床相关问题 逆转录病毒引起的 CMV 视网膜炎的治疗 免疫抑制。我们将通过以下方式评估这一假设和预测： 首先进行一系列旨在表征 疾病的演变。具体来说，我们将探讨组织病理学 和 MAIDS 各个阶段视网膜炎的病毒学特征，检查 与疾病相关的视网膜炎症的性质，以及 识别易受 MCMV 感染的视网膜细胞。 其他研究将集中于免疫调节剂对 视网膜炎的速度和严重程度。这些将包括 MAIDS 引起的 免疫抑制、特定免疫细胞亚群的耗竭和过继 病毒特异性效应子的转移以及抗逆转录病毒的作用 已知会引起人类骨髓毒性的药物。最后，我们 将研究更昔洛韦对 MCMV 视网膜炎的影响并确定 视网膜细胞在病毒传播过程中充当病毒储存库 用这种抗病毒药物治疗。本研究项目的长期目标 是定义进化过程中发生的致病事件 因逆转录病毒感染而免疫抑制的人发生 CMV 视网膜炎，因此 可以开发更多创新的治疗方法来改善 治疗这种严重威胁视力的疾病。