Ocular HSV: Role of virus and IL-2 in Optic neuritis

描述：脱髓鞘疾病构成一系列免疫病理综合征，髓鞘是大脑、视神经和脊髓中神经细胞纤维的脂肪覆盖物，被破坏。与髓鞘退化相关的主要疾病之一是多发性硬化(MS)。MS的首发症状是视力障碍，视神经脱髓鞘所致的视神经病变(ON)是MS患者视力和神经功能障碍的常见原因，ON可作为MS后续病程的早期预后因素。由于MS患者的脑脊液和血清中IL-2水平升高，提示IL-2可能在MS的病理过程中发挥作用，我们探讨了表达小鼠IL-2的重组1型单纯疱疹病毒(HSV-1)感染对MS的影响。我们的初步研究表明，根据视觉诱发皮质电位(VECP)和尸检组织学检查，这种感染导致脱髓鞘。而单纯野生型HSV感染、HSV-IL-4和HSV-干扰素-伽马病毒(与HSV-IL-2相同，但表达IL-4或干扰素-γ，而不表达IL-2)感染均不能引起脱髓鞘。对脑和脊髓细胞浸润的分析表明，与对照组相比，HSV-IL-2感染组激活的T细胞和IL-12产生CD11b+反应增强。根据我们的初步数据，我们提出了一个工作假说，即HSV-IL-2表达IL-2可以招募和激活CD8+T细胞和巨噬细胞渗透到中枢神经系统。刺激后，CD8+T细胞直接导致脱髓鞘，巨噬细胞通过表达IL-12并将免疫反应推向TH1反应来加剧这一过程。为了进一步阐明HSV-IL-2诱导脱髓鞘的生物学和免疫学机制，我们的具体目的包括：1.明确HSV-IL-2感染小鼠中枢神经系统脱髓鞘的过程。2.确定IL-2产生和细胞浸润物在脱髓鞘中的相对作用。3.确定表达IL-4的重组HSV-1(HSV-IL-4)是否对HSV-IL-2诱导的脱髓鞘有保护作用，而表达干扰素-γ的重组病毒是否对脱髓鞘有保护作用。

DESCRIPTION: Demyelinating diseases constitute a spectrum of immunopathologic syndromes in which, myelin, the fatty covering of nerve cell fibers in the brain, optic nerve, and spinal cord, is destroyed. One of the major diseases associated with degradation of the myelin sheath is multiple sclerosis (MS). Visual disturbances are initial manifestation of MS and optic neuropathy (ON) due to demyelination of optic nerve is a common cause of visual and neurologic dysfunction in young adults diagnosed with MS. ON can be used as an early prognostic factor during the subsequent course of MS. As MS patients have elevated levels of IL-2 in their CSF and sera, which suggests that IL-2 may play a role in the pathology of MS, we explored the effects of infection of mice with a recombinant herpes simplex virus type 1 (HSV-1) expressing murine interleukin-2 (HSV-IL-2). Our Preliminary Studies show that this infection results in demyelination, as determined by visual-evoked cortical potentials (VECPs) and histologic examination at autopsy. In contrast, neither wild- type (wt) HSV infection alone nor HSV-IL-4, nor HSV-IFN-gamma virus (identical to HSV-IL-2 but expressing IL-4 or IFN-gamma instead of IL-2) infection caused demyelination. Analysis of the cellular infiltrates in the brain and spinal cord indicates enhanced activated T cells and IL-12 producing CD11b+ responses in HSV-IL-2 infected group compared with mice infected with control viruses. Based on our preliminary data, we have formulated the working hypothesis that expression of IL-2 by HSV-IL-2 recruits and activates CD8+ T-cells and macrophage infiltrates to the CNS. Following stimulation the CD8+ T cells directly cause demyelination, with the macrophages exacerbating the process by expressing IL-12 and pushing the immune response toward a TH1 response. Our detailed specific aims to further elucidate the biological and immunological mechanisms responsible for HSV-IL-2 induced demyelination include: 1. Define the demyelination process in the CNS of HSV-IL-2-infected mice. 2. Determine the relative roles of IL-2 production and cellular infiltrates in demyelination. 3. Determine if a recombinant HSV-1 expressing IL-4 (HSV-IL-4) can protect against HSV-IL-2-induced demyelination, while a similarly made recombinant virus expressing IFN-gamma is not beneficial.