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

产品说明：脱髓鞘疾病构成一系列免疫病理综合征，其中髓磷脂（脑、视神经和脊髓中神经细胞纤维的脂肪覆盖物）被破坏。与髓鞘降解相关的主要疾病之一是多发性硬化症（MS）。视觉障碍是MS的初始表现，并且由于视神经脱髓鞘引起的视神经病变（ON）是诊断为MS的年轻成人中视觉和神经功能障碍的常见原因。ON可以用作MS后续过程中的早期预后因子。由于MS患者的CSF和血清中具有升高的IL-2水平，这表明IL-2可能在MS的病理学中起作用，我们探索了用表达鼠白细胞介素-2（HSV-IL-2）的重组单纯疱疹病毒1型（HSV-1）感染小鼠的效果。我们的初步研究表明，这种感染导致脱髓鞘，通过视觉诱发皮层电位（VECP）和尸检组织学检查确定。相比之下，单独的野生型（wt）HSV感染、HSV-IL-4、HSV-IFN-γ病毒（与HSV-IL-2相同，但表达IL-4或IFN-γ而不是IL-2）感染均不引起脱髓鞘。脑和脊髓中细胞浸润的分析表明，与对照病毒感染的小鼠相比，HSV-IL-2感染组中活化的T细胞和产生IL-12的CD 11b+应答增强。基于我们的初步数据，我们已经形成了工作假设，即HSV-IL-2的IL-2表达募集并激活CD 8 + T细胞和巨噬细胞浸润CNS。在刺激后，CD 8 + T细胞直接引起脱髓鞘，巨噬细胞通过表达IL-12并将免疫应答推向TH 1应答而加剧该过程。我们的具体目标是进一步阐明HSV-IL-2诱导脱髓鞘的生物学和免疫学机制，包括：1。定义HSV-IL-2感染小鼠中枢神经系统的脱髓鞘过程。2.确定IL-2产生和细胞浸润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）是否可以防止HSV-IL-2诱导的脱髓鞘，而表达IFN-γ的类似重组病毒则没有益处。

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.