Mechanisms of HSK amelioration

单纯疱疹病毒性角膜炎(HSK)是引起儿童传染性失明的主要原因之一。 美国。视力丧失最常见的原因是复发性间质 疾病，与原发单纯疱疹病毒不同，似乎是免疫- 介导性角膜破坏。大多数实验模型都专注于 原发而不是复发性角膜炎。我们研究了一个复发的HSK模型 模仿人类复发的HSK的许多临床和免疫学特征。 虽然目前的数据表明，初发期和复发性HSK相似，但有 在临床病理、病毒抗原分布、细胞 一些细胞因子和趋化因子在角膜内的渗透作用 和对疫苗治疗的反应，因此表明在 这两种疾病是不一样的。在过去的15年里，我们和其他几个人 实验室已经描述了关于HSK复发的大部分已知情况。 基于我们关于共刺激分子的作用的最新数据 在HSK中发挥作用，因为我们已经演示了CD28在HSK中的核心作用 调解这种疾病，但同时也参与了抑制 潜伏期后病毒自发重新激活。我们还表明CD137L是 可能参与了疾病的改善。这些数据进一步支持了这样的观点 HSK是由Th1表型的CD4细胞介导的，更重要的是， Th2T细胞与较少的疾病密切相关。为了测试这些 假设我们将：(1)确定促炎分子的作用 IL-6、KC(IL-8)、IP10(CXCL10)和CCL4在HSK复发中的作用 发病机制。(2)确定共刺激相互作用在两者中所起的作用 HSK复发和病毒潜伏期的维持。(3)我们还将确定 无论是针对或促进这些相互作用的治疗干预， 将使用疫苗接种范例来改善疾病。派生的信息 这些研究将有助于更好地理解复发的生物学机制。 小鼠身上的HSK，进而引申到人类疾病。此外，这些研究可能 可能会提出更有效的免疫疗法，旨在改善人类 HSK病。

Herpetic stromal keratitis (HSK) is a leading cause of infectious blindness in the United States. Visual loss most commonly results from recurrent stromal disease, as opposed to primary HSK and appears to be the result of immune- mediated corneal destruction. Most experimental models have focused on primary rather than recurrent keratitis. We study a model of recurrent HSK that mimics many clinical and immunological features of recurrent HSK in humans. While current data indicates that primary and recurrent HSK are similar, there are significant differences in the clinical pathology, viral antigen distribution, cellular infiltration within the cornea, importance of both some cytokines and chemokines and responses to vaccine therapy, thus suggesting that the immune responses in these two diseases is not identical. Over the past 15+ years our and a few other labs have characterized much of what is known concerning recurrent HSK. Based on our most recent data concerning the role that costimulatory molecules play in HSK as we have demonstrated the central role that CD28 plays in mediating this disease, but at the same time is involved in suppressing spontaneous viral reactivation from latency. We have also shown that CD137L is likely involved in disease amelioration. These data further support the notion that HSK is mediated by CD4+ cells of the Th1 phenotype and that more importantly, Th2 T cells are strongly associated with less disease. In order to test these hypotheses we will: (1) Determine the role that the proinflammatory molecules IL-6, KC (IL-8), IP10 (CXCL10), and CCL4 play in recurrent HSK disease pathogenesis. (2) Determine the role that co-stimulatory interactions play in both recurrent HSK and in maintenance of viral latency. (3) We will also determine whether therapeutic intervention, either targeting or promoting these interactions, will ameliorate disease using a vaccination paradigm. The information derived from these studies will lead to a better understanding of the biology of recurrent HSK in mice and by extension human disease. Furthermore, these studies could possibly suggest more effective immunotherapies designed to ameliorate human HSK disease.