Mechanisms of HSK amelioration

单纯疱疹性角膜基质炎（HSK）是一种主要的传染性失明的原因， 美国的视力丧失最常见的原因是复发性间质 疾病，而不是原发性HSK，似乎是免疫的结果- 介导的角膜破坏。大多数实验模型都集中在 而不是复发性角膜炎。我们研究了一个复发性HSK模型， 与人类复发性HSK的许多临床和免疫学特征相似。 虽然目前的数据表明，原发性和复发性HSK是相似的， 在临床病理学、病毒抗原分布、细胞免疫学和免疫学方面存在显著差异。 角膜内浸润，一些细胞因子和趋化因子的重要性 和对疫苗治疗的反应，从而表明， 这两种疾病并不相同。在过去的15年里，我们和其他一些人 实验室已经确定了许多关于复发性HSK的特征。 根据我们最近的数据，共刺激分子 我们已经证明了CD 28在HSK中的核心作用， 但与此同时，它也参与了抑制 从潜伏期自发病毒再激活。我们还表明，CD 137 L是 可能与疾病改善有关。这些数据进一步支持了以下观点： HSK由Th 1表型的CD 4+细胞介导，更重要的是， Th 2 T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）、IP 10（CXCL 10）和CCL 4在复发性HSK疾病中的作用 发病机制(2)确定共刺激相互作用在这两个过程中的作用。 复发性HSK和维持病毒潜伏期。(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， 将通过接种疫苗来改善疾病。导出的信息 从这些研究将导致更好地了解生物学的复发性 HSK在小鼠和人类疾病的延伸。此外，这些研究可以 可能提示更有效的免疫疗法，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.