Mechanisms of HSK amelioration

描述（由申请人提供）：疱疹性间质角膜炎（HSK）是美国感染性失明的主要原因。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，似乎是免疫介导的角膜破坏的结果。大多数实验模型关注的是原发性角膜炎，而不是复发性角膜炎。我们研究了一个复发性HSK模型，该模型模拟了人类复发性HSK的许多临床和免疫学特征。虽然目前资料显示原发性和复发性HSK相似，但在临床病理、病毒抗原分布、角膜内细胞浸润、某些细胞因子和趋化因子的重要性以及对疫苗治疗的反应等方面存在显著差异，提示这两种疾病的免疫反应并不相同。在过去的15年里，我们和其他一些实验室已经描述了许多关于复发性HSK的已知特征。根据我们关于共刺激分子在HSK中所起作用的最新数据，我们已经证明了CD28在介导这种疾病中起核心作用，但同时也参与抑制潜伏期的自发病毒再激活。我们还表明CD137L可能参与疾病的改善。这些数据进一步支持HSK是由Th1表型的CD4+细胞介导的，更重要的是，Th2 T细胞与较少的疾病密切相关。为了验证这些假设，我们将：(1)确定促炎分子IL-6、KC （IL-8）、IP10 （CXCL10）和CCL4在复发性HSK疾病发病机制中的作用。(2)确定共刺激相互作用在复发性HSK和维持病毒潜伏期中的作用。(3)我们还将确定治疗性干预，无论是靶向还是促进这些相互作用，是否会使用疫苗接种模式来改善疾病。从这些研究中获得的信息将有助于更好地理解小鼠和人类疾病中复发性HSK的生物学。此外，这些研究可能建议设计更有效的免疫疗法来改善人类HSK疾病。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Herpes virus infection of the cornea leads to a disease termed herpetic stromal keratitis (HSK) and is a leading cause of infectious blindness and is the result of herpes-induced inflammation of the cornea. The studies in this application will address the role that proteins which activate and control inflammatory immune responses play during HSK with an eye towards developing possible therapies for this disease. We will also test a vaccine construct that we believe will lead to significantly less corneal disease during infections with herpes virus.