Amelioration of recurrent herpes keratitis

描述（由申请人提供）：疱疹性基质角膜炎（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基质疾病，而不是原发性HSK，似乎是免疫介导的角膜破坏的结果。大多数实验模型都集中在原发性而不是复发性角膜炎。我们研究了一种在近交系NIH小鼠中复发性HSK的模型，该模型模仿了人类复发性HSK的许多临床和免疫学特征。虽然目前的数据表明，原发性和复发性HSK是相似的，但在临床病理学、病毒抗原分布和角膜内细胞浸润以及对疫苗治疗的反应方面存在显著差异，这表明这两种疾病的免疫反应并不相同。在过去的3年多的目前的赠款，我们已经报告：1）IL- 1和TNF α是必要的复发性疾病。2)复发性HSK小鼠角膜中存在Th 1和Th 2细胞混合群。3)复发性HSK对CD 4和CD 8 T细胞的需求因小鼠品系而异。4)我们可以通过接种突变的HSV-1病毒成功地改善疾病。基于我们的研究结果和从其他人的工作中所知道的，我们建议进一步测试的假设，复发性HSK主要是由CD 4 + T细胞的Th 1表型介导的。为了验证这一假设，我们将：（1）确定IL-6和趋化因子在复发性疾病中的作用。(2)确定需要哪些共刺激相互作用来激活和再刺激介导复发性HSK的细胞，以及针对这些相互作用的治疗干预是否会改善疾病。(3)在用野生型HSV-1感染之前（预防性）和之后（治疗性），表征用HSV-1突变株接种小鼠产生的免疫应答，着眼于确定该免疫应答是否涉及选择性刺激Th 2细胞。并确定疫苗接种是否减少了潜伏感染的神经元的数量。(4)使用HSV-1和OVA特异性TCR转基因T细胞（DO-11.10、OT-I、OT-II）的卵清蛋白（OVA）表达株开发小鼠模型，以表征病毒假抗原特异性T细胞的活化、迁移、细胞因子谱和可能的耐受化方案。从这些研究中获得的信息将导致更好地了解小鼠复发性HSK的生物学，并扩展到人类疾病。此外，这些研究可能会提出更有效的免疫疗法，旨在改善人类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 in inbred NIH mice 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 and cellular infiltration within the cornea, and responses to vaccine therapy suggesting that the immune responses in these two diseases is not identical. During the past 3+ years of the current grant we have reported: 1) That IL- 1 and TNFalpha are necessary for recurrent disease. 2) That there is a mixed population of Th1 and Th2 cells present in the corneas of mice with recurrent HSK. 3) That recurrent HSK has variable requirements for CD4 and CD8 T cells that depend on mouse strain. 4) That we can successfully ameliorate disease by vaccination with mutant HSV-1 viruses. Based on our results and what is known from others work we propose to further test the hypothesis that recurrent HSK is primarily mediated by CD4+ T cells of the Th1 phenotype. In order to test this hypothesis we will: (1) Determine the role that IL-6 and chemokines play in recurrent disease. (2) Determine which co stimulatory interactions are needed to activate and restimulate the cells that mediate recurrent HSK and whether therapeutic intervention targeting these interactions will ameliorate disease. (3) Characterize the immune response generated by vaccination with mutant strains of HSV-1 in mice both prior to (prophylactic) and after (therapeutic) infection with wild-type HSV-1 with an eye towards determining if that immune response involves the selective stimulation of Th2 cells. And to determine whether vaccination reduces the number of latently infected neurons. (4) Develop a mouse model using ovalbumin (OVA) expressing strains of HSV-1 and OVA-specific TCR transgenic T cells (DO-11.10, OT-I, OT-II) to characterize the activation, migration, cytokine profile, and possible tolerization protocols of viral pseudo-antigen specific T cells. 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.