Ocular HSV-1, Stromal Keratitis, & T Cell Costimulation

性状（由申请人提供）：单纯疱疹病毒1型（HSV-1） 角膜感染导致在感觉器官中建立潜伏感染 和自主神经节。HSV-1间歇性重新激活， 角膜感染角膜基质的反复炎症可导致 单纯疱疹性角膜基质炎（HSK）是一种免疫炎症过程， 失明。为了达到最佳活化，T细胞还需要共刺激。 抗原受体信号。已知组成型受体如CD 28 为初始T细胞提供共刺激。我们还表明，4-1BB， 可诱导受体，为活化和记忆T细胞提供共刺激。 然而，共刺激受体是否在急性、潜伏和 复发性HSV-1感染和HSK中的HSV-1感染尚不清楚。尚不清楚 通过阻断共刺激诱导T细胞能量是否可以预防HSK。 我们的目标是确定T细胞共刺激分子在疱疹中的作用 感染，以确定参与HSK发病机制的因素， 探讨阻断共刺激对HSK的治疗潜力。 提出了三个具体的目标：1）检验共刺激分子的假设， 受体4-1BB和CD 28参与调节急性HSV-1感染， 潜伏期和复发。2]确定 共刺激受体4-1BB和CD 28在原发性肝癌发病机制中的作用 HSK。3]测试阻断共刺激在以下方面有效的假设： 预防HSK。 这种方法（共刺激的抑制）应该是特异性的， 与使用免疫抑制药物相比是无毒的。这些研究将 有助于理解致盲眼的免疫机制 条件，HSK，并允许制定治疗策略， 和其它眼部炎性疾病。

DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) corneal infection leads to establishment of a latent infection in the sensory and autonomic ganglia. HSV-1 reactivates at intervals and causes recurrent corneal infection. Repeated inflammation in the corneal stroma can lead to herpetic stromal keratitis (HSK), an immune inflammatory process that results in blindness. For optimal activation, T cells require costimulation in addition to antigen receptor signals. Constitutive receptors such as CD28 are known to provide costimulation to naive T cells. We have also shown that 4-1BB, an inducible receptor, provides costimulation to activated and memory T cells. However, whether costimulatory receptors play a role in acute, latent, and recurrent HSV-1 infection, and in HSK, is not known. It is also not known whether induction of T-cell energy by blocking costimulation can prevent HSK. Our goals are to determine the role of T-cell costimulatory molecules in herpes infection, to identify factors involved in the pathogenesis of HSK, and to investigate the therapeutic potential of blocking costimulation in HSK. Three specific aims are proposed: 1] Test the hypothesis that the costimulatory receptors, 4-1BB and CD28, are involved in modulating acute HSV-1 infection, latency, and recurrence using 4-1BB- and/or CD28-deficient mice. 2] Determine the roles of the costimulatory receptors 4-1BB and CD28 in the pathogenesis of HSK. 3] Test the hypothesis that blocking costimulation is effective in preventing HSK. This approach (inhibition of costimulation) should be both specific and nontoxic, compared to the use of immunosuppressive drugs. These studies will aid in understanding the immunological mechanisms involved in the blinding eye condition, HSK, and allow development of strategies for the treatment of this and other ocular inflammatory diseases.