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

眼 HSV-1、基质性角膜炎、

基本信息

批准号：
7286219
负责人：
BYOUNG S KWON
金额：
$ 21.3万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2008-12-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：单纯疱疹病毒类型1（HSV-1）角膜感染会导致在感觉中建立潜在感染和自主神经节。 HSV-1以间隔重新激活并导致复发角膜感染。角膜基质中反复的炎症会导致疱疹性基质角膜炎（HSK），一种免疫炎症过程，导致在失明中。为了获得最佳激活，T细胞还需要共刺激到抗原受体信号。已知构成性受体（例如CD28）为幼稚的T细胞提供共刺激。我们还显示了4-1BB，一个可诱导的受体，为激活和记忆T细胞提供了共刺激。但是，共刺激受体是否在急性，潜在和复发性HSV-1感染以及在HSK中尚不清楚。也不知道是否通过阻止共刺激来诱导T细胞能量可以防止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，以识别涉及HSK发病机理的因素，并研究阻断HSK共刺激的治疗潜力。提出了三个具体目的：1]检验costumulation的假设 4-1BB和CD28受体参与调节急性HSV-1感染，使用4-1BB-和/或CD28缺陷小鼠的潜伏期和复发。 2]确定共刺激受体4-1BB和CD28在发病机理中的作用 HSK。 3]检验了阻止共刺激有效的假设防止HSK。这种方法（抑制共刺激）应该是特定的，并且与使用免疫抑制药物相比，无毒。这些研究会有助于理解盲目涉及的免疫机制条件，hsk并允许制定策略以治疗和其他眼部炎症性疾病。