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Mechanisms of HSK amelioration

HSK改善机制

基本信息

批准号：
8597431
负责人：
Patrick M Stuart
金额：
$ 33.08万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8597431
关键词：
Address Antigens Biology Blindness CCL2 gene CCL3 gene CCL4 gene CD28 gene CD4 Positive T Lymphocytes CD80 gene CXCR3 gene Cell surface Cells Cellular Infiltration Cicatrix Clinical Clinical Pathology Comparative Study Cornea Corneal Diseases Country Data Defective Viruses Dendrites Disease Epithelial Experimental Models Eye Generations Genes Glycoproteins Herpesviridae Herpesvirus 1 Herpetic Keratitis Human IL8 gene Immune Immune response Immunotherapy Incidence Infection Inflammation Inflammatory Inflammatory Infiltrate Interleukin-6 Keratitis Keratoplasty Laboratories Lead Macrophage Inflammatory Protein-1 Maintenance Mediating Modeling Molecular Profiling Mus NIH Mouse Pathogenesis Pathology Phenotype Play Proteins Recording of previous events Recurrence Recurrent disease Relative (related person)Reporting Resistance Role Simplexvirus T-Lymphocyte TNFRSF5 gene TNFSF5 gene Testing Therapeutic Intervention Time United States Vaccinated Vaccination Vaccine Therapy Vaccines Viral Viral Antigens Virus Virus Diseases Virus Latency Woman Work base chemokine cytokine design genital herpes human disease improved macrophage neovascularization prevent prophylactic reactivation from latency response success vaccine evaluation virus host interaction

项目摘要

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.

单纯疱疹病毒性角膜炎(HSK)是引起儿童传染性失明的主要原因之一。美国。视力丧失最常见的原因是复发性间质疾病，与原发单纯疱疹病毒不同，似乎是免疫- 介导性角膜破坏。大多数实验模型都专注于原发而不是复发性角膜炎。我们研究了一个复发的HSK模型模仿人类复发的HSK的许多临床和免疫学特征。虽然目前的数据表明，初发期和复发性HSK相似，但有在临床病理、病毒抗原分布、细胞一些细胞因子和趋化因子在角膜内的渗透作用和对疫苗治疗的反应，因此表明在这两种疾病是不一样的。在过去的15年里，我们和其他几个人实验室已经描述了关于HSK复发的大部分已知情况。基于我们关于共刺激分子的作用的最新数据在HSK中发挥作用，因为我们已经演示了CD28在HSK中的核心作用调解这种疾病，但同时也参与了抑制潜伏期后病毒自发重新激活。我们还表明CD137L是可能参与了疾病的改善。这些数据进一步支持了这样的观点 HSK是由Th1表型的CD4+细胞介导的，更重要的是， Th2T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)、IP10(CXCL10)和CCL4在HSK复发中的作用发病机制。(2)确定共刺激相互作用在两者中所起的作用 HSK复发和病毒潜伏期的维持。(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，将使用疫苗接种范例来改善疾病。派生的信息这些研究将有助于更好地理解复发的生物学机制。小鼠身上的HSK，进而引申到人类疾病。此外，这些研究可能可能会提出更有效的免疫疗法，旨在改善人类 HSK病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CD137 costimulation is associated with reduced herpetic stromal keratitis and with developing normal CD8+ T cells in trigeminal ganglia.

CD137 共刺激与疱疹性基质角膜炎的减少以及三叉神经节中正常 CD8 T 细胞的发育有关。

DOI：
10.1099/jgv.0.001756
发表时间：
2022
期刊：
The Journal of general virology
影响因子：
0
作者：
Yin,Xiao-Tang;Baugnon,NicholasK;Krishnan,Rohini;Potter,ChloeA;Yarlagadda,Sudha;Keadle,TammieL;Stuart,PatrickM
通讯作者：
Stuart,PatrickM

CD28 Costimulation Is Required for Development of Herpetic Stromal Keratitis but Does Not Prevent Establishment of Latency.

CD28 共刺激对于疱疹性基质性角膜炎的发展是必需的，但不能阻止潜伏期的建立。

DOI：
10.1128/jvi.00659-19
发表时间：
2019
期刊：
Journal of virology
影响因子：
5.4
作者：
Yin,Xiao-Tang;Baugnon,NicholasK;Potter,ChloeA;Tai,Shannon;Keadle,TammieL;Stuart,PatrickM
通讯作者：
Stuart,PatrickM

Herpes simplex keratitis: challenges in diagnosis and clinical management.

单纯疱疹性角膜炎：诊断和临床管理方面的挑战。