T regulatory Cells in HSV Immunity and Immunopathology

HSV 免疫和免疫病理学中的 T 调节细胞

• 批准号: 7986136
• 负责人: Barry T. Rouse
• 金额: $ 35.65万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986136
• 关键词: Accounting; Affect; Antigens; Blindness; Chronic; Clinic; Commit; Cornea; Data; Disease; Epigenetic Process; Equilibrium; Event; Eye; Eye Infections; Galactose Binding Lectin; Galectin 1; Grant; Human; Immune; Immune response; Immunity; Individual; Infection; Inflammatory; Injury; Integration Host Factors; Keratitis; Lesion; Modeling; Pathogenesis; Pathology; Pattern; Pharmaceutical Preparations; Phenotype; Play; Population; Procedures; Publishing; Reaction; Regulation; Regulatory T-Lymphocyte; Role; Severities; Simplexvirus; Staging; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tissues; Transgenic Mice; Translating; Treatment Efficacy; Viral; Virus; Virus Diseases; Virus Replication; clinically relevant; design; immunopathology; immunoregulation; in vivo; mouse model; research study; response; therapeutic vaccine

DESCRIPTION (provided by applicant): Whether or not a virus infection is successfully controlled by the host or causes notable tissue damage in some or all individuals is a clinically relevant issue that lacks full understanding. In some instances, injury is a direct consequence of virus replication, but more commonly the host response to the virus accounts for much or even the majority of the tissue damage. This can be extensive and prolonged if the infection is difficult to control. Many viral and host factors influence the balance of events that culminate in immunity or pathology. In circumstances where viruses do cause exuberant tissue damage, it is important to identify the mechanisms that account for the injury that occurs and develop ways to counteract the problem. With chronic tissue damaging virus infections there is more need for therapeutic vaccines and immunomodulation therapy that can redirect established response patterns so that the tissue wounding is minimized and immunity restored. To achieve this latter objective, we hypothesize that finding a practical approach to expand the number and functions of regulatory T cells in vivo will represent a valuable means to counteract chronic inflammatory reactions caused by viruses. We choose this objective because past studies by many groups, including ourselves supported by this grant, have established that regulatory T cells of various types play a beneficial role to limit tissue damage during immune inflammatory reactions to self or extrinsic antigens that include viruses. The aims of this proposal are to evaluate procedures that will expand and activate regulatory T cells (Treg) so that the severity and duration of viral induced immunopathological lesions can be controlled. The model we shall use is a blinding immunoinflammatory lesion in the cornea of the eye that results from ocular infection with the herpes simplex virus (HSV). The disease is referred as to as stromal keratitis (SK). The experimental mouse model reflects a similar lesion caused by HSV in the human eye and which is a significant cause of blindness. Prior studies had demonstrated that the lesion severity of SK in the mouse model was influenced by FoxP3+T cells, although how or where the Treg exert their beneficial influence remains uncertain. Experiments are planned to verify the protective role of Treg at various stages of SK pathogenesis and to evaluate if the Treg that influence events during SK need to be antigen specific or not. We shall also evaluate the hypothesis that enhancing the number and function of Treg represents a valuable means of therapy that could ultimately translate to the clinic. Treg expansion will be achieved by causing conventional naove or pre-committed non-regulatory T cells to convert to become FoxP3+ and regulatory in function. This objective is supported by published and preliminary data, but the approach has not been optimized, nor have additional strategies been used that expand the converted population and cause the converted Treg to sustain their regulatory function. Experiments will be pursued to achieve the latter objectives by combining the antigen stimulation and FTY720 drug treatment that causes Treg conversion with additional maneuvers that expand Treg and stabilize their converted phenotype. Past and ongoing studies also documented that galectin-1 and galectin-9 play a significant role in modulating the expression of viral induced immunoinflammatory lesions acting at least in part by affecting Treg numbers and function. Experiments are planned to further define how galectins 1 and 9 act in vivo and might be used therapeutically to diminish the consequences of HSV induced tissue damage. The specific aims are 1 To demonstrate at which stage in SK pathogenesis Treg manipulation will influence the expression of virus induced immunopathology. 2 To develop procedures that can convert and expand uncommitted T cells to become Foxp3+Treg and show the value of this to inhibit viral induced immunoinflammatory lesions. 3 To further define the participation of galectins during the pathogenesis of SK and to determine how endogenously produced and exogenously administered galectins 1 and 9 act to modulate lesion severity. Key words immunity; immunopathology: regulatory T cells; herpes simplex virus; Stromal keratitis; galectins PUBLIC HEALTH RELEVANCE: This project is designed to explore potential clinically useful approaches that will cause the body to expand and activate a subset of T lymphocytes that will act to diminish the pathological consequences of chronic tissue damaging virus infections.

描述（由申请人提供）：病毒感染是否被宿主成功控制或在部分或所有个体中引起显著组织损伤是一个临床相关问题，缺乏充分了解。在某些情况下，损伤是病毒复制的直接后果，但更常见的是，宿主对病毒的反应占组织损伤的大部分甚至大部分。如果感染难以控制，这可能是广泛和长期的。许多病毒和宿主因素影响免疫或病理学事件的平衡。在病毒确实导致组织过度损伤的情况下，重要的是要确定导致损伤发生的机制，并开发解决问题的方法。对于慢性组织损伤病毒感染，更需要治疗性疫苗和免疫调节疗法，其可以重定向已建立的反应模式，使得组织创伤最小化并恢复免疫力。为了实现后一个目标，我们假设找到一种实用的方法来扩大体内调节性T细胞的数量和功能，这将是一种有价值的手段来抵消病毒引起的慢性炎症反应。我们选择这一目标是因为许多小组（包括我们自己）过去的研究已经确定，各种类型的调节性T细胞在对自身或外源性抗原（包括病毒）的免疫炎症反应中对限制组织损伤起着有益的作用。 该提案的目的是评估将扩增和激活调节性T细胞（Treg）的程序，以便可以控制病毒诱导的免疫病理学病变的严重程度和持续时间。我们将使用的模型是眼睛角膜中的致盲性免疫炎性病变，其由单纯疱疹病毒（HSV）眼部感染引起。这种疾病被称为基质角膜炎（SK）。实验小鼠模型反映了HSV在人眼中引起的类似病变，这是失明的重要原因。先前的研究表明，小鼠模型中SK的病变严重程度受到FoxP 3 +T细胞的影响，尽管Treg如何或在何处发挥其有益的影响仍然不确定。实验计划验证Treg在SK发病机制的各个阶段的保护作用，并评估影响SK期间事件的Treg是否需要是抗原特异性的。我们还将评估增强Treg的数量和功能代表最终可以转化为临床的有价值的治疗手段的假设。Treg扩增将通过使常规的幼稚或预定型的非调节性T细胞转化为FoxP 3+和功能上的调节性T细胞来实现。这一目标得到了已发表和初步数据的支持，但该方法尚未优化，也没有使用额外的策略来扩大转化的群体并使转化的Treg维持其调节功能。将进行实验以通过将抗原刺激和引起Treg转化的FTY 720药物治疗与扩增Treg并稳定其转化表型的额外操作组合来实现后一个目标。 过去和正在进行的研究还证明，半乳糖凝集素-1和半乳糖凝集素-9在调节病毒诱导的免疫炎性病变的表达中起重要作用，至少部分地通过影响Treg数量和功能起作用。计划进行实验以进一步确定半乳糖凝集素1和9如何在体内起作用，并可能在治疗上用于减少HSV诱导的组织损伤的后果。具体目的是1证明在SK发病机制的哪个阶段Treg操纵会影响病毒诱导的免疫病理学表达。2开发可以将未定型T细胞转化和扩增为Foxp 3 +Treg的程序，并显示其抑制病毒诱导的免疫炎症病变的价值。3进一步确定半乳糖凝集素在SK发病机制中的作用，并确定内源性产生和外源性给药的半乳糖凝集素1和9如何调节病变的严重程度。免疫;免疫病理学;调节性T细胞;单纯疱疹病毒;基质性角膜炎;半乳糖凝集素 公共卫生相关性：该项目旨在探索潜在的临床有用的方法，这些方法将导致身体扩张并激活T淋巴细胞亚群，从而减少慢性组织损伤病毒感染的病理后果。