Define the role of dendritic cells in HTLV-1 associated neuroinflammatory disease

定义树突状细胞在 HTLV-1 相关神经炎症性疾病中的作用

• 批准号: 7750583
• 负责人: Pooja Jain
• 金额: $ 37.36万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750583
• 关键词: Activated Lymphocyte; Adult; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antiviral Agents; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Blocking Antibodies; CD58 gene; CD8B1 gene; Cell Communication; Cell Culture System; Cell physiology; Cells; Characteristics; Chronic; Clinical; Complex; Cross Presentation; Cytotoxic T-Lymphocytes; Demyelinating Diseases; Dendritic Cells; Dendritic cell activation; Development; Disease; Disease Progression; Etiology; Failure; Generations; HIV-1; HLA A*0201 antigen; Hepatitis Viruses; Human T-lymphotropic virus 1; Immune; Immune response; Immune system; Immunity; Immunodominant Epitopes; Immunologic Memory; Immunologics; In Vitro; Individual; Infection; Inflammatory; Investigation; Lead; Light; Link; MHC Class II Genes; Mediating; Modeling; Molecular Mimicry; Multiple Sclerosis; Neuraxis; Neurons; Neuropathogenesis; Pathogenesis; Patients; Peptides; Peripheral Blood Mononuclear Cell; Physiological; Play; Primary Cell Cultures; Process; Proteins; Public Health; Regulation; Research; Risk Factors; Role; Route; Satellite Viruses; Severity of illness; Signal Transduction; Simplexvirus; Spinal Cord Diseases; Synapses; T cell response; T-Cell Leukemia; T-Lymphocyte; Taxes; Therapeutic; Translational Research; Tropical Spastic Paraparesis; Viral; Viral Load result; Virus; Virus Diseases; acquired immunity; cell injury; exhaust; hnRNP protein A1; human CREB1 protein; lymphocyte proliferation; macrophage; nervous system disorder; neuroinflammation; novel vaccines; pathogen; peripheral tolerance; prevent; public health relevance; research and development; response

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are the most potent antigen presenting cells and are recognized as key regulators of the immune system, linking both stimulatory and inhibitory components of normal immunity. While DCs are well characterized with respect to primary and secondary immune responses, their unique role in coordinating central and peripheral tolerance is not fully delineated. It is increasingly evident that the failure of DCs' ability to maintain tolerance can lead to autoimmune and/or inflammatory diseases. Consequently, human T cell leukemia virus type 1 (HTLV-1) has been used as a model pathogen to explore the role of DCs in virus- induced neuroinflammation. HTLV-1 is the etiologic agent of two immunologically distinct diseases; adult T cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic demyelinating disease with underlying autoimmune condition in the central nervous system with similarities to multiple sclerosis. The progression of HAM/TSP is characterized by an intense proliferation of chronically activated CD8+ cytotoxic T lymphocytes (CTLs), 90% of which are specific for the HTLV-1 transactivator protein Tax. Several clinical observations suggest that Tax-specific CTL response is at best ineffective and may actually be detrimentally contributing to the neuropathogenesis of HAM/TSP by cross-reacting with neuronal antigens or through bystander cell damage. The genesis (antigen presentation and costimulation), priming (normal or defective), and quality (effector versus exhausted) of this hyperactivated CTL response remain incompletely characterized. DCs are of particular importance with respect to HTLV-1 neuropathogenesis as the development of HAM/TSP is associated with rapid maturation of DCs. HTLV-1 is also known to infect DCs both in vitro and in HAM/TSP patients suggesting that DCs play a critical role in HAM/TSP pathogenesis. The HYPOTHESIS of this proposal is that continuous presentation of Tax peptide by activated DCs to naive T cells and modulation of DC functions by Tax play important role in the induction and regulation of Tax-specific CTL response characteristic of HAM/TSP. The SPECIFIC AIMS to this hypothesis will 1) define the process involved in Tax presentation during direct DC infection and cross-presentation from HTLV-1-infected T cells with respect to the alterations in the biologic, physiologic, and immunologic function of DCs and induction of Tax-specific CTL response; and 2) utilize ex vivo analyses to validate the central role of DCs in regulating antiviral efficacy of CD8+ T cells in HAM/TSP patients within the context of proviral load and Tax expression, the two major risk factors in disease progression. Collectively, these studies will define the involvement of DCs in a virus-associated autoimmune/neuroinflammatory disease and highlight critical functional interactions among immune cells during acquired immunity to a viral agent. Additional information derived from these studies will facilitate the translational research development of novel vaccine and therapeutic initiatives to prevent and/or treat HTLV-1-induced neuroinflammatory disease as well as similar diseases of other etiologies. PUBLIC HEALTH RELEVANCE: The proposed studies are relevant to public health and will reveal significant information concerning the dendritic cells-regulated T cell responses during complex autoimmune/neuroinflammatory diseases such as HAM/TSP and multiple sclerosis. Additionally the results of these studies will shed light on the dynamics of immune cell interactions during chronic viral infections such as HTLV-1, HIV-1, hepatitis virus and herpes simplex virus.

描述（由申请人提供）：树突状细胞（DC）是最有效的抗原呈递细胞，被认为是免疫系统的关键调节因子，连接正常免疫的刺激和抑制成分。虽然 DC 在初级和次级免疫反应方面得到了很好的表征，但它们在协调中枢和外周耐受方面的独特作用尚未完全阐明。越来越明显的是，树突状细胞维持耐受能力的失败可能导致自身免疫和/或炎症性疾病。因此，人类 T 细胞白血病病毒 1 型 (HTLV-1) 已被用作模型病原体来探索 DC 在病毒诱导的神经炎症中的作用。 HTLV-1 是两种免疫学上不同的疾病的病原体；成人 T 细胞白血病和 HTLV-1 相关脊髓病/热带痉挛性截瘫 (HAM/TSP)。 HAM/TSP 是一种慢性脱髓鞘疾病，具有中枢神经系统潜在自身免疫性疾病，与多发性硬化症相似。 HAM/TSP 的进展特点是慢性激活的 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 剧烈增殖，其中 90% 对 HTLV-1 反式激活蛋白 Tax 具有特异性。一些临床观察表明，Tax 特异性 CTL 反应充其量是无效的，实际上可能通过与神经元抗原交叉反应或通过旁观者细胞损伤，对 HAM/TSP 的神经发病机制产生有害影响。这种过度激活的 CTL 反应的起源（抗原呈递和共刺激）、启动（正常或有缺陷）和质量（效应物与耗尽）仍未完全表征。 DC 对于 HTLV-1 神经发病机制特别重要，因为 HAM/TSP 的发育与 DC 的快速成熟相关。 HTLV-1 还已知在体外和 HAM/TSP 患者中感染 DC，这表明 DC 在 HAM/TSP 发病机制中发挥着关键作用。该提案的假设是，激活的 DC 向初始 T 细胞持续呈递 Tax 肽以及 Tax 对 DC 功能的调节在 HAM/TSP 的 Tax 特异性 CTL 反应特征的诱导和调节中发挥着重要作用。该假设的具体目标将 1) 定义直接 DC 感染期间的 Tax 呈递过程以及 HTLV-1 感染的 T 细胞的交叉呈递过程，涉及 DC 的生物学、生理学和免疫功能的改变以及诱导特定税收的 CTL 响应； 2) 利用离体分析来验证 DC 在调节 HAM/TSP 患者中 CD8+ T 细胞的抗病毒功效方面的核心作用，其中原病毒载量和 Tax 表达是疾病进展的两个主要危险因素。总的来说，这些研究将定义树突状细胞在病毒相关自身免疫/神经炎症疾病中的参与，并强调在对病毒因子获得性免疫过程中免疫细胞之间的关键功能相互作用。从这些研究中获得的更多信息将促进新型疫苗和治疗方案的转化研究开发，以预防和/或治疗 HTLV-1 诱导的神经炎症性疾病以及其他病因的类似疾病。公共健康相关性：拟议的研究与公共健康相关，并将揭示有关复杂自身免疫/神经炎症疾病（例如 HAM/TSP 和多发性硬化症）期间树突状细胞调节的 T 细胞反应的重要信息。此外，这些研究的结果将揭示慢性病毒感染（如 HTLV-1、HIV-1、肝炎病毒和单纯疱疹病毒）期间免疫细胞相互作用的动态。