QUANTIFYING THE BALANCE BETWEEN VACCINE-INDUCED T CELL PROTECTION AND PATHOLOGY

量化疫苗诱导的 T 细胞保护与病理学之间的平衡

• 批准号: 9204367
• 负责人: RUSTOM NOSHIR ANTIA
• 金额: $ 38.7万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204367
• 关键词: Acute; Address; Adoptive Transfer; Antibodies; Antigens; Antiviral Agents; Avidity; Biological Models; Blocking Antibodies; CD8-Positive T-Lymphocytes; Cell division; Cells; Combined Modality Therapy; Complex; Cytoprotection; Data; Death Rate; Development; Dissection; Dose; Drug usage; Environment; Epitopes; Equilibrium; Generations; Grant; HIV; Health; Hepatitis C; Human; Immune; Immune response; Immunity; Immunology; Infection; Infection Control; Intervention; Lymphocyte Count; Lymphocytic choriomeningitis virus; Measurement; Memory; Modeling; Mus; Outcome; PDCD1LG1 gene; Pathogenesis; Pathology; Pathway interactions; Play; Population; Property; Proteins; Ribavirin; Role; System; T Virus; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Vaccination; Vaccines; Variant; Viral load measurement; Virus; Virus Diseases; Work; adaptive immune response; base; biological systems; cell killing; clinical application; exhaustion; experimental study; habituation; killings; mathematical model; mouse model; novel; novel strategies; pathogen; public health relevance; response; treatment strategy; vaccination strategy; vaccine candidate; vaccine-induced immunity

DESCRIPTION: Persistent virus infections (such as the hepatitis C virus and HIV) remain major problems for human health, and have not yielded to traditional approaches for the generation of vaccines. T cell responses are thought to play a key role in the immune response against many persistent viral infections, and are the focus of many vaccine candidates. A key problem is our incomplete understanding of the circumstances under which the T cell response following infection results in protection and when it causes pathology. Our approach involves going from the current qualitative description to a quantitative models for understanding the dynamics of the virus and T cell response during persistent virus infections. The development of quantitative models is particularly important in immunology and pathogenesis for two reasons: first, the populations of virus and the T cells of the adaptive immune response can change over a thousand fold in magnitude during the course of infection; second, the non-linear interactions between the components of the system (pathogens, cells and molecules of the immune response) can result in complex dynamics that cannot be intuited from qualitative descriptions alone. Because of the complexity of biological systems, it is essential for mathematical models to be validated. We will test our models by confronting them with experimental data from Lymphocytic choriomeningitis virus (LCMV) infections of mice. We will validate our models by fitting the models to data on the dynamics of virus and immune responses during persistent LCMV infections, as well as generating and experimentally testing novel predictions of the model. The LCMV system is particularly amenable to studying protection and pathology following vaccination because the ease of adoptive transfer of defined virus-specific T cell populations into recipient mice allows manipulation of both the numbers and properties of the T cells, as well as the host environment, thus facilitating dissection of the factors that control vius and reduce pathology. We will apply our quantitative mathematical models to explore novel strategies for treatment and vaccination against persistent pathogens. These strategies involve the combined use of antiviral drugs and immune-modulating antibodies that reactivate the T cell response. We will test these strategies in the LCMV experimental system.

描述：持续性病毒感染（例如丙型肝炎病毒和艾滋病毒）仍然是人类健康的主要问题，并且尚未屈服于传统的疫苗产生方法。 T细胞反应被认为在许多持续性病毒感染的免疫反应中起关键作用，并且是许多候选疫苗的重点。一个关键问题是我们对感染后T细胞反应导致保护以及何时引起病理的情况不完全理解。我们的方法涉及从当前的定性描述到定量模型，以了解持续性病毒感染期间病毒和T细胞反应的动力学。定量模型的发展在免疫学和发病机理中尤为重要，原因有两个：首先，在感染过程中，病毒和自适应免疫反应的T细胞的大小可能会变化超过一千倍。其次，系统组件之间的非线性相互作用（病原体，细胞和免疫反应的分子）可能会导致复杂的动力学，而这些动力学不能单独从定性描述中直觉。由于生物系统的复杂性，对数学模型的验证至关重要。我们将通过与小鼠的淋巴细胞脉络膜宿主炎病毒（LCMV）感染的实验数据相遇来测试我们的模型。我们将通过将模型拟合到持续性LCMV感染期间病毒和免疫反应动力学的数据来验证我们的模型，并生成和实验测试模型的新预测。 LCMV系统尤其适合研究疫苗接种后的保护和病理学，因为将定义的病毒特异性T细胞群体的继承转移到受体小鼠中允许操纵T细胞的数量和特性，以及宿主环境的数量和特性，从而促进控制VIUS和减少病理学的因素的剥离。我们将运用定量数学模型来探索针对持续病原体的治疗和疫苗接种的新策略。这些策略涉及抗病毒药物的综合使用以及重新激活T细胞反应的免疫调节抗体。我们将在LCMV实验系统中测试这些策略。