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

描述：持续的病毒感染(如丙型肝炎病毒和艾滋病毒)仍然是人类健康的主要问题，并没有屈服于传统的疫苗生产方法。T细胞反应被认为在对抗许多持续性病毒感染的免疫反应中发挥关键作用，也是许多候选疫苗的重点。一个关键的问题是我们对感染后的T细胞反应在什么情况下产生保护作用以及在什么情况下导致病理的理解不够全面。我们的方法包括从目前的定性描述到定量模型，以了解持续病毒感染期间病毒和T细胞反应的动态。定量模型的发展在免疫学和发病机制中特别重要，原因有两个：第一，病毒种群和适应性免疫反应的T细胞在感染过程中可以变化一千倍以上；第二，系统组件(病原体、免疫反应的细胞和分子)之间的非线性相互作用可能导致复杂的动力学，仅凭定性描述是不能直观的。由于生物系统的复杂性，对数学模型进行验证是非常必要的。我们将通过与小鼠的淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染的实验数据对抗来测试我们的模型。我们将通过将模型与持续LCMV感染期间病毒和免疫反应的动态数据进行匹配，以及生成和实验测试模型的新预测来验证我们的模型。LCMV系统特别适合于研究疫苗接种后的保护和病理，因为定义的病毒特异性T细胞群体易于过继转移到受体小鼠中，允许操纵T细胞的数量和属性以及宿主环境，从而有助于剖析控制VIUS和减少病理的因素。我们将应用我们的定量数学模型来探索针对持久性病原体的治疗和疫苗接种的新策略。这些策略包括联合使用抗病毒药物和免疫调节抗体，以重新激活T细胞反应。我们将在LCMV实验系统上对这些策略进行测试。

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.