Quantitative models of CD8+ T-cell memory

描述(申请人提供)：虽然免疫记忆是脊椎动物免疫反应的中心特征，但许多基本问题在很大程度上仍未得到解答。例如，我们真的不知道在没有与病原体重新刺激的情况下，给定病原体的记忆细胞群会维持多久，或者记忆的衰退如何依赖于接触新的病原体。我们想要这些问题的定量答案，这需要发展数学模型。模型需要与实验接触。要做到这一点，需要开发工具来分析实验数据(如CFSE数据)，以允许模型得到验证。我们的长期目标是建立一幅免疫记忆如何发挥作用的量化图景。这样的图景对于设计各种情况下的疫苗接种方案很重要，例如在人口老龄化的情况下。具体目标1：我们将开发工具，从CFSE测量中定量描述异质细胞群体的分裂和死亡(它告诉我们细胞的数量以及它们经历的分裂数量)。具体目标2：我们将开发和验证CD8 T细胞记忆寿命的模型。这一具体目标有三个组成部分。1.我们将在实验上验证我们目前的模型(在我们之前的拨款中制定)。2.到目前为止开发的模型在几年的时间范围内有效。我们将扩展该模型，以生成对人类寿命的免疫记忆的更完整描述。我们将通过开发考虑交叉反应刺激和复制衰老的模型来实现这一点。3.我们将通过考虑老龄化人口的记忆力丧失、最佳强化策略以及多种儿童疫苗的交付顺序来考虑我们的模型对疫苗接种的影响。

DESCRIPTION (provided by applicant): While immune memory is a central feature of the immune response of vertebrates, many fundamental questions remain largely unanswered. For example we don't really know how long memory cell populations for a given pathogen will be maintained in the absence of restimulation with that pathogen, or how the decline of memory depends on exposure to new pathogens. We would like quantitative answers to these questions, and this requires the development of mathematical models. Models need to be brought into contact with experiments. To do this one needs to develop tools to analyze experimental data (such as CFSE data) in ways which allow the models to be validated. Our long-term goal is to establish a quantitative picture of how immune memory works. Such a picture is important for the design of vaccination protocols in various situations, such as in an aging population. Specific Aim 1: We will develop tools to quantitatively describe division and death of a heterogeneous population of cells from CFSE measurements (which tells us the number of cells as well as the number of divisions they have undergone). Specific Aim 2: We will develop and validate models for the longevity of CD8+ T cell memory. There are three components to this specific aim. 1. We will experimentally validate our current model (formulated in our previous grant). 2. The model developed so far works over the time scale of a few years. We will extend the model to generate a more complete description of immunological memory over the lifespan of humans. We will do this by developing models which consider cross-reactive stimulation and replicative senescence. 3. We will consider the implications of our models for vaccination by considering the loss of memory in an ageing population, the optimal boosting strategy as well as the order of delivery of multiple childhood vaccines.