To model crossreacting T-memory of virus-infected mice

模拟病毒感染小鼠的交叉反应 T 记忆

• 批准号: 7102281
• 负责人: Franco Celada
• 金额: $ 50.27万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102281
• 关键词: T cell receptor; T lymphocyte; anergy; apoptosis; biological models; cross immunity; developmental immunology; host organism interaction; immunologic memory; laboratory mouse; leukocyte activation /transformation; mathematical model; model design /development; virus diseases

DESCRIPTION (provided by applicant): The present project is a competitive continuation of grant Al 054455-01, and seeks to develop the IMMSIM computer model of host responses to its full potential as a supporting and predictive tool for infection research. This effort is carried out through a close multidisciplinary cooperation of modelers with immunologists working with viruses of the pox and arenavirus family, which both belong to the A category; therefore, the simulation may become of interest in the framework of the current NIAID Biodefense Research protocols. Two issues are central for the understanding of anti-virus responses: the changeable clonal hierarchy of T cell memory introduced by viral crossreactivity and the possible changes in efficiency of the defense. In both areas breakthroughs have been made in the last few years, which will eventually have important consequences in the planning of protection strategies. By incorporating these new T cell features, the model has enhanced its ability to simulate both acute and memory immune responses to infection. Hence the results of each series of runs can serve as verification of an hypothesis generated in vivo, or as the source of a new predictive hypothesis that will have to be challenged by in vivo experiments. The study will focus on: a) the nature of clonal dominance and clonal attrition, asking whether the signal for induced apoptosis is originated by competition for local resources or by global population constraints; b) the reasons for the apparent asymmetry of the effects of crossreactions, when two viral infections are enacted in reversed order; c) the shrinking of the clonal memory repertoire caused by heterologous challenge and/or attrition, and the evaluation of the biological consequences; and d) the possible advantage of using heterologous challenges (T- but not B-crossreacting) that could avoid neutralization by circulating antibodies and reach the immunocompetent cells with a full dose of antigenic stimulus, thus yielding a more predictable protection. Thus we propose the following specific aims: 1) to increase IMMSIM's modelling flexibility by incorporating the capability to modulate the level of T activation in relation to a number of factors of the stimulus; create a sufficiently large and degenerate repertoire of clonotypes in order to model T cell specificity and crossreactivity, in particular to simulate private specificities' responses to "unrelated" viruses in vivo. 2) To run in machina immune responses to viral infections; to study the cases of npnsymmetric crossreaction with the relative affinity of clones to the infecting virus. 3) To quantify by in vivo and in vitro experiments the two factors concurring in the phenomenon of attrition. 4) To compare, in parallel in vivo-in machina procedures, the relative efficiency of homologous or heterologous T-cell-crossreactive (but B-cell- foreign) challenges to organisms pre-sensitized to a given virus. The relevance of this study to public health and to medicine in general stems from the introduction, to the well-established practice of vaccination, of new findings regarding cross-reactivity between different viruses and between the immune responses to different viruses. In particular, this study focuses on the pox and arena viruses, which have been designated as "A-category" public health concerns.

描述(由申请人提供)：本项目是资助金Al 054455-01的竞争性延续，旨在开发宿主反应的IMMSIM计算机模型，以充分发挥其作为感染研究的支持和预测工具的潜力。这项工作是通过模型师与免疫学家密切的多学科合作来进行的，这些免疫学家研究的都是属于A类的痘和禽流感病毒家族的病毒；因此，模拟可能成为当前NIAID生物防御研究协议框架中的感兴趣的对象。两个问题是理解抗病毒反应的核心：由病毒交叉反应引入的T细胞记忆的多变的克隆性层次和防御效率的可能变化。过去几年在这两个领域都取得了突破，这最终将对保护战略的规划产生重要影响。通过纳入这些新的T细胞特征，该模型增强了模拟感染的急性和记忆免疫反应的能力。因此，每一系列运行的结果可以作为体内产生的假说的验证，或者作为必须通过体内实验挑战的新预测性假说的来源。这项研究将集中于：a)克隆显性和克隆消耗的性质，询问诱导细胞凋亡的信号是由局部资源竞争还是全球种群限制产生的；b)当两种病毒感染以相反的顺序发生时，交叉反应效果明显不对称的原因；c)异源挑战和/或克隆消耗引起的克隆记忆库的萎缩，以及生物学后果的评估；以及d)使用异源挑战(T-但不是B-交叉反应)的可能优势，这种挑战可以避免循环抗体的中和，并通过全量抗原刺激到达免疫活性细胞，从而产生更可预测的保护。因此，我们提出了以下具体目标：1)通过结合与刺激的一些因素相关的T激活水平的调节能力来增加IMMSIM的建模灵活性；创建足够大的和退化的克隆型谱，以便对T细胞特异性和交叉反应进行建模，特别是模拟体内个体特异性对“无关”病毒的反应。2)运行对病毒感染的机械免疫反应；研究克隆对感染病毒的相对亲和力与非对称交叉反应的情况。3)通过体内实验和体外实验对两种因素同时存在的磨损现象进行量化。4)比较同源或异种T细胞交叉反应(但外源B细胞)对对给定病毒预先敏感的生物体的相对效率。这项研究与公共卫生和一般医学的相关性源于引入了关于不同病毒之间以及对不同病毒的免疫反应之间的交叉反应的新发现，以及疫苗接种的成熟做法。特别是，这项研究的重点是痘和竞技场病毒，这两种病毒已被指定为A类公共卫生问题。