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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

基本信息

批准号：
7677883
负责人：
Franco Celada
金额：
$ 49.19万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7677883
关键词：
Accounting Acute Affinity Antibodies Antigen-Presenting Cells Antigens Antiviral Agents Apoptosis Area Arenavirus Avidity B-Lymphocytes Binding Biological Case Study Categories Cell Death Cells Computer Simulation Dose Epitopes Evaluation Family Frequencies Grant Immune Immune response Immunocompetent Immunologist In Vitro Infection Interdisciplinary Study Interferons Lymphocytic choriomeningitis virus Medicine Memory Memory Loss Modeling Mus National Institute of Allergy and Infectious Disease Nature Organism Pichinde virus Population Poxviridae Procedures Protocols documentation Public Health Publications Relative (related person)Research Resources Role Running Scientist Series Signal Transduction Simulate Source Specificity Stimulus T memory cell T-Cell Immunologic Specificity T-Lymphocyte Time Vaccination Vaccinia virus Viral Virus Virus Diseases Work biodefense cross reactivity flexibility in vivo interest multidisciplinary receptor research study response simulation stem tool trait

项目摘要

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。这项工作是通过建模者与免疫学家的密切多学科合作进行的，这些免疫学家与痘病毒和沙粒病毒家族的病毒一起工作，这两种病毒都属于A类;因此，模拟可能会在当前NIAID生物防御研究协议的框架内变得有趣。两个问题是理解抗病毒反应的核心：由病毒交叉反应性引入的T细胞记忆的可变克隆层次和防御效率的可能变化。过去几年来，这两个领域都取得了突破，最终将对保护战略的规划产生重要影响。通过结合这些新的T细胞特征，该模型增强了模拟急性和记忆免疫反应的能力。因此，每个系列运行的结果可以作为体内生成的假设的验证，或者作为必须通过体内实验挑战的新预测假设的来源。这项研究将侧重于：a）克隆优势和克隆损耗的性质，询问诱导细胞凋亡的信号是由对局部资源的竞争还是由全局种群约束引起的; B）当两种病毒感染以相反的顺序发生时，交叉反应的效应的明显不对称的原因; c）异源挑战和/或磨损引起的克隆记忆库的缩小，以及生物学后果的评估;和d）使用异源攻击（T-而不是B-交叉反应）的可能优点，其可以避免被循环抗体中和，并以全剂量的抗原刺激物到达免疫活性细胞，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）通过结合调节与刺激的许多因素相关的T激活水平的能力来增加IMMSIM的建模灵活性;创建足够大且退化的克隆型库，以模拟T细胞特异性和交叉反应性，特别是模拟体内对“无关”病毒的私人特异性反应。2)进行病毒感染的机器免疫反应;研究克隆与感染病毒的相对亲和力的非对称交叉反应的情况。3)通过体内和体外实验对磨损现象中同时存在的两个因素进行定量。4)在平行体内机器程序中，比较同源或异源T细胞交叉反应（但B细胞外源）挑战对给定病毒预致敏的微生物的相对效率。这项研究与公共卫生和医学的相关性一般源于引入，疫苗接种的良好实践，关于不同病毒之间的交叉反应性和对不同病毒的免疫反应之间的新发现。特别是，这项研究的重点是痘病毒和竞技场病毒，这已被指定为“A类”公共卫生问题。