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: 6800117
• 负责人: Franco Celada
• 金额: $ 37.48万
• 依托单位: HOSPITAL FOR JOINT DISEASES ORTHO INST
• 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 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6800117
• 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): This project seeks to develop the IMMSIM model of host responses to its full potential as a supporting and predictive tool for infection research. This effort is carried out by a multidisciplinary cooperation of mathematical modelers and immunologists working with viruses of the pox and arenavirus families, which both belong to the A category, and hence the simulator may become of interest in the frame of the current NIAID Biodefense Research protocols. Two issues are central for the understanding of anti-virus responses: the multi-threshold mechanism of T cell activation, and the changeable clonal hierarchy of T cell memory. In both areas breakthroughs have been made in the last year, with important consequences for protection strategies. With the new T cell features incorporated, the model shall be tested for reliability in reproducing bench results and hypotheses, and its predictions shall be challenged by means of ad hoc in vivo or in vitro 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 of local resources (antigen, lymphokines) or by global population constraints; b) the reasons for the apparent asymmetry of the effects of crossreactions, when two viral infections are enacted in opposite order; and c) the possible advantage of using heterologous (but not B-crossreacting) instead of homologous vaccines, in order to avoid neutralization by circulating antibodies and thus to reach a more predictable protection.

描述（由申请人提供）：该项目旨在开发宿主反应的IMMSIM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。 这项工作是由数学建模人员和免疫学家与痘病毒和沙粒病毒家族的病毒进行多学科合作进行的，这两种病毒都属于A类，因此模拟器可能会在当前NIAID生物防御研究协议的框架中引起兴趣。 两个问题是理解抗病毒反应的核心：T细胞激活的多阈值机制和T细胞记忆的可变克隆层次。 去年在这两个领域都取得了突破，对保护战略产生了重要影响。 随着新的T细胞特征的纳入，应测试模型在再现实验室结果和假设方面的可靠性，并应通过专门的体内或体外实验对其预测进行挑战。 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否起源于局部资源的竞争（抗原、淋巴因子）或受总体群体限制; B）当两种病毒感染以相反顺序发生时，交叉反应效应的明显不对称性的原因;和c）使用异源（但不是B-交叉反应的）而不是同源疫苗的可能优点，以避免被循环抗体中和，从而达到更可预测的保护。