MODELLING CELL MEDIATED IMMUNE RESPONSES IN THE COMPUTER

在计算机中模拟细胞介导的免疫反应

• 批准号: 2453669
• 负责人: Franco Celada
• 金额: $ 19.71万
• 依托单位: HOSPITAL FOR JOINT DISEASES ORTHO INST
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2453669
• 关键词: MHC class I antigen; T cell receptor; antigen presenting cell; antigens; artificial intelligence; biological models; cell transplantation; cell type; cellular immunity; computer program /software; computer simulation; computer system design /evaluation; dendritic cells; foreign body reaction; humoral immunity

DESCRIPTION: (Adapted from the applicant's abstract) Impressive advances in computer technology have opened the way to the simulation in machina of complex biological systems. In immunology, this has proven helpful as it can foster both critical phases of generating and testing novel hypotheses. At variance with "conventional" models based upon differential equations, the applicant has reproduced the dynamics of the humoral response by means of cellular automata, where discrete entities cooperate and develop according to elementary local rules. The success of this model in tackling several "hot" aspects currently debated among immunologists signals that the time is ripe for the exploration of the complex and challenging cell-mediated immunity. The subject of this proposal is a computer simulation of the immune response to viral infection and to foreign cells. This requires an extensive upgrading of our IMMSIM code, including the introduction of infective antigens, target cells, dendritic cells, CD8 T cell receptors and class I MHCs. The body is represented by a bi-dimensional space subdivided into sites where all interactions take place in discrete time steps. Interactions are probablistic occurrences between cells that take place via their receptors, on the basis of complementarity between binary bit strings. These interactions may lead to destruction, presentation, stimulation or tolerance. As in the living organism, a virus-specific Tc precursor will become anergic by meeting a Class I-bearing infected target cell but will mature to a serial killer upon binding to a DC that has attracted a Th cell, whose lymphokines will act on both Tc and DC. The outcome of each event depends on a number of parameters of largely unknown biological weight. Their effects will be tested experimentally by running the same response serially, varying one parameter at a time, and comparing the results to ascertained immunological behaviors. This will allow us to identify the critical nodes of the virus/response progress and then to use the model to challenge further fundamental aspects, such as viral mutation, lymphoid cell infection, and, ultimately, the cooperative/competitive interplay between the cellular and humoral response against the same invader.

描述：（改编自申请人的摘要）令人印象深刻的进步， 计算机技术为机械模拟开辟了道路， 复杂的生物系统。 在免疫学中，这已被证明是有帮助的，因为它 可以促进产生和测试新假设的关键阶段。 与基于微分方程的“传统”模型不同， 本申请人通过以下方法再现了体液应答的动力学 在细胞自动机中，离散的实体相互合作， 根据当地的基本规则。 这种模式在解决当前几个“热点”方面的成功 免疫学家之间的争论表明， 探索复杂和具有挑战性的细胞介导的免疫。 这项提案的主题是计算机模拟免疫反应 病毒感染和外来细胞。 这需要一个广泛的 升级我们的IMMSIM代码，包括引入传染性 抗原、靶细胞、树突细胞、CD 8 T细胞受体和I类 MHC。 身体由一个二维空间表示， 所有相互作用都在离散的时间步骤中发生的地点。 相互作用是细胞之间的概率事件，通过 它们的受体，基于二进制位串之间的互补性。 这些相互作用可能导致破坏、呈现、刺激或 宽容 如在活生物体中，病毒特异性Tc前体将 通过遇到携带I类感染的靶细胞而变得无反应性， 在与已经吸引Th细胞的DC结合后成熟为连环杀手， 其淋巴因子将作用于Tc和DC两者。 每个事件的结果取决于许多参数， 未知的生物重量 他们的影响将通过实验进行测试， 连续运行相同的响应，每次改变一个参数，以及 将结果与确定的免疫学行为进行比较。 这将 使我们能够确定病毒/应对进展的关键节点， 然后使用模型来挑战进一步的基本方面，例如 病毒突变，淋巴细胞感染，最终， 细胞和体液反应之间的合作/竞争相互作用 同一个入侵者。