A hybrid multi-compartment model of granuloma formation and T cell priming in tuberculosis.
A hybrid multi-compartment model of granuloma formation and T cell priming in tuberculosis.
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DOI：
10.1016/j.jtbi.2011.03.022
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发表时间：
2011-07-07
影响因子：
2
通讯作者：
Kirschner, Denise
中科院分区：
文献类型：
--
作者：
Marino, Simeone;El-Kebir, Mohammed;Kirschner, Denise
结核病是一个全球性的健康问题，有 20 亿人感染结核分枝杆菌（Mtb，引起结核病的细菌）。感染的标志是出现主要在肺部响应感染而形成的免疫细胞的有组织结构。肉芽肿在物理上含有并在免疫学上抑制无法清除的细菌。我们开发了几种模型，在空间上表征宿主与分枝杆菌相互作用的动态，并确定了控制肉芽肿形成和发展的机制。特别是，我们发表了几种基于药物的结核病肉芽肿形成模型 (ABM)，其中包括 T 细胞群、巨噬细胞以及关键细胞因子和趋化因子效应分子的许多亚型。这些 ABM 研究强调了 T 细胞相关机制在感染进展中的重要作用，例如 T 细胞募集的程度和时间以及巨噬细胞激活。在这些模型中，从现象学角度捕捉了来自肺引流淋巴结 (LN) 的 T 细胞的启动和募集。除了这些 ABM 研究之外，我们还开发了几种使用 ODE 的多器官模型来检查肺和淋巴结之间的细胞运输。虽然我们可以预测时间动态行为，但这些模型与肉芽肿的空间方面没有耦合。为此，我们开发了一种混合的多器官模型：肺室的 ABM 和代表淋巴结室的非线性 ODE 系统。这种混合多器官方法研究肺中结核肉芽肿的形成和淋巴结中的免疫启动，使我们能够剖析使用单室或多室 ODE 系统无法实现的保护机制。这项工作的主要发现是，被称为抗原呈递细胞的重要细胞从肺到淋巴结的运输是保护性免疫的关键控制机制：整个感染结果可以通过关键免疫细胞迁移率来调节。我们的混合多器官实施表明，效应 CD4+ T 细胞可以将系统从持续感染中拯救出来，并在肉芽肿完全形成后进行清除。这可以作为潜伏感染个体的有效免疫治疗策略。
Tuberculosis is a worldwide health problem with 2 billion people infected with Mycobacterium tuberculosis (Mtb, the bacteria causing TB). The hallmark of infection is the emergence of organized structures of immune cells forming primarily in the lung in response to infection. Granulomas physically contain and immunologically restrain bacteria that cannot be cleared. We have developed several models that spatially characterize the dynamics of the host–mycobacterial interaction, and identified mechanisms that control granuloma formation and development. In particular, we published several agent-based models (ABMs) of granuloma formation in TB that include many subtypes of T cell populations, macrophages as well as key cytokine and chemokine effector molecules. These ABM studies emphasize the important role of T-cell related mechanisms in infection progression, such as magnitude and timing of T cell recruitment, and macrophage activation. In these models, the priming and recruitment of T cells from the lung draining lymph node (LN) was captured phenomenologically. In addition to these ABM studies, we have also developed several multi-organ models using ODEs to examine trafficking of cells between, for example, the lung and LN. While we can predict temporal dynamic behaviors, those models are not coupled to the spatial aspects of granuloma. To this end, we have developed a multi-organ model that is hybrid: an ABM for the lung compartment and a non-linear system of ODE representing the lymph node compartment. This hybrid multi-organ approach to study TB granuloma formation in the lung and immune priming in the LN allows us to dissect protective mechanisms that cannot be achieved using the single compartment or multi-compartment ODE system. The main finding of this work is that trafficking of important cells known as antigen presenting cells from the lung to the lymph node is a key control mechanism for protective immunity: the entire spectrum of infection outcomes can be regulated by key immune cell migration rates. Our hybrid multiorgan implementation suggests that effector CD4+ T cells can rescue the system from a persistent infection and lead to clearance once a granuloma is fully formed. This could be effective as an immunotherapy strategy for latently infected individuals.
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影响因子：
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