University of Michigan Medical School, Department of Microbiology and Immunology, 1150 West Medical Ctr Dr, 6730 MSB2, Ann Arbor, MI 48109, USA.
J Theor Biol. 2011 Jul 7;280(1):50-62. doi: 10.1016/j.jtbi.2011.03.022. Epub 2011 Apr 1.
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 multi-organ 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.
结核病是一个全球性的健康问题，有 20 亿人感染了结核分枝杆菌（Mtb，引起结核病的细菌）。感染的标志是免疫细胞的有组织结构的出现，这些结构主要在肺部形成，以响应感染。肉芽肿在物理上包含和免疫上限制不能被清除的细菌。我们已经开发了几种模型来空间描述宿主-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，我们发表了几个关于结核肉芽肿形成的基于主体的模型（ABM），其中包括许多 T 细胞群体、巨噬细胞以及关键的细胞因子和趋化因子效应分子的亚型。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 细胞募集的幅度和时间，以及巨噬细胞的激活。在这些模型中，从肺部引流淋巴结（LN）募集 T 细胞的启动和募集是从现象学上捕获的。除了这些 ABM 研究外，我们还使用 ODE 开发了几种多器官模型来研究例如肺和 LN 之间细胞的迁移。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联系。为此，我们开发了一种混合的多器官模型：一个用于肺部的 ABM 和一个表示淋巴结的非线性 ODE 系统。这种肺部的多器官模型和 LN 的混合非线性 ODE 系统可以用于研究结核病肉芽肿的形成和 LN 的免疫启动，从而可以剖析使用单一隔室或多隔室 ODE 系统无法实现的保护机制。这项工作的主要发现是，从肺部到淋巴结的重要抗原呈递细胞的迁移是保护性免疫的关键控制机制：感染结果的整个范围可以通过关键免疫细胞的迁移率来调节。我们的混合多器官模型表明，效应 CD4+T 细胞可以从持续感染中拯救系统，并在完全形成肉芽肿后导致清除。对于潜伏感染的个体来说，这可能是一种有效的免疫治疗策略。
