Regulation Of Immunopathology In Bacterial And Parasitic Disease

细菌和寄生虫病免疫病理学的调节

• 批准号: 7964415
• 负责人: Alan Sher
• 金额: $ 80.83万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964415
• 关键词: Acquired Immunodeficiency Syndrome; Aerosols; Affect; Animals; Anti-Retroviral Agents; Bacteria; CD4 Positive T Lymphocytes; Cell Count; Cells; Clinical; Clinical Research; Complication; Data; Development; Disease; Employee Strikes; Exhibits; Flow Cytometry; Genus Mycobacterium; Goals; Granuloma; HIV; HIV Infections; HIV-1; Host resistance; ITGAM gene; Immune; Immune response; Immunologics; Immunosuppression; Impairment; Individual; Infection; Infection Control; Infection prevention; Infectious Agent; Inflammatory; Interferon-alpha; Interferons; Lead; Lung; Lymphopenia; Messenger RNA; Modeling; Mus; Mycobacterium tuberculosis; Myelogenous; Necrosis; Opportunistic Infections; Outcome; Parasitic Diseases; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Play; Poly ICLC; Population; Population Study; Production; Regulation; Relative (related person); Role; Route; Steroids; Structure; Supportive care; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tuberculosis; United States National Institutes of Health; Up-Regulation; Work; base; chemokine; cytokine; design; high risk; immunopathology; macrophage; monocyte; monocyte chemoattractant protein 1 receptor; mycobacterial; pathogen; prevent; receptor; reconstitution; response; therapy design

Most individuals exposed to Mycobacterium tuberculosis either never become infected or are able control infection maintaining the bacteria in a latent state walled off inside structures called granulomas. Active tuberculosis occurs in a subset of infected subjects when immunologic control breaks down. Immunologic approaches for preventing infection or disease have focussed on the critical role played by CD4+T cells and macrophages in host resistance to mycobacteria although there has been less information concerning the function of the latter cell population in disease exacerbation. Evidence for such a role was obtained this year in a project aimed at studying the effects of exogeneously induced Type 1 IFN on murine tuberculosis. In this study, we treated mice infected by the aerosol route intranasally with poly-ICLC, an agent designed to stimulate prolonged, high-level production of type I IFN. Drug-treated, infected wild-type, but not IFN alpha, beta receptor deficient animals, displayed marked elevations in lung bacillary loads accompanied by widespread pulmonary necrosis without detectable impairment of Th1 effector function. Importantly, lungs from Poly-ICLC-treated mice exhibited a striking increase in CD11b+F4/80+Gr1int monocyte/macrophages. These cells displayed decreased MHC II expression and enhanced bacterial levels relative to the same subset purified from infected, untreated controls. Moreover, both the Poly-ICLC triggered pulmonary recruitment of the CD11b+F4/80+Gr1int population and the accompanying exacerbation of infection correlated with type I IFN-induced upregulation of mRNA for the chemokine Ccl2 and required host expression of its receptor, CCR2. The above findings suggest that type I IFN induction, by promoting the accumulation of a permissive myeloid population in the lung, can detrimentally affect the outcome of M. tuberculosis infection and suggest that drugs that stimulate type I IFN should be utilized with caution in patients exposed to this pathogen. Immune Reconstitution Inflammatory Syndrome (IRIS) is the rapid and paradoxical worsening of pathology seen in HIV-1 infected individuals after initiation of anti-retroviral therapy (ART). With the increasing use of ART for mass treatment of AIDS in developing regions, this complication has emerged as a major problem in the management of HIV infection. IRIS is more common in patients with severe CD4 T cell lymphopenia and patients with mycobacterial and other opportunistic infection are at particularly high risk of developing this severe pathologic response. The factors that lead to the induction of IRIS and the mechanisms of its immunopathogenesis are poorly understood, so currently patient treatment during IRIS episodes is limited to supportive care and broad steroid based immunosuppression. In a collaborative study study initiated with Drs.Irini Sereti and Mario Roederer we have been using multiparameter flow cytometry to characterize T cell populations in ART treated HIV patients at the NIH clinical center in order to identify phenotypic changes predictive of IRIS development. The initial study population consists of a group of 45 HIV+1 individuals with low CD4 T cell counts and a variety of potential IRIS pre-disposing conditions. The T cell phenotypic data gathered so far comparing the sub-set of patients developing IRIS with those that did not, indicate higher levels of the activation marker PD-1 on CD4+ T cells in the IRIS group at the start of ART treatment. This data supports the hypothesis that the presence of a highly activated T cell phenotype at the time of ART initiation, possibly due to excessive antigenic stimulation from co-infection, may be a pre-disposing factor for IRIS.

暴露于结核分枝杆菌的大多数个体永远不会感染，或者能够控制感染，以维持细菌的潜在状态，该潜在状态被围困的内部结构，称为肉芽肿。当免疫控制分解时，活跃的结核病发生在感染受试者的一部分中。预防感染或疾病的免疫学方法集中在CD4+T细胞和巨噬细胞在宿主对分枝杆菌抗性中的关键作用，尽管关于后一种细胞种群在疾病加剧中的功能的信息较少。今年在一个旨在研究额外诱导的1型IFN对鼠结核病的影响的项目中获得了这种作用的证据。在这项研究中，我们用鼻内室内的多聚-ICLC（一种旨在刺激I型I型IFN的长时间高水平产生的药物）治疗了被气溶胶途径感染的小鼠。药物治疗的，感染的野生型，但没有IFNα，β受体缺乏动物，显示出肺杆菌负荷的明显升高，伴随着广泛的肺坏死，而没有可检测到的TH1效应功能。重要的是，来自多聚-ICLC治疗的小鼠的肺在CD11b+F4/80+GR1INT单核细胞/巨噬细胞中表现出惊人的增加。这些细胞表现出降低的MHC II表达和增强的细菌水平，相对于受感染的未处理对照纯化的相同子集。此外，多-ICLC触发了CD11b+F4/80+GR1INT种群的肺募集，以及随附的感染加剧与I型IFN诱导的趋化因子CCL2的mRNA上调相关，其受体CCR2的宿主表达和宿主表达。以上发现表明，通过促进肺中允许性髓样人群的积累，I型IFN诱导可能会对结核分枝杆菌感染的结果有害影响，并表明应在暴露于该病原体的患者中谨慎使用刺激I型IFN的药物。 免疫重构炎症综合征（IRIS）是启动抗网状病毒疗法（ART）后，HIV-1感染个体在感染HIV-1感染的个体中的快速和自相矛盾的恶化。随着艺术在发展中的大规模治疗中，这种并发症已成为艾滋病毒感染管理的主要问题。 虹膜在严重的CD4 T细胞淋巴细胞减少症患者中更为常见，分枝杆菌和其他机会性感染的患者患这种严重的病理反应的风险尤其高。导致虹膜诱导的因素及其免疫致病发生的机制知之甚少，因此目前在虹膜发作期间的患者治疗仅限于支持性护理和基于类固醇的广泛免疫抑制。 在一项由Drs.irini Sereti和Mario Roederer发起的合作研究中，我们一直在使用多参数流式细胞仪来表征NIH临床中心ART治疗的HIV患者中T细胞群体的表征，以识别表型变化的预测性的IRIS发育。最初的研究人群由一组45个HIV+1个个体组成，CD4 T细胞计数低，并且各种潜在的IRIS预疾病前疾病。迄今为止收集的T细胞表型数据比较了虹膜发育的患者的子集的子集，这表明在艺术治疗开始时，虹膜组的CD4+ T细胞上的激活标记物PD-1水平更高。该数据支持以下假设：在艺术启动时，高度激活的T细胞表型的存在可能是由于来自共感染的过度抗原刺激，可能是IRIS的预先分解因子。