India International Center for Excellence in Research

印度国际卓越研究中心

• 批准号: 7964701
• 负责人: Thomas Nutman
• 金额: $ 121.39万
• 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/7964701
• 关键词: Address; Antigens; Area; C-Type Lectins; CCL18 gene; CD4 Positive T Lymphocytes; Cells; Communicable Diseases; Country; Cytotoxic T-Lymphocyte-Associated Protein 4; Developed Countries; Developing Countries; Development; Down-Regulation; Elephantiasis; Emerging Communicable Diseases; Endemic Diseases; Exhibits; Family; Filarial Elephantiases; Fostering; Future; Galactose; Goals; HIV; Hand; Helminths; Human; Hydrocele; Hypersensitivity skin testing; Immune response; India; Individual; Infection; Institution; Integration Host Factors; Interferons; Interleukin-17; Legal patent; Ligands; Lymphatic; Lymphedema; Malaria; Mali; Mediating; Medical Research; Mycobacterium tuberculosis; Nitric Oxide Synthase; Parasites; Pathogenesis; Pathology; Patients; Pattern; Phenotype; Physicians; Production; Research; Role; Scientist; Site; T-Lymphocyte; T-Lymphocyte Subsets; Tissues; Training; Tuberculin Test; Tuberculosis; Uganda; Up-Regulation; arginase; chemokine; cytokine; filaria; in vivo; interleukin-23; international center; macrophage; mannose receptor; monocyte; mycobacterial; pathogen; programs; resistin; response

The goal of the ICER (International Centers for Excellence in Research) program is to develop a sustained research program in areas of high infectious disease burden through partnerships with scientists and physicians in developing countries in three countries, Mali, Uganda, and India. The stated goal of the ICER program was to partner with in-country scientists to address major endemic diseases and foster research in areas such as malaria, HIV, filarial infections and tuberculosis. The hope was to build sustainable research programs by providing a long-term commitment, thus allowing difficult research challenges to be addressed, and, importantly, to train local scientists so that they are prepared to tackle emerging and re-emerging infectious diseases into the future. By the expression patterns of arginase 1 (Arg 1)/NO synthase 2 (Nos2), alternative activation markers, and cytokines in monocytes from filaria infected (INF) and uninfected (UN) individuals ex vivo and in response to filarial antigen, we have shown that monocytes from INF exhibit significantly diminished expression of Nos2 and significantly enhanced expression of Arg 1. These changes were associated with significantly increased expression of resistin, mannose receptor C type 1 (MRC 1), macrophage galactose type C lectin (MGL), and chemokine ligand 18 (CCL18). In response to BmA, purified monocytes from infected individuals also expressed significantly lower levels of IL 12 and IL 18 but, in contrast, exhibited significantly higher levels of expression of TGFβ, IL 10, and SOCS 1. Inhibition of arginase resulted in significantly diminished expression of resistin, MRC 1, MGL, and CCL18 as well as significantly enhanced expression of Nos2, IL 12, and IL 18 suggesting that arginase is involved in the establishment of the alternatively activated phenotype and immunoregulatory function of monocytes. Thus, patent human filarial infection is associated with the expansion of monocytes characterized by an arginase dependent 'alternatively' activated immunoregulatory phenotype. As lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele and elephantiasis we have elucidated the role of CD4+ T cell subsets in the development of lymphatic pathology by examining, of cytokines in individuals with filarial lymphedema and compared them to responses from asymptomatic, infected individuals. Parasite antigen but not control antigen induced significantly higher production of the prototypical Th1-type cytokines IFNg and TNFa in patients with lymphedema compared to asymptomatic individuals. Interestingly, the expression of the Th17 family of cytokines IL-17A, IL-17F, IL-21 and IL-23 was also significantly upregulated by BmA stimulation in lymphedema patients. On the other hand, expression of natural regulatory T cell markers - Foxp3 and GITR - was significantly impaired in lymphedema patients. While we did not find any significant differences in the expression of TLRs following parasite Ag stimulation, BmA induced significant upregulation of Nod1 and Nod2 in patients with lymphedema. Our findings implicate increased Th1/Th17 responses, decreased Tregs as well as NLR in the pathogenesis of filarial lymphedema. Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of a tissue invasive helminth may modulate the predominant Th1 (IFN γ mediated) response needed to control Mycobacterium tuberculosis (Mtb) infection. By analyzing the cellular responses to mycobacterial antigens (in patients with latent tuberculosis with or without filarial infection, we were able to demonstrate that filarial infection coincident with Mtb significantly diminishes Mtb specific Th1 (IL 12/IFN γ) and Th17 (IL 23/IL 17) responses that was related to increased expression of CTLA 4 and PD 1. Blockade of CTLA 4 restored production of both IFN γ and IL 17, while PD 1 blockade restored IFN γ production only. Thus, coincident filarial infection exerted a profound inhibitory effect on protective mycobacterial-specific Th1 and Th17 responses in latent tuberculosis and suggests a mechanism by which concomitant filarial (and other systemic helminth) infections predispose to the development of active tuberculosis in humans. The factors governing latency in tuberculosis are not well understood, but appear to include pathogen and host factors. To study the role of Th1, Th2 and Th17 responses in latent tuberculosis, we examined the immune responses of those tuberculin skin test positive (PPD+; latent TB) or skin test negative (PPD- healthy contacts) individuals to PPD, Mtb culture filtrate antigen (Mtb CFA) or anti-CD3. While PPD- and Mtb CFA-specific Th1 and Th2 cytokines were not significantly different between the two groups, Th17 cytokines IL-17 and IL23 were significantly decreased in PPD+ individuals. This cytokine modulation is associated with significantly increased expression of CTLA-4 as well as Foxp3 in response to PPD and Mtb CFA. While CTLA-4 blockade had no significant effect on IL-17 and IL-23 production of PPD+ individuals, depletion of Tregs significantly increased the production of both cytokines. Thus, latent Tb is characterized by an increased activity of Tregs and a coincident downregulation of Th17 cells.

ICER（国际卓越研究中心）计划的目标是通过与马里、乌干达和印度这三个国家的发展中国家的科学家和医生合作，在传染病高负担领域制定持续的研究计划。 ICER 计划的既定目标是与国内科学家合作，解决重大地方病并促进疟疾、艾滋病毒、丝虫感染和结核病等领域的研究。希望通过提供长期承诺来建立可持续的研究计划，从而解决困难的研究挑战，并且重要的是培训当地科学家，使他们做好准备应对未来新出现和重新出现的传染病。 通过精氨酸酶 1 (Arg 1)/NO 合酶 2 (Nos2)、替代激活标记物和来自丝虫感染 (INF) 和未感染 (UN) 个体的单核细胞离体和对丝虫抗原的反应的细胞因子的表达模式，我们表明来自 INF 的单核细胞表现出 Nos2 表达显着减少和 Arg 1 表达显着增强。这些变化与丝虫抗原显着增加有关。 抵抗素、甘露糖受体 C 型 1 (MRC 1)、巨噬细胞半乳糖 C 型凝集素 (MGL) 和趋化因子配体 18 (CCL18) 的表达。响应 BmA，来自感染个体的纯化单核细胞也表达显着较低水平的 IL 12 和 IL 18，但相反，表现出显着较高水平的 TGFβ、IL 10 和 SOCS 1 表达。精氨酸酶的抑制导致抵抗素、MRC 1、MGL 和 CCL18 表达显着减少，以及 Nos2、IL 12 和 IL 18 表达显着增强，表明 精氨酸酶参与单核细胞替代激活表型和免疫调节功能的建立。因此，明显的人丝虫感染与单核细胞的扩增有关，其特征在于精氨酸酶依赖性“交替”激活的免疫调节表型。 由于淋巴丝虫病可能与淋巴水肿、鞘膜积液和象皮病等严重病理学的发展有关，我们通过检查丝虫性淋巴水肿个体的细胞因子并将其与无症状感染个体的反应进行比较，阐明了 CD4+ T 细胞亚群在淋巴病理学发展中的作用。与无症状个体相比，寄生虫抗原而非对照抗原诱导淋巴水肿患者产生显着更高的原型 Th1 型细胞因子 IFNg 和 TNFa。有趣的是，在淋巴水肿患者中，BmA 刺激也显着上调了细胞因子 IL-17A、IL-17F、IL-21 和 IL-23 的 Th17 家族的表达。另一方面，天然调节性 T 细胞标记物 Foxp3 和 GITR 的表达在淋巴水肿患者中显着受损。虽然我们没有发现寄生虫 Ag 刺激后 TLR 表达存在任何显着差异，但 BmA 诱导淋巴水肿患者 Nod1 和 Nod2 显着上调。我们的研究结果表明丝虫性淋巴水肿的发病机制中 Th1/Th17 反应增加、Treg 和 NLR 减少。 结核分枝杆菌 (Mtb) 和丝虫双重感染非常普遍，组织侵袭性蠕虫的存在可能会调节控制结核分枝杆菌 (Mtb) 感染所需的主要 Th1（IFN γ 介导）反应。通过分析对分枝杆菌抗原的细胞反应（在有或没有丝虫感染的潜伏性结核病患者中，我们能够证明，丝虫感染与 Mtb 一致显着减弱 Mtb 特异性 Th1 (IL 12/IFN γ) 和 Th17 (IL 23/IL 17) 反应，这与 CTLA 4 和 PD 1 表达增加有关。 CTLA 4 恢复了 IFN γ 和 IL 17 的产生，而 PD 1 阻断仅恢复了 IFN γ 的产生。因此，同时丝虫感染对潜伏性结核病中保护性分枝杆菌特异性 Th1 和 Th17 反应产生了深远的抑制作用，并提示了一种机制，通过该机制，同时丝虫（和其他系统性蠕虫）感染易于发展为活动性结核病。 人类结核病。 控制结核病潜伏期的因素尚不清楚，但似乎包括病原体和宿主因素。为了研究 Th1、Th2 和 Th17 反应在潜伏性结核病中的作用，我们检查了结核菌素皮试阳性（PPD+；潜伏性结核）或皮试阴性（PPD-健康接触者）个体对 PPD、Mtb 培养滤过抗原（Mtb CFA）或抗 CD3 的免疫反应。虽然 PPD- 和 Mtb CFA 特异性 Th1 和 Th2 细胞因子在两组之间没有显着差异，但 PPD+ 个体中 Th17 细胞因子 IL-17 和 IL23 显着降低。这种细胞因子调节与响应 PPD 和 Mtb CFA 的 CTLA-4 以及 Foxp3 表达显着增加相关。虽然 CTLA-4 阻断对 PPD+ 个体的 IL-17 和 IL-23 产生没有显着影响，但 Tregs 的消耗显着增加了两种细胞因子的产生。因此，潜伏 Tb 的特点是 Tregs 活性增加，同时 Th17 细胞下调。