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、乌干达和印度三个发展中国家的科学家和医生建立伙伴关系，在高传染病负担地区制定可持续的研究计划。ICER计划的既定目标是与国内科学家合作，解决主要的地方病，并促进疟疾、艾滋病毒、丝虫病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，更重要的是，培训当地科学家，使他们准备好应对未来新出现和重新出现的传染病。 通过在来自丝虫感染（INF）和未感染（UN）个体的离体单核细胞中以及响应于丝虫抗原的单核细胞中的精氨酸酶1（Arg 1）/一氧化氮合酶2（Nos 2）、替代活化标记物和细胞因子的表达模式，我们已经表明来自INF的单核细胞表现出Nos 2的表达显著降低和Arg 1的表达显著增强。这些变化与β-半乳糖苷酶、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（CCL 18）的表达显著增加相关。响应于BmA，来自感染个体的纯化的单核细胞也表达显著较低水平的IL 12和IL 18，但相反，表现出显著较高水平的TGF、IL 10和SOCS 1表达。抑制α-淀粉酶导致α-淀粉酶n、MRC 1、MGL和CCL 18的表达显著降低，以及Nos 2、IL 12和IL 18的表达显著增强，表明α-淀粉酶参与了单核细胞的交替活化表型和免疫调节功能的建立。因此，专利的人丝虫感染与单核细胞的扩增有关，其特征在于依赖于“替代”激活的免疫调节表型。 由于淋巴丝虫病可能与严重病理学的发展有关，如水肿、鞘膜积液和象皮肿，我们通过检查丝虫性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CD 4 + 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水肿患者中原型Th 1型细胞因子IFNg和TNFa的产生显著更高。有趣的是，Th 17家族细胞因子IL-17 A、IL-17 F、IL-21和IL-23的表达在水肿患者中也被BmA刺激显著上调。另一方面，自然调节性T细胞标志物Foxp 3和GITR的表达在水肿患者中显著受损。虽然我们没有发现任何显着差异的TLRs的表达后寄生虫银刺激，BmA诱导显着上调Nod 1和Nod 2的患者水肿。Th 1/Th 17反应增强、TcR和NLR降低与丝虫性水肿的发病机制有关。 结核分枝杆菌（Mtb）和丝虫合并感染是非常普遍的，和存在的组织侵入性蠕虫可能会调节占主导地位的Th 1（IFN介导的）反应需要控制结核分枝杆菌（Mtb）感染。通过分析对分枝杆菌抗原的细胞应答（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同时发生显著减少了与CTLA 4和PD 1的表达增加相关的Mtb特异性Th 1（IL 12/IFN）和Th 17（IL 23/IL 17）应答。CTLA 4的阻断恢复了IFN和IL 17的产生，而PD 1阻断仅恢复了IFN的产生。因此，并发丝虫感染对潜伏性结核病中分枝杆菌特异性Th 1和Th 17保护性反应产生了深刻的抑制作用，并提示了伴随丝虫（和其他全身蠕虫）感染易导致人类活动性结核病发展的机制。 结核病潜伏期的控制因素尚不清楚，但似乎包括病原体和宿主因素。为了研究Th 1、Th 2和Th 17应答在潜伏性结核病中的作用，我们检测了那些结核菌素皮肤试验阳性（PPD+;潜伏性TB）或皮肤试验阴性（PPD-健康接触者）个体对PPD、Mtb培养滤液抗原（Mtb CFA）或抗CD 3的免疫应答。虽然PPD和Mtb CFA特异性Th 1和Th 2细胞因子在两组之间没有显著差异，但Th 17细胞因子IL-17和IL 23在PPD+个体中显著降低。这种细胞因子调节与响应于PPD和Mtb CFA的CTLA-4以及Foxp 3的显著增加的表达相关。虽然CTLA-4阻断对PPD+个体的IL-17和IL-23产生没有显著影响，但Tcl 3的消耗显著增加了两种细胞因子的产生。因此，潜伏性Tb的特征在于增加的Tb活性和同时下调的Th 17细胞。