Remodeling of lymph node-derived cytokine responses at the infected tissue site

受感染组织部位淋巴结源性细胞因子反应的重塑

• 批准号: 7532039
• 负责人: Deborah J Fowell
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532039
• 关键词: Accounting; Antigens; Blood; CCL1 gene; CCL7 gene; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Dendritic Cells; Dermis; Disease; Ear; Effector Cell; Ensure; Event; Face; Homing; Immune; Immune response; Immunity; Immunotherapy; In Situ; Infection; Inflammation; Inflammatory; Interleukin-4; Intervention; Leishmania major; Lesion; Localized; Mediating; Modeling; Modification; Peripheral; Production; Protozoa; Public Health; Recording of previous events; Recruitment Activity; Regulation; Series; Signal Transduction; Site; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Translating; antimicrobial; base; chemokine; chemokine receptor; concept; cytokine; design; extracellular; immunoregulation; in vivo; lymph nodes; macrophage; novel; pathogen; response; tool

DESCRIPTION (provided by applicant): Compartmentalization of the immune response ensures tight regulation of T cell activation in the lymph node (LN) and precise effector T cell delivery and function at sites of inflammation. In the LN, naive helper (Th) CD4+ T cells acquire specialized functions and acquire distinct homing potential. Therefore both function and subsequent localization of effector cells appears to be pre-determined during differentiation in the LN. Our recent studies with the protozoa Leishmania major suggest that such tissue-specific accumulation of cytokine secreting effector cells can be subverted by a pathogen at the infected tissue site. L. major imposes a selective T cell cytokine response at the infected tissue site, independent of pathogen effects on LN priming of the repertoire. The early cytokine repertoire exiting the LN (a mixture of IL-4 and IFN3 producers) is modified at the infected tissue to operationally include IL-4 but not IFN3 producers. We hypothesize that L. major manipulates the immune response at the tissue site by subverting the accumulation or activity of leishmaniacidal, IFN3-producing, immune effectors. We have made three key observations that give us a novel handle on the regulation of responses at the infection site. Firstly, L. major inhibits the expression of Type 1 chemokines in the infected dermis, in part through direct action on the infected macrophage. Secondly, L. major induces the expression of two Type 2 chemokines, CCL1 and CCL7. Finally, local IL-4 production negatively regulates IFN3 production in the infected ear. Using a unique set of tools to track, in situ, an emerging immune response to L. major, this proposal seeks to identify key components of this early pathogen-host encounter that modulate the Th cytokine repertoire in the infected tissue. Specific Aim 1 will test a series of hypotheses accounting for changes in cytokine repertoire: differential recruitment/retention of immune effectors or entry into the tissue but subsequent functional modification. Specific Aim 2 will test the hypothesis is that L. major modulates the chemokine milieu resulting in the recruitment of IL-4 producers but not leishmaniacidal IFN3-producers. In turn, IL-4 production amplifies the restriction by compounding the selective chemokine milieu and/or directly inhibiting Th1 effector function. The concept of cytokine editing at the infected tissue site has important implications for immune therapy. Developing ways of harnessing a diverse LN repertoire to retune immune responses at the infection site, by manipulating the type of effectors recruited to the site, has great therapeutic potential for many disease states. PUBLIC HEALTH REVELANCE L. major imposes a selective T cell cytokine response at the infected tissue site, independent of pathogen effects on LN priming of the repertoire. Understanding pathogen-specific mechanisms of regulation at the tissue site therefore becomes key to the design of appropriate therapeutics. Developing ways of harnessing a diverse lymph node repertoire to retune immune responses at the infection site, by manipulating the type of effectors recruited to the site, has great therapeutic potential for many disease states.

描述（由申请人提供）：免疫应答的区室化确保了淋巴结（LN）中T细胞活化的严格调节以及炎症部位的精确效应T细胞递送和功能。在LN中，初始辅助（Th）CD 4 + T细胞获得专门的功能并获得不同的归巢潜能。因此，效应细胞的功能和随后的定位似乎是在LN分化期间预先确定的。我们最近的研究与原生动物利什曼原虫重大表明，这种组织特异性积累的细胞因子分泌效应细胞可以被破坏的病原体在感染的组织部位。L. major在感染的组织部位施加选择性T细胞细胞因子应答，而不依赖于病原体对LN激发库的影响。离开LN的早期细胞因子库（IL-4和IFN 3生产者的混合物）在感染组织处被修饰以可操作地包括IL-4但不包括IFN 3生产者。我们假设L. major通过破坏杀利什曼原虫、产生IFN 3的免疫效应物的积累或活性来操纵组织部位的免疫应答。我们已经做了三个关键的观察，给了我们一个新的处理在感染部位的反应调节。首先，L.主要抑制感染真皮中1型趋化因子的表达，部分是通过直接作用于感染的巨噬细胞。其次，L.主要诱导两种2型趋化因子CCL 1和CCL 7的表达。最后，局部IL-4的产生负调节感染耳中IFN 3的产生。使用一套独特的工具来跟踪，在原位，一个新兴的免疫反应，以L。主要的，这个建议旨在确定这种早期病原体-宿主相遇的关键组成部分，调节Th细胞因子库在感染的组织。具体目标1将测试解释细胞因子库变化的一系列假设：免疫效应物的差异募集/保留或进入组织但随后功能修饰。具体目标2将检验假设是L。major调节趋化因子环境，导致IL-4产生者的募集，但不导致杀利什曼原虫的IFN-3产生者的募集。反过来，IL-4的产生通过复合选择性趋化因子环境和/或直接抑制Th 1效应器功能来放大限制。在感染组织部位进行细胞因子编辑的概念对免疫治疗具有重要意义。开发利用不同LN库的方法，通过操纵募集到该部位的效应物的类型来重新调节感染部位的免疫应答，对许多疾病状态具有巨大的治疗潜力。公共卫生监督major在感染的组织部位施加选择性T细胞细胞因子应答，而不依赖于病原体对LN激发库的影响。因此，了解组织部位的病原体特异性调节机制成为设计适当疗法的关键。开发利用不同淋巴结库的方法，通过操纵募集到该部位的效应物的类型来重新调节感染部位的免疫应答，对许多疾病状态具有巨大的治疗潜力。