Enhancement of CD8 T Cell Immunity by IL-7 Therapy

IL-7 疗法增强 CD8 T 细胞免疫力

• 批准号: 7198242
• 负责人: Marulasiddappa Suresh
• 金额: $ 21.67万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198242
• 关键词: Acute; Address; Affect; Antigens; Apoptosis; Apoptotic; Arenaviridae; Arenavirus; Arts; BCL2L11 gene; Biological Assay; Biological Warfare; Bioterrorism; Bunyaviridae; CD8B1 gene; Categories; Cells; Cellular Immunity; Cessation of life; Clinical; Clonal Expansion; Data; Development; Disease; Effector Cell; Family; Filoviridae; Filovirus; Flaviviridae; Generations; Human; Immune; Immune response; Immunity; Immunotherapeutic agent; Infection; Interleukin-7; Knockout Mice; Lassa Fever; Lassa fever virus; Lassa virus; Lymphocytic choriomeningitis virus; Lymphoid; Maintenance; Memory; Modality; Molecular; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Numbers; Old World Arenaviruses; Organ; Orthobunyavirus; Phase; Population; Poxviridae; Rate; Rodent; Role; Seminal; Sum; Symptoms; T memory cell; T-Lymphocyte; Time; Transgenic Organisms; Vaccine Design; Vaccines; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; base; day; insight; interest; mortality; mouse model; pathogen; response; size; therapeutic vaccine; vaccine evaluation

DESCRIPTION (provided by applicant): Viral hemorrhagic fever (VHP) in humans is caused by several etiologic agents including arenaviruses, bunyaviruses, and filoviruses. These agents have been classified as category A pathogens by the NIAID because of their potential of being used for intentional exposure in acts of bioterrorism and biological warfare. In addition to the high rate of morbidity and mortality associated with these infections, clinical disease is characterized by rapid onset of symptoms and death. Therefore, there is a critical need to develop effective vaccines and immunotherapeutic strategies to combat these often-fatal infections. The Old World arenaviruses include Lassa virus and the prototypic lymphocytic choriomeningitis virus (LCMV). Similar to LCMV, CDS T cell-mediated immunity is likely to be important for defense against Lassa fever and therefore, vaccines against these agents need to elicit potent CDS T cell memory. Typically, CDS T cell responses can be divided into three distinct phases: (1) expansion phase when naive T cells get activated to undergo clonal expansion and differentiation into effector cells; (2) contraction phase when ~95% of the effector CDS T cells undergo apoptosis, and (3) memory phase during which the remaining 5% of the CDS T cells are maintained as memory T cells for extended periods of time. These memory CDS T cells confer protective immunity against re- infection by rapidly expanding and differentiating into effector cells. The development of protective immunity depends upon the generation of a critical number of memory CDS T cells, and there is high level of interest to boost the number of vaccine-induced memory T cells. Using the well-characterized mouse model of LCMV infection, we have obtained strong preliminary data that IL-7 therapy during the contraction phase of the CDS T cell response led to a substantial enhancement in the number of virus-specific memory CDS T cells. Understanding the mechanisms underlying the IL-7- induced enhancement in CDS T cell memory is the focus of this application. The specific aims are to determine the: (1) effects of IL-7 therapy on the 'quantity' and 'quality' of long-term CDS T cell memory in both lymphoid and non-lymphoid organs using the state-of-the-art phenotypic and functional assays; (2) cellular and molecular basis of IL-7-induced enhancement of CDS T cell memory. Specific aim 2 will be addressed by examining the effect of IL-7 therapy on the proliferation and apoptosis of LCMV-specific CDS T cells and investigating the role of BCL-2, MCL-1, and BIM in regulating IL-7-induced effects using transgenic and knockout mice. The proposed studies should aid in the rational design of vaccines that can engender potent CDS T cell memory and protect against poxvirus and arenaviral infections.

描述（由申请人提供）：人类病毒性出血热（VHP）由多种病原体引起，包括沙粒病毒、布尼亚病毒和丝状病毒。这些病原体已被 NIAID 归类为 A 类病原体，因为它们有可能被用于生物恐怖主义和生物战行为中的故意暴露。除了与这些感染相关的高发病率和死亡率之外，临床疾病的特点是症状和死亡迅速出现。因此，迫切需要开发有效的疫苗和免疫治疗策略来对抗这些往往致命的感染。旧世界沙粒病毒包括拉沙病毒和原型淋巴细胞脉络膜脑膜炎病毒（LCMV）。与 LCMV 类似，CDS T 细胞介导的免疫可能对于防御拉沙热很重要，因此针对这些病原体的疫苗需要引发有效的 CDS T 细胞记忆。通常，CDS T 细胞反应可分为三个不同的阶段： (1) 扩增阶段，此时幼稚 T 细胞被激活进行克隆扩增并分化为效应细胞； (2) 收缩期，约 95% 的效应 CDS T 细胞发生凋亡；(3) 记忆期，其中剩余 5% 的 CDS T 细胞在较长时间内保持为记忆 T 细胞。这些记忆 CDS T 细胞通过快速扩增并分化为效应细胞，提供针对再次感染的保护性免疫。保护性免疫的发展取决于关键数量的记忆 CDS T 细胞的产生，人们对增加疫苗诱导的记忆 T 细胞的数量非常感兴趣。使用已充分表征的 LCMV 感染小鼠模型，我们获得了强有力的初步数据，表明 CDS T 细胞反应收缩期的 IL-7 治疗导致病毒特异性记忆 CDS T 细胞数量大幅增加。了解 IL-7 诱导 CDS T 细胞记忆增强的机制是本申请的重点。具体目标是确定：(1) IL-7 治疗对淋巴和非淋巴器官中长期 CDS T 细胞记忆的“数量”和“质量”的影响，使用最新状态表型和功能分析； (2)IL-7诱导CDS T细胞记忆增强的细胞和分子基础。具体目标 2 将通过检查 IL-7 治疗对 LCMV 特异性 CDS T 细胞增殖和凋亡的影响以及研究 BCL-2、MCL-1 和 BIM 在调节 IL-7 诱导效应中的作用来解决使用转基因和基因敲除小鼠。拟议的研究应有助于合理设计疫苗，从而产生有效的 CDS T 细胞记忆并预防痘病毒和沙粒病毒感染。