Broad based intervention to improve CD8-mediated protection

广泛的干预措施可改善 CD8 介导的保护

• 批准号: 8376417
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 45.15万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 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/8376417
• 关键词: Adult; Age; Aging; Animals; Antigen-Antibody Complex; Antigens; Attenuated; Biology; CD8B1 gene; Cell Maturation; Cell physiology; Collaborations; Communicable Diseases; Complex; Coronavirus; Data; Defect; Disease Outbreaks; Elderly; Epidemic; Francisella; Granzyme; Herpesvirus Type 3; Human; Immune; Immune system; Immunity; Immunization; Impairment; Infection; Interleukin-12; Interleukin-2; Intervention; Knowledge; Lead; Leadership; Learning; Lesion; Life; Listeria; Literature; Lymphocyte; Lymphocytic choriomeningitis virus; Lytic; Mediating; Modeling; Monkeypox; Monkeypox virus; Monkeys; Morbidity - disease rate; Mus; Organism; Pacific Northwest; Pathway interactions; Population; Predisposition; Proteins; Rodent; Signal Transduction; Streptococcus pneumoniae; T cell differentiation; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Vaccination; Vaccinia; Vaccinia virus; Vaccinium; Virus Diseases; Vulnerable Populations; West Nile virus; age related; aged; base; biodefense; experience; granzyme B; immunoregulation; immunosenescence; improved; influenzavirus; knowledge of results; mortality; pathogen; perforin; programs; research study; senescence; skills

T-cell immunity is known to wane with old age, and this defect is likely to impair protection against primary infection with a wide variety of pathogens. New results from the Nikolich lab strongly suggest that defects in effector T-cell differentiation underlie the age-related susceptibility to the West Nile virus (WNV). Moreover, preliminary results suggest that similar defects may exist in old mice infected with vaccinia virus (VACV). While much remains to be learned about the basic biology of this defect(s), its phenotypic manifestation is the reduced expression of the key effector molecules of the lytic pathway (Perforin/Granzyme B) and IFNy. Dr. Nikolich has made numerous important contributions to the biology of CDS T-cells in adult and aged organisms in the context of immunity and infection, and will deploy his knowledge and leadership skills to lead this Project and the entire P01. Aims are : (i) to investigate the mechanistic features and the breadth of the putative common T-cell defect(s) that underlie age-related susceptibility to different bioattack agents (by broadening the studies to Listeria, monkeypox and Francisella models); (ii) to examine whether therapy of effector T-cell maturation can be achieved by correcting lytic complex and IFNy defects and whether such intervention can restore protective immunity to old mice. In collaboration with Projects 1.1, 1.2 & 1.3, we shall then synthesize the results and knowledge to select the most efficient treatment(s); and (iii) to test in aged monkeys he most efficacious treatment validated in rodents, using the monkeypox virus model.

众所周知，T 细胞免疫力会随着年龄的增长而减弱，这种缺陷可能会削弱针对 原发感染有多种病原体。尼科利奇实验室的新结果强烈表明 效应 T 细胞分化缺陷是与年龄相关的西尼罗河病毒 (WNV) 易感性的基础。 此外，初步结果表明，感染牛痘病毒的老年小鼠可能也存在类似的缺陷 （疫苗接种）。虽然关于这种缺陷的基本生物学还有很多有待了解，但其表型 表现是裂解途径关键效应分子的表达减少 （穿孔素/颗粒酶 B）和 IFNy。 Nikolich 博士对生物学做出了许多重要贡献 成人和老年生物体中的 CDS T 细胞在免疫和感染的背景下，并将部署他的 领导这个项目和整个 P01 的知识和领导技能。目的是： (i) 调查 与年龄相关的常见 T 细胞缺陷的机制特征和范围 对不同生物攻击剂的敏感性（通过将研究范围扩大到李斯特菌、猴痘和弗朗西斯菌） 模型）； (ii) 检查是否可以通过纠正裂解来实现效应 T 细胞成熟的治疗 复合物和 IFNy 缺陷以及这种干预是否可以恢复老年小鼠的保护性免疫力。在 与项目 1.1、1.2 和 1.3 合作，然后我们将综合结果和知识来选择 最有效的治疗； (iii) 在老年猴子中测试他最有效的治疗方法 啮齿动物，使用猴痘病毒模型。