Investigate the impact of physiological microbial exposure on regulatory T cell-mediated immune regulation

研究生理微生物暴露对调节性 T 细胞介导的免疫调节的影响

• 批准号: 10727298
• 负责人: Li-Fan Lu
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727298
• 关键词: Ablation; Animal Experimentation; Animal Experiments; Animals; Antigens; Autoimmunity; Biological Assay; Biomedical Research; Cell Separation; Cellular biology; Chronic Disease; Clinical Trials; Communities; Data; Dedications; Development; Disease; Environment; Exhibits; Exposure to; Fostering; Foundations; Functional disorder; Funding Opportunities; Future; Genetic; Germ-Free; Health; Heterogeneity; Homeostasis; Human; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunity; Immunological Models; Immunologics; Immunology; Immunophenotyping; In Vitro; Inbreeding; Infection; Infectious Agent; Inflammation; Knowledge; Laboratories; Laboratory Animals; Laboratory mice; Location; Lymphoid; Mediating; Microbe; Modeling; Mucosal Immune System; Mus; Nature; Pathologic; Phenotype; Physiological; Pilot Projects; Population; Protocols documentation; Recording of previous events; Regulatory T-Lymphocyte; Reliability of Results; Reporting; Reproducibility; Reproducibility of Results; Research; Research Personnel; Role; Science; Shapes; Signal Transduction; Solid; Suppressor-Effector T-Lymphocytes; T cell therapy; T-cell receptor repertoire; Tissues; Viral; Work; animal care; autoimmune inflammation; commensal microbes; comparative; dietary; experience; gain of function; germ free condition; immunoregulation; in vivo; insight; interest; loss of function; microbial; microbiome; mouse model; new therapeutic target; pathogen; pre-clinical research; preclinical study; prevent; programs; repository; single cell sequencing; transcriptome

Rigorous biocontainment prevents laboratory mice from being infected with natural pathogens and allows researchers to perform animal experiments in a reliable and reproducible manner. However, such specific pathogen-free (SPF) mice do not necessily model immune responses that occur in nature, and this may contribute to the often-reported disconnect between pre-clinical research and human clinical trials. Athough many key advances in biomedical research have been made possible by the study of SPF mice, there is now compelling evidence that microbial or viral experience can greatly impact immune pathophysiology. In past two decades, regulatory T (Treg) cells have emerged as a dedicated immune population crucial for the negative regulation of immune responses. Considering that Treg cell homeostasis and function can be greatly influenced by unique signals present in different tissue environments, it is conceiable that the microbial exposure outside the current laboratory setting could heavily impact Treg cells and their ability not only to establish immunological tolerance against ‘‘self’’ or innocuous foreign antigens, but also to keep in check effector immune responses to pathogens. To gain a better understanding of Treg cell-mediated immune regulation in a more physiological setting, we have worked closely with the Animal Care Program at UC San Diego to establish a new protocol to generate, maintain, and extensively characterize a stable repository of physiological microbe-exposed environmentally conditioned (PC) animals. By taking this approach, two well-establsihed mouse models that affords Treg cell isolation and Treg cell-specific ablation will be first adapted to the “dirty” condition. Next, through performing extensive comparative immune phenotype analysis and single-cell sequencing studies of Treg cells isolated from both lymphoid and non-lymphoid tissues in SPF mice and PC mice, the impact of physiological microbial exposure on Treg cell biology will be determined. Finally, we will examine the suppressor function of Treg cells from PC mice to maintain immune homeostasis and to control ongoing inflammation in comparison with their SPF counterparts. Together, our study will not only further extend our fundamental knowledge of Treg cell-dependent immune regulation but also provide critical insights into the possibilities and limitations of targeting Treg cells to treat a wide array of human immunological diseases. .

严格的生物防护措施可防止实验室小鼠感染天然病原体， 研究人员以可靠和可重复的方式进行动物实验。然而，这种具体 无病原体（SPF）小鼠不能模拟自然界中发生的免疫反应，这可能 导致临床前研究和人体临床试验之间经常报告的脱节。尽管 通过对SPF小鼠的研究，生物医学研究的许多关键进展成为可能， 现在令人信服的证据表明，微生物或病毒的经验可以大大影响免疫病理生理学。在 在过去的二十年里，调节性T（Treg）细胞已经成为一种对免疫系统至关重要的专用免疫群体。 免疫反应的负调节。考虑到Treg细胞的稳态和功能可能是 受存在于不同组织环境中的独特信号的极大影响，可以想象， 当前实验室环境之外的微生物暴露可能会严重影响Treg细胞及其抗肿瘤能力 不仅要建立对“自身”或无害的外来抗原的免疫耐受性，而且要保持免疫耐受性。 检查对病原体的效应免疫反应。为了更好地了解Treg细胞介导的 为了在更生理的环境中进行免疫调节，我们与动物护理计划密切合作， 加州大学圣地亚哥分校建立一个新的协议，以产生，维持和广泛表征稳定的 生理微生物暴露环境条件（PC）动物的储存库。通过采取这一 方法，两个完善的小鼠模型，提供Treg细胞分离和Treg细胞特异性消融 将首先适应“脏”条件。其次，通过进行广泛的比较免疫， 表型分析和单细胞测序研究从淋巴和淋巴细胞中分离的Treg细胞 SPF小鼠和PC小鼠的非淋巴组织，生理微生物暴露对Treg细胞的影响 生物学将被确定。最后，我们将检查来自PC小鼠的Treg细胞的抑制功能， 维持免疫稳态，并控制持续的炎症，与SPF相比， 同行总之，我们的研究不仅将进一步扩展我们对Treg的基础知识， 细胞依赖性免疫调节，但也提供了重要的见解的可能性和局限性， 靶向Treg细胞以治疗多种人类免疫性疾病。 .