Targeting the IL-2/regulatory T cell axis for autoimmune disease prevention in realistic animal models

靶向 IL-2/调节性 T 细胞轴在真实动物模型中预防自身免疫性疾病

• 批准号: 10062808
• 负责人: Daniel J Campbell
• 金额: $ 67.93万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-20 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062808
• 关键词: Acute; Address; Alopecia Areata; American; Animal Model; Antigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Biology; CD34 gene; Cell physiology; Cells; Chronic; Crohn' s disease; Daclizumab; Development; Disease; Effector Cell; Environment; Environmental Exposure; Experimental Genetics; Exposure to; FOXP3 gene; Functional disorder; Generations; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Growth Factor; Hematopoietic Stem Cell Transplantation; Human; IL2 Signaling Pathway; IL2RA gene; Immune; Immune System Diseases; Immune Tolerance; Immune system; Immunogenetics; Immunology; Immunotherapy; Incidence; Infection; Infrastructure; Insulin-Dependent Diabetes Mellitus; Interleukin 2 Receptor; Interleukin-2; Laboratory mice; Maintenance; Molecular; Monitor; Monoclonal Antibodies; Multiple Sclerosis; Mus; Natural Immunity; Pathologic; Pathway interactions; Phenotype; Physiological; Public Health; Receptor Signaling; Regulatory T-Lymphocyte; Research; Research Institute; Research Personnel; Resources; Rheumatoid Arthritis; Role; Self Tolerance; Standard Model; System; T-Lymphocyte; Therapeutic; Tissues; Translating; Universities; Vaccination; Vitiligo; Washington; Work; acute infection; chronic infection; disorder prevention; drug development; effective therapy; genetic manipulation; humanized mouse; immune function; immunopathology; immunoreaction; insight; mouse model; novel; pathogen; prevent; receptor; response; restoration; therapy outcome; translational study

Project Summary Pathological autoimmunity occurs when the immune system attacks healthy tissue, causing immunopathology and tissue dysfunction. There are over 80 recognized autoimmune diseases that afflict 25-50 million Americans, and this represents a significant financial and public health burden. The experimental mouse has been a standard model of autoimmune research for several decades. However, although research in mice has led to most of the fundamental insights into the development and function of the mammalian immune system, restoration of self-tolerance has been relatively easy to achieve in mouse models of autoimmune disease and many of these findings have been difficult to translate into effective therapies for human autoimmunity. This is likely due to 1) Fundamental differences in immune pathways responsible for tolerance induction in mouse vs. human, and 2) Differences in the immune environment between carefully housed and monitored experimental mice and the more heterogeneous and daunting immune challenges faced by humans, who are exposed to continual acute and chronic infection along with an array of environmental exposures that can damage tissues and provoke immune reactions. This highlights the need to study immune tolerance in animal models that more closely resemble human immune systems, and account for each of these important factors. The goal of this proposal is to use novel and realistic mouse models that more closely mirror human immune function to study tolerance induction via manipulation of the IL-2/TR cells axis, and identify critical parameters that influence the outcome of therapies aimed at preventing or ameliorating autoimmune disease.

项目概要 当免疫系统攻击健康组织，引起免疫病理学时，就会发生病理性自身免疫 和组织功能障碍。有超过 80 种公认的自身免疫性疾病困扰着 25-5000 万人 美国人，这代表着巨大的财政和公共卫生负担。实验小鼠有 几十年来一直是自身免疫研究的标准模型。然而，尽管对小鼠的研究 导致对哺乳动物免疫系统的发育和功能的大部分基本见解， 在自身免疫性疾病和小鼠模型中，自我耐受性的恢复相对容易实现 其中许多发现很难转化为人类自身免疫的有效疗法。这是 可能是由于 1) 导致小鼠和小鼠耐受诱导的免疫途径存在根本差异。 人类，以及 2) 精心饲养和监测的实验之间免疫环境的差异 小鼠和人类面临的更加异质和令人畏惧的免疫挑战，人类暴露于 持续的急性和慢性感染以及一系列可能损害组织的环境暴露 并引发免疫反应。这凸显了在动物模型中研究免疫耐受性的必要性 更类似于人类的免疫系统，并解释了这些重要因素中的每一个。目标是 该提案是使用新颖且真实的小鼠模型来更接近地反映人类免疫功能 通过操纵 IL-2/TR 细胞轴研究耐受诱导，并确定关键参数 影响旨在预防或改善自身免疫性疾病的治疗结果。