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: 10307124
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307124
• 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.

项目摘要 当免疫系统攻击健康组织时，病理自身免疫会发生 和组织功能障碍。有80多种公认的自身免疫性疾病，折磨了25-50亿 美国人，这代表了重大的财务和公共卫生负担。实验鼠标具有 几十年来一直是自身免疫研究的标准模型。但是，尽管在小鼠中的研究有 导致大多数基本见解对哺乳动物免疫系统的发展和功能， 在自身免疫性疾病的小鼠模型和 这些发现中的许多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VS耐受性诱导的免疫途径的基本差异。 人类和2）经过精心安装和受监测的实验的免疫环境的差异 小鼠和人类面临的更异质和艰巨的免疫挑战，他们暴露于 持续的急性和慢性感染以及一系列会损害组织的环境暴露 并引起免疫反应。这凸显了需要研究动物模型中的免疫耐受性的需求 更类似于人类免疫系统，并说明这些重要因素中的每一个。目标 该建议是使用新颖而现实的鼠标模型，这些模型更紧密地反映了人类免疫功能 通过操纵IL-2/TR细胞轴研究耐受性诱导，并确定关键参数 影响旨在预防或改善自身免疫性疾病的疗法的结果。

项目成果

An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice.

• DOI: 10.1126/sciimmunol.aba5264
• 发表时间: 2020-08-14
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Khoryati L;Pham MN;Sherve M;Kumari S;Cook K;Pearson J;Bogdani M;Campbell DJ;Gavin MA
• 通讯作者: Gavin MA

Regulatory T Cells Maintain Selective Access to IL-2 and Immune Homeostasis despite Substantially Reduced CD25 Function.

• DOI: 10.4049/jimmunol.1901520
• 发表时间: 2020-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Hayes ET;Hagan CE;Khoryati L;Gavin MA;Campbell DJ
• 通讯作者: Campbell DJ

In Vivo Expansion of Antigen-Specific Regulatory T Cells through Staggered Fc.IL-2 Mutein Dosing and Antigen-Specific Immunotherapy.

通过交错 Fc.IL-2 突变蛋白剂量和抗原特异性免疫疗法体内扩增抗原特异性调节 T 细胞。

• DOI: 10.4049/immunohorizons.2100051
• 发表时间: 2021
• 期刊: ImmunoHorizons
• 作者: Pham,MinhN;Khoryati,Liliane;Jamison,BraxtonL;Hayes,Erika;Sullivan,JennaM;Campbell,DanielJ;Gavin,MarcA
• 通讯作者: Gavin,MarcA