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

项目摘要 当免疫系统攻击健康组织时，就会发生病理性自身免疫，导致免疫病理 和组织功能障碍。有80多种公认的自身免疫性疾病困扰着2500万到5000万人 这是一个巨大的财政和公共卫生负担。实验用的小鼠有 几十年来一直是自身免疫研究的标准模型。然而，尽管对老鼠的研究已经 导致了对哺乳动物免疫系统的发展和功能的大多数基本见解， 在自身免疫性疾病的小鼠模型中，恢复自我耐受相对容易 这些发现中的许多很难转化为治疗人类自身免疫的有效方法。这是 这可能是由于1)诱导小鼠和小鼠耐受的免疫途径的根本不同。 人类，以及2)精心安置和监测的实验动物之间免疫环境的差异 老鼠以及人类面临的更多异质和令人生畏的免疫挑战，这些人暴露在 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的必要性 更接近于人类的免疫系统，并解释了这些重要因素中的每一个。的目标是 这项建议是使用新的和现实的小鼠模型，更接近地反映人类的免疫功能 研究通过操纵IL-2/TR细胞轴诱导耐受，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。

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.