Replenishment of the Innate Immune System

描述(申请人提供)：巨噬细胞和树突状细胞在一生中不断补充，是先天免疫系统的重要组成部分。长期以来，它们被认为是在骨髓中产生的，严格依赖于生长和分化因素。然而，我们的新发现表明，在全身感染期间，一种特殊的机制发挥作用。高纯度的造血细胞在含有Toll样受体(TLR)配体而不含其他因素的刺激下，可产生巨噬细胞和树突状细胞。TLR因其在成熟效应细胞上的表达和识别细菌/病毒产物的能力而引起了人们的极大关注。我们的初步结果表明，TLR在干细胞上表达，并为产生天然免疫系统的细胞提供了一种原始但高效的机制。这个为期两年的项目将利用特殊的敲入和同源品系的小鼠，结合细胞分离和培养技术，准确地确定哪些干细胞和祖细胞表达功能性TLR。老鼠和人类的细胞将暴露在病毒、炭疽和细菌产品中，以了解反应模式的范围。随后的实验将揭示单个祖细胞在接触这些物质时是如何增殖和分化的，以及巨噬细胞的产生是如何以牺牲其他血细胞类型为代价的。该项目将逐步从简单的实验设计转向复杂的整体动物研究。其目的是了解感染是否扭曲了正常的分化模式，以便快速恢复先天免疫系统。携带TLR的细胞与自身免疫和与这一新研究相关的一系列其他疾病有关。这些研究肯定会提供基本信息，但也可能提出增强先天免疫系统的新方法。总结：即使是植物和简单的生物体也有一些抵御疾病的能力，并使用被称为“先天免疫系统”的系统。人类也受到先天免疫系统的保护，尽管它没有免疫实现的那么复杂，但它可以快速感知并对细菌和病毒做出反应。这个项目是基于一项令人兴奋的发现，即在感染期间先天免疫系统如何恢复。这些发现还可能表明，感染会损害骨髓中的骨骼和干细胞。

DESCRIPTION (provided by applicant): Macrophages and dendritic cells are constantly replenished throughout life and represent important components of the innate immune system. They were long thought to be produced within bone marrow in strict dependence on growth and differentiation factors. However, our new findings suggest that a special mechanism comes into play during times of systemic infection. When stimulated in culture with ligands for the Toll-like receptors (TLR) but no other factors, highly purified hematopoietic cells give rise to macrophages and dendritic cells. TLR have attracted considerable attention because of their display on mature effector cells and their ability to recognize bacterial/viral products. Our preliminary results indicate that TLR are expressed on stem cells and provide a primitive but highly effective mechanism for producing cells of the innate immune system. This two year project will exploit special knock-in and congenic strains of mice together with cell sorting and culture techniques to determine precisely which stem and progenitor cells express functional TLR. Cells from mice and humans will be exposed to viruses, anthrax and bacterial products to learn the range of response patterns. Subsequent experiments will reveal how individual progenitors proliferate and differentiate when exposed to these substances, as well as how macrophage production can occur at the expense of other blood cell types. The project will progressively move from simple experimental designs to complex whole animal studies. The aim is to learn if infections skew normal differentiation patterns so that the innate immune system can be quickly restored. TLR bearing cells are being implicated in autoimmunity and a wide range of other diseases relevant to this new line of investigation. These studies are certain to provide fundamental information, but could also suggest new means to augment the innate immune system. Lay Summary: Even plants and simple organisms have some defense against disease, and use what is referred to as the "innate immune system". Humans are also protected by an innate immune system, and although it is not as sophisticated as that achieved with immunization, it can quickly sense and respond to bacteria and viruses. This project is based on an exciting discovery about how the innate immune system may be restored during infection. The findings may also suggest a way that bones and stem cells in the bone marrow are harmed by infections.