Replenishment of the Innate Immune System

描述（申请人提供）：巨噬细胞和树突状细胞在整个生命过程中不断补充，是先天免疫系统的重要组成部分。长期以来，人们一直认为它们是在骨髓中产生的，严格依赖于生长和分化因子。然而，我们的新发现表明，在全身性感染期间，一种特殊的机制起了作用。在没有其他因素的toll样受体（TLR）配体刺激下，高度纯化的造血细胞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现及其识别细菌/病毒产物的能力而引起了广泛的关注。我们的初步结果表明，TLR在干细胞上表达，为先天免疫系统细胞的产生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小鼠的特殊敲入和同源菌株，以及细胞分选和培养技术，精确地确定哪些干细胞和祖细胞表达功能性TLR。来自小鼠和人类的细胞将暴露于病毒、炭疽和细菌产物中，以了解反应模式的范围。随后的实验将揭示个体祖细胞在暴露于这些物质时如何增殖和分化，以及巨噬细胞的产生如何以牺牲其他血细胞类型为代价。该项目将逐步从简单的实验设计转向复杂的全动物研究。目的是了解感染是否扭曲了正常的分化模式，从而使先天免疫系统能够迅速恢复。携带TLR的细胞与自身免疫和与这一新的研究路线相关的广泛的其他疾病有关。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。即使是植物和简单的生物也有一些防御疾病的能力，它们使用的是所谓的“先天免疫系统”。人类还受到先天免疫系统的保护，尽管它不像免疫那样复杂，但它可以迅速感知细菌和病毒并作出反应。这个项目是基于一个令人兴奋的发现，即先天免疫系统如何在感染期间恢复。这一发现也可能表明骨髓中的骨骼和干细胞受到感染的一种方式。

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.