The Immune Response in Mast Cell Deficient Mice

描述(申请人提供)：在特定的社会、压力和疾病状态下，大脑肥大细胞的数量增加。同样重要的是，发现大脑肥大细胞可以穿过血脑屏障。虽然肥大细胞最为人所知的是它们在介导过敏反应中的作用，但越来越明显的是，它们在抵御细菌感染方面也发挥着保护作用。肥大细胞是异质性的，它们的介体含量取决于它们的微环境，这表明应该将大脑肥大细胞作为一个独特的群体来研究--与外围的肥大细胞不同。本申请建议开发一种小鼠模型，该模型将用于理解大脑中肥大细胞的现象学和功能后果。试验数据表明，肥大细胞缺陷动物对细菌感染缺乏完全的急性时相反应(APR)。为了研究肥大细胞在建立免疫反应中的作用，我们探索了两种社会/行为/内分泌条件，在这些条件下，大脑肥大细胞数量增加：同居范式和应激范式。接下来，我们测试假设，先前暴露(这增加了大脑肥大细胞数量)导致肥大细胞丰富的大脑部位对免疫系统挑战的反应改变。具体地说，我们问当肥大细胞在大脑中的数量增加时，肥大细胞的数量和激活状态是否会增加。为了验证大脑肥大细胞具有免疫学后果的假设，我们确定肥大细胞数量的增加是否会导致肥大细胞丰富的大脑区域的T细胞监视发生变化。我们建议在肥大细胞缺陷小鼠、它们的野生型后代和肥大细胞重组动物中测试这些假设。这项应用将决定肥大细胞是否在大脑中发挥免疫反应的作用。

DESCRIPTION (provided by applicant): The number of brain mast cells increases under specific social, stressful, and disease states. Also important, is the discovery that brain mast cells can cross the BBB. Although mast cells are best known for their role in mediating allergic reactions, it has become increasingly evident that they also play a protective role in defense against bacterial infection. Mast cells are heterogeneous, and their mediator content is dependent on their microenvironment, suggesting that brain mast cells should be studied as a unique population - as distinct from those in the periphery. The present application proposes to develop a mouse model which will be used in understanding the phenomenology and functional consequences of mast cells in the brain. Pilot data indicate that mast cell deficient animals lack a complete Acute Phase Response (APR) to bacterial infection. To examine the involvement of mast cells in mounting an immune response, we explore 2 social/behavioral/endocrine conditions in which the brain mast cell population is augmented: a cohabitation paradigm and a stress paradigm. Next, we test the hypothesis that prior exposure (which increases brain mast cell numbers) results in altered response to challenge of the immune system in mast cell rich brain loci. Specifically, we ask whether the mast cell number, activation state is augmented when their numbers in the brain are elevated. To test the hypothesis that brain mast cells have immunological consequences, we determine if increased mast cell numbers results in altered T cell surveillance in mast cell rich brain regions. We propose to test these hypotheses in mast cell deficient mice, in their wild type littermates and in mast cell reconstituted animals. This application will determine whether mast cells play a role in mounting an immune response in the brain.