The Immune Response in Mast Cell Deficient Mice

描述（由申请人提供）：在特定的社交、压力和疾病状态下，脑肥大细胞的数量会增加。同样重要的是发现脑肥大细胞可以穿过血脑屏障。尽管肥大细胞因其在介导过敏反应中的作用而闻名，但越来越明显的是，它们在防御细菌感染方面也发挥着保护作用。肥大细胞是异质的，它们的介质含量取决于它们的微环境，这表明脑肥大细胞应该作为一个独特的群体来研究——与周围的肥大细胞不同。本申请提出开发一种小鼠模型，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，肥大细胞缺陷的动物缺乏对细菌感染的完整急性期反应（APR）。为了检查肥大细胞在免疫反应中的参与，我们探索了两种社会/行为/内分泌条件，其中脑肥大细胞群体增加：同居范式和压力范式。接下来，我们测试了以下假设：先前暴露（增加脑肥大细胞数量）会导致肥大细胞丰富的脑位点对免疫系统挑战的反应发生改变。具体来说，我们询问当大脑中肥大细胞的数量增加时，肥大细胞的数量和激活状态是否会增加。为了检验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富含肥大细胞的大脑区域的 T 细胞监视发生改变。我们建议在肥大细胞缺陷小鼠、其野生型同窝小鼠和肥大细胞重组动物中测试这些假设。该应用将确定肥大细胞是否在大脑中产生免疫反应中发挥作用。

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.