Lymphotoxin Beta Receptor in Intestinal Inflammation

描述（由申请人提供）：粘膜免疫系统是一个复杂的淋巴区室网络，其功能是保护宿主免受病原体的入侵。然而，必须严格控制这些免疫反应，因为不适当的免疫反应会损伤粘膜，并对肠道功能产生不利影响。在本提案中，我们将研究分离淋巴滤泡（ILF）的功能和起源，ILF 是最近受到重视的粘膜免疫系统成员。 ILF 是小肠中有组织的淋巴结构，类似于派尔氏淋巴结 (PP)，并具有滤泡相关上皮 (FAE)。 ILF 的组织结构和细胞组成表明 ILF 促进抗原、抗原呈递细胞和淋巴细胞的有效相互作用。我们最近证明，ILF 在粘膜组织的淋巴室中是独特的，因为它们的形成可以通过腔刺激诱导。因此，ILF 代表了免疫诱导位点的诱导库，可以通过操纵其以治疗方式塑造免疫反应。 在第一个具体目标中，我们将检查 ILF 内的细胞群，并检查这些 ILF 细胞群介导的免疫反应表型。我们将通过从 ILF 中分离细胞群并检查描绘功能性淋巴细胞和树突状细胞亚群的细胞表面标记物的表达来实现这些目标。我们将检查分离的 ILF 细胞亚群响应激活刺激而产生的细胞因子，并且我们将检查 ILF 树突状细胞群驱动 T 淋巴细胞亚群分化的能力。 在第二个具体目标中，我们将检查需要具有足够淋巴毒素的 B 淋巴细胞的 ILF 形成阶段、经历抗原的 B 淋巴细胞在 ILF 形成中的作用以及 CCR6 在 ILF 形成中的作用。为了实现这些目标，我们将在没有外源抗原的情况下检查 B 细胞受体转基因小鼠中 ILF 的形成。我们将检查用淋巴毒素充足或缺乏的 B 淋巴细胞选择性重建的骨髓嵌合小鼠中 ILF 的形成。我们将检查 CCR6 缺陷小鼠和用 CCR6 足够的细胞亚群选择性重建的骨髓嵌合小鼠中 ILF 的形成。 该提案的长期目标是确定以治疗方式操纵 ILF 形成的途径。

DESCRIPTION (provided by applicant): The mucosal immune system is a complex network of lymphoid compartments that function to protect the host from invading pathogens. However, these immune responses must be tightly controlled, as inappropriate immune responses can damage the mucosa, and adversely impact intestinal function. In this proposal we will investigate the function and genesis of isolated lymphoid follicles (ILFs), a recently appreciated member of the mucosal immune system. ILFs are organized lymphoid structures in the small intestine resembling Peyer's patches (PP), and possessing a follicle associated epithelium (FAE). The organized structure and cellular composition of ILFs suggests that ILFs facilitate effective interactions of antigen, antigen presenting cells, and lymphocytes. We have recently demonstrated that ILFs are unique amongst the mucosal organized lymphoid compartments in that their formation can be induced by lumenal stimuli. Therefore, ILFs represent an inducible reservoir of immune inductive sites, which could be manipulated to shape immune responses in a therapeutic manner. In the first specific aim we will examine the cellular populations within ILFs and examine the phenotype of immune responses mediated by these ILF cellular populations. We will accomplish these goals by isolating cellular populations from ILFs and examining the expression of cell surface markers that delineate functional lymphocyte and dendritic cell subsets. We will examine the cytokine production by isolated ILF cellular subpopulations in response to activating stimuli, and we will examine the ability of ILF dendritic cell populations to drive the differentiation of T-lymphocytes subsets. In the second specific aim we will examine the stage of ILF formation in which lymphotoxin sufficient Blymphocytes are required, the role of antigen experienced B-lymphocytes in ILF formation, and the role of CCR6 in ILF formation. To accomplish these goals we will examine ILF formation in B-cell receptor transgenic mice in the absence of exogenous antigen. We will examine ILF formation in bone marrow chimeric mice selectively reconstituted with lymphotoxin sufficient or deficient B-lymphocytes. We will examine ILF formation in CCR6 deficient mice, and in bone marrow chimeric mice selectively reconstituted with CCR6 sufficient cellular subpopulations. Long-term objectives of this proposal are to define pathways which will allow manipulation of ILF formation in a therapeutic manner.