Lymphotoxin Beta Receptor in Intestinal Inflammation

描述(申请人提供)：粘膜免疫系统是一个复杂的淋巴隔间网络，其功能是保护宿主免受病原体的侵袭。然而，这些免疫反应必须严格控制，因为不适当的免疫反应可能会损害粘膜，并对肠道功能产生不利影响。在这项建议中，我们将研究分离淋巴滤泡(ILF)的功能和起源，ILF是最近被认可的粘膜免疫系统的成员。 ILF是小肠中类似Peyer‘s Patches(PP)的有组织的淋巴结构，具有滤泡相关上皮(FAE)。ILF的组织结构和细胞组成表明ILF促进了抗原、抗原提呈细胞和淋巴细胞之间的有效相互作用。我们最近证明，ILF在黏膜组织的淋巴间隔室中是独特的，因为它们的形成可以由管腔刺激诱导。因此，ILF代表了一个可诱导的免疫诱导部位的储存库，这些部位可以被操纵来以治疗的方式塑造免疫反应。 在第一个特定目标中，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的表型。我们将通过从ILF中分离细胞群体和检测描绘功能性淋巴细胞和树突状细胞亚群的细胞表面标记的表达来实现这些目标。我们将检测分离的ILF细胞亚群对激活刺激的反应产生的细胞因子，以及ILF树突状细胞群体驱动T淋巴细胞亚群分化的能力。 在第二个特定目标中，我们将研究ILF形成的阶段，在该阶段需要淋巴毒素充足的B淋巴细胞，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测B细胞受体转基因小鼠ILF的形成。我们将检查骨髓嵌合小鼠ILF的形成，这些嵌合小鼠选择性地用淋巴毒素充足或缺乏的B淋巴细胞重建。我们将检测CCR6缺陷小鼠的ILF形成，以及选择性地重建CCR6充足细胞亚群的骨髓嵌合小鼠。 这项建议的长期目标是定义允许以治疗性方式操纵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.