Lymphotoxin Beta Receptor in Intestinal Inflammation

描述（由申请方提供）：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入侵病原体的侵害。然而，这些免疫反应必须严格控制，因为不适当的免疫反应会损害粘膜，并对肠道功能产生不利影响。在这个建议中，我们将调查的功能和孤立的淋巴滤泡（ILF），粘膜免疫系统最近赞赏的成员的发生。 ILF是小肠中类似于派尔集合淋巴结（PP）的有组织的淋巴结构，并且具有滤泡相关上皮（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。我们最近已经证明，ILF是独特的粘膜组织的淋巴样隔室中，它们的形成可以诱导内腔刺激。因此，ILF代表免疫诱导位点的诱导型储库，其可以被操纵以治疗方式形成免疫应答。 在第一个具体目标中，我们将检查ILF内的细胞群体，并检查由这些ILF细胞群体介导的免疫应答的表型。我们将通过从ILF中分离细胞群并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志物的表达来实现这些目标。我们将研究细胞因子的生产孤立的ILF细胞亚群在激活刺激，我们将研究ILF树突状细胞群体的能力，驱动T淋巴细胞亚群的分化。 在第二个具体的目标，我们将检查ILF形成的阶段，其中需要足够的B-lymphocyte，抗原经历的B-淋巴细胞在ILF形成中的作用，和CCR 6在ILF形成中的作用。为了实现这些目标，我们将研究在缺乏外源性抗原的情况下B细胞受体转基因小鼠中ILF的形成。我们将研究ILF形成的骨髓嵌合小鼠选择性重建与足够的或缺乏的B淋巴细胞。我们将检查CCR 6缺陷小鼠中ILF的形成，并在骨髓嵌合小鼠中选择性地用CCR 6重建足够的细胞亚群。 该提案的长期目标是确定允许以治疗方式操纵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.