Lymphotoxin Beta Receptor in Intestinal Inflammation

肠道炎症中的淋巴毒素β受体

• 批准号: 7898172
• 负责人: Rodney D Newberry
• 金额: $ 3.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898172
• 关键词: Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bone Marrow; Cell surface; Cellular Structures; Complex; Crohn' s disease; Data; Dendritic Cells; Disease; Enzyme-Linked Immunosorbent Assay; Epithelium; Family member; Flow Cytometry; Goals; Immune; Immune response; Immune system; Immunoglobulin A; Immunoglobulin Isotypes; Immunologics; In Vitro; Inflammatory; Inflammatory disease of the intestine; Intestines; Invaded; Ligation; Lymphocyte; Lymphocyte Function; Lymphocyte Subset; Lymphocyte antigen; Lymphoid; Lymphoid Follicle; Measures; Mediating; Mucous Membrane; Mus; Pathway interactions; Phenotype; Population; Production; Receptors, Antigen, B-Cell; Research Personnel; Role; Shapes; Site; Small Intestines; Staging; Stimulus; Structure; Structure of aggregated lymphoid follicle of small intestine; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Transgenic Mice; Tumor Necrosis Factor-Beta; base; chemokine receptor; cytokine; experience; lymphotoxin beta receptor; member; pathogen; programs; reconstitution; response

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.

描述（由申请人提供）：粘膜免疫系统是一个复杂的淋巴舱网络，可保护宿主免受入侵病原体的作用。但是，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，并对肠功能产生不利影响。在此提案中，我们将研究分离的淋巴卵泡（ILF）的功能和起源，这是粘膜免疫系统的最近成员。 ILF是类似于Peyer斑块（PP）的小肠中有组织的淋巴结构，并具有相关的上皮（FAE）。 ILF的有组织的结构和细胞组成表明，ILF促进了抗原，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在粘膜有组织的淋巴区室中是独一无二的，因为它们的形成可以由腔刺激诱导。因此，ILF代表了免疫感应部位的诱导液，可以操纵以治疗方式塑造免疫反应。 在第一个特定目的中，我们将检查ILF中的细胞群体，并检查由这些ILF细胞种群介导的免疫反应的表型。我们将通过从ILF中分离细胞群来实现这些目标，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的表达。我们将通过响应激活刺激来检查通过分离的ILF细胞亚群来检查细胞因子的产生，我们将检查ILF树突状细胞群体驱动T淋巴细胞亚群分化的能力。 在第二个特定目的中，我们将研究ILF形成的阶段，其中淋巴细胞毒素需要足够的腹膜细胞，抗原经历的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，我们将在没有外源性抗原的情况下检查B细胞受体转基因小鼠中的ILF形成。我们将检查骨髓嵌合小鼠中的ILF形成，其与淋巴毒素足够或不足的B淋巴细胞有选择地重构。我们将检查CCR6缺乏小鼠的ILF形成，以及在CCR6有足够的细胞亚群中选择性重构的骨髓嵌合小鼠中的ILF形成。 该提案的长期目标是定义途径，该途径将允许以治疗方式操纵ILF形成。