Origins of specialized Mucosal Lymphocyte Subsets and Immunoglobulin Isotypes

特殊粘膜淋巴细胞亚群和免疫球蛋白同种型的起源

• 批准号: 7245960
• 负责人: MICHAEL FREDERICK CRISCITIELLO
• 金额: $ 16.2万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245960
• 关键词: Adult; Advocate; African; Allergens; Allergic; Amphibia; Animal Model; Animals; Antibodies; Antigen Receptors; Antigens; Architecture; Autoimmunity; Award; Biological Response Modifiers; Biology; Cells; Communicable Diseases; Comprehension; Crohn' s disease; Data; Data Set; Dependence; Development; Disease; Educational process of instructing; Equilibrium; Evolution; Failure; FarGo; Food; Generations; Genetic; Goals; Gut associated lymphoid tissue; Hypersensitivity; Immune; Immune Tolerance; Immune system; Immunity; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin Isotypes; Immunoglobulin M; Immunoglobulins; Immunohistochemistry; Immunology; In Situ Hybridization; Individual; Intestines; Investigation; Knowledge; Lamina Propria; Left; Length; Light; Lymphocyte; Lymphocyte Subset; Lymphoid; Lymphoid Tissue; Mammals; Maps; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mucosal Immunity; Mus; Natural History; Nurses; Oral; Oral Administration; Organism; Phylogenetic Analysis; Physicians; Physiological; Physiology; Plasma Cells; Play; Population; Postdoctoral Fellow; Postdoctoral Individual National Research Service Award; Purpose; Rana; Recording of previous events; Regulation; Research; Research Personnel; Role; Route; Running; Secure; Seeds; Shark; Stimulus; Strategic Planning; Surface; System; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymectomy; Thymus Gland; Time; Tissue Model; Tissue Stains; Tissues; Training; Ulcerative Colitis; Upper arm; Vertebrates; Work; Xenopus; Xenopus sp.; analog; base; career; cold blooded vertebrate; comparative; fundamental research; gastrointestinal epithelium; human disease; insight; interest; intraperitoneal; macrophage; man; member; novel strategies; oral tolerance; pathogen; preference; professor; programs; receptor; response; tool

DESCRIPTION (provided by applicant): The mammalian mucosal immune system is the largest lymphoid compartment, encounters the most diverse antigenic load, and is breached or infected by the great majority of infectious diseases worldwide. Studies of gut associated lymphoid tissues (GALT) in mouse and man have provided much insight into the specialized lymphocyte subsets and immunoglobulin (Ig) isotypes that manage the balance between tolerance to food antigens and commensals and activation against pathogen. However little is known of comparative immunology of GALT. This is especially true in the cold-blooded vertebrates where the system arose. I propose to test the hypothesis that specialized T cell subsets and Ig isotypes in the gut are an ancient and fundamental part of our immune system that were necessary early in the history of adaptive immunity. The shark and frog GALT are the models in which this hypothesis will be tested. In shark the molecular characterization of intestinal lymphocytes will focus on the repertoire of special subsets such as the new NAR-TcR T cell. Tissue staining will map these cells anatomically within the gut epithelia or lamina propria. The second aim will employ the experimental advantages and immunological tools of the African clawed frog system to investigate which isotypes and mechanisms are conserved in the humoral mucosal compartment. Oral immunizations will test route of administration, thymus dependence of class switch, generation of oral tolerance in the periphery and light chain isotype function. GALT study in lower vertebrates will teach us what is phylogenetically basic in mediating defense and tolerance. Additionally, we will gain insight into the early lymphocyte subpopulations and repertoires of the adaptive immune system. By allowing me protected time for this fundamental research as a new Assistant Professor, a stronger application will be possible for my first R01 in three years. This work will seed my independent career investigating the origins and natural history of our immune system to better able the physician to modify repertoires for the amelioration of disease. A unifying theme in the four cornerstones of NIAID's strategic plan is the need for a better comprehension of lymphocyte regulation from the extremes of failure of the repertoire to autoimmunity and allergy, and comparative work studying GALT immunology in model primitive vertebrates is ripe to yield such understanding.

描述（由申请人提供）：哺乳动物粘膜免疫系统是最大的淋巴细胞室，遇到最多样化的抗原负荷，并被世界上绝大多数传染病破坏或感染。对小鼠和人肠道相关淋巴组织（GALT）的研究，使我们对特定的淋巴细胞亚群和免疫球蛋白（Ig）同型有了更深入的了解，这些淋巴细胞亚群和免疫球蛋白同型管理着对食物抗原和共生体的耐受性与对病原体的激活之间的平衡。然而，对GALT的比较免疫学知之甚少。这在系统产生的冷血脊椎动物中尤其如此。我建议测试这样一个假设，即肠道中专门的T细胞亚群和Ig同种型是我们免疫系统的一个古老而基本的部分，在适应性免疫的早期历史中是必要的。鲨鱼和青蛙的GALT是检验这一假设的模型。在鲨鱼中，肠道淋巴细胞的分子特征将集中在特殊亚群的曲目上，如新的NAR-TcR T细胞。组织染色将绘制这些细胞在肠上皮或固有层内的解剖图。第二个目标将利用非洲爪蛙系统的实验优势和免疫学工具来研究体液粘膜室中哪些同种型和机制是保守的。口服免疫将测试给药途径、胸腺对类转换的依赖性、外周口服耐受的产生和轻链同型功能。低等脊椎动物GALT的研究将告诉我们什么是系统发育基础的防御和耐受。此外，我们将深入了解早期淋巴细胞亚群和适应性免疫系统的功能。