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区室，遇到最多样化的抗原负荷，并且被全世界绝大多数传染病破坏或感染。对小鼠和人类肠道相关淋巴组织 (GALT) 的研究为了解特殊淋巴细胞亚群和免疫球蛋白 (Ig) 同型提供了深入了解，这些亚型负责管理对食物抗原和共生体的耐受性与针对病原体的激活之间的平衡。然而，人们对 GALT 的比较免疫学知之甚少。对于该系统产生的冷血脊椎动物来说尤其如此。我提议检验这样的假设：肠道中的特化 T 细胞亚群和 Ig 同种型是我们免疫系统的古老而基本的组成部分，在适应性免疫历史的早期是必需的。鲨鱼和青蛙 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于特殊亚群的所有组成部分，例如新的 NAR-TcR T 细胞。组织染色将在解剖学上绘制肠道上皮或固有层内这些细胞的图谱。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哪些同种型和机制在体液粘膜区室中是保守的。口服免疫将测试给药途径、类别转换的胸腺依赖性、外周口服耐受的产生和轻链同种型功能。低等脊椎动物的 GALT 研究将告诉我们什么是介导防御和耐受的系统发育基础。此外，我们还将深入了解早期淋巴细胞亚群和适应性免疫系统的全部功能。 通过给我作为新助理教授的这项基础研究提供保护的时间，三年内我的第一个 R01 将有可能获得更强大的应用。这项工作将为我的独立职业生涯奠定基础，研究我们免疫系统的起源和自然史，以便医生能够更好地修改治疗方案以改善疾病。 NIAID 战略计划的四个基石中的一个统一主题是需要更好地理解淋巴细胞从自身免疫和过敏的极端失败到自身免疫和过敏的调节，而研究模型原始脊椎动物 GALT 免疫学的比较工作已经成熟，可以产生这样的理解。