Human B1 Lymphopoiesis

人类 B1 淋巴细胞生成

• 批准号: 8385892
• 负责人: THOMAS L ROTHSTEIN
• 金额: $ 20.88万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385892
• 关键词: Address; Adopted; Adoptive Transfer; Adult; Animals; Antibodies; Autoantibodies; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biological Models; Bone Marrow; CD5 Antigens; Cell Count; Cell Differentiation process; Cell physiology; Cells; Coculture Techniques; Degenerative Disorder; Development; Disease; Elderly; Engineering; Evaluation; Fostering; Foundations; Functional disorder; Future; Gene Expression; Goals; Hand; Health; Hematopoietic; Hematopoietic stem cells; Host Defense; Human; Human Characteristics; Human Identifications; Immune; Immune response; Immunocompromised Host; Immunoglobulin M; Immunoglobulins; Immunosuppressive Agents; In Vitro; Infection; Infectious Agent; Inflammatory; Interleukin-10; Knowledge; Laboratories; Lead; Lupus; Lymphocyte; Lymphopoiesis; MS4A1 gene; Malignant Neoplasms; Mesenchymal; Mus; Nature; Phenotype; Play; Population; Production; Reaction; Regulation; Role; Signal Transduction; Sorting - Cell Movement; Staging; Stem cells; System; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Transcript; Umbilical Cord Blood; Work; adaptive immunity; base; cytokine; design; high risk; innate immune function; meetings; microbial; novel strategies; patient population; peripheral blood; progenitor; reconstitution; therapy design

DESCRIPTION (provided by applicant): This project concerns identification of the hematopoietic progenitor cell that gives rise to B1 cells, a specialized subpopulation of B cells. B1 cells are responsible for producing so-called "natural" antibodies that protect against microbial infection prior to the onset of adaptive immunity and appear to play a protective role in some degenerative diseases. B1 cells differ from conventional B cells in many other important ways, including stimulation of T cells, production of immunosuppressive IL-10, and skewing of pro-inflammatory T cell differentiation. In mice, B1 cells constitute a distinct lymphocyte lineage that is generated by a unique lymphopoietic progenitor, separate and apart from the progenitor that gives rise to conventional B2 cells. The applicant laboratory has now discovered the phenotypic identity of human B1 cells, as described in more detail elsewhere. With the true nature of human B1 cells in hand, the objective of this application is to identify the specific hematopoietic/lymphopoietic origin of human B1 cells, and to support or refute the hypothesis that human B1 cells, like their murine counterparts, derive from a unique progenitor. Identifying and characterizing the B1 cell progenitor holds out the promise of being able to manipulate the development, and hence modulate the number and/or function, of mature B1 cells, to enhance or diminish the special natural antibodies, and the special effects on T cells, produced by B1 cells, in health and disease, through specific B1 progenitor cell-directed therapies. To achieve this goal, several specific aims will be pursued to: 1) Establish a model system for lymphopoiesis that fosters the development of B1 cells from cord blood and/or bone marrow hematopoietic stem cells through adoptive transfer to immunocompromised animals, supplemented by in vitro studies of B1 cell development from hematopoietic stem cells co-cultured with mesenchymal cells; 2) Identify the earliest progenitor that specifically produces B1 cells and not B2 cells through sort-purification and differentiation of phenotypically defined populations from cord blood and bone marrow; and, 3) Characterize the identified progenitor that produces human B1 cells by evaluating endogenous gene expression through single cell PCR of specific transcripts and comparison with profiles of defined lymphopoietic stages, along with evaluation of the features that characterize progenitor-generated mature B1 cells, and examination of exogenous cytokine influences on B1 cell development. Understanding the origin of human B1 cells, which have only recently been identified in normal and patient populations, is critical to understanding B1 cell development and B1 cell physiology and pathophysiology, which can lead to novel strategies for therapeutic manipulation of B1 cell numbers and function to protect against infectious and other diseases. PUBLIC HEALTH RELEVANCE: A specialized population of B lymphocytes, termed B1 cells, produces so-called "natural" antibodies that protect against microbial infection but are associated with autoimmunity. Although well described in animals, B1 cells were only recently identified in humans by the applicant laboratory which determined the phenotype, or address, of these immune cells. We now propose to identify the human B1 cell progenitor which is the stem cell for B1 cells and gives rise to this specialized population; identification and characterizatio of the human B1 cell progenitor will make it possible to design B1 cell-directed therapies to increase protective natural antibodies or decrease autoimmune reactions.

描述（由申请人提供）：该项目涉及识别造血祖细胞，该细胞引起了B1细胞，B1细胞是B细胞的专门亚群。 B1细胞负责产生所谓的“天然”抗体，这些抗体在自适应免疫发作之前预防微生物感染，并在 一些退化性疾病。 B1细胞在许多其他重要方面与常规B细胞不同，包括刺激T细胞，免疫抑制IL-10以及促炎性T细胞分化的偏斜。在小鼠中，B1细胞构成一个独特的淋巴细胞谱系 这是由独特的淋巴祖先产生的，该祖细胞与祖细胞分开并与传统的B2细胞产生。如今，申请人实验室已经发现了人B1细胞的表型认同，如其他地方更详细描述。借助人类B1细胞的真实本质，该应用的目的是识别人B1细胞的特定造血/淋巴细胞的起源，并支持或反驳人类B1细胞（如其鼠类鼠）像鼠类鼠类一样，源自独特的祖先。识别和表征B1细胞祖细胞的承诺能够操纵成熟B1细胞的发育，并因此调节成熟B1细胞的数量和/或功能，以增强或减少特殊的自然抗体，以及通过特定的B1幼虫细胞递减的特定细胞在健康和疾病中产生的T细胞对T细胞产生的特种抗体。为了实现这一目标，将实现以下几个特定目标：1）建立一个淋巴细胞的模型系统，从而从脐带血和/或骨髓造血干细胞中促进了B1细胞的发展，通过过继转移到免疫强化动物中，并通过对B1细胞在b1细胞中的发展补充，从而补充了B1细胞中的B1细胞中的B1细胞，并伴有血小板的细胞共构成乳细胞，这些细胞均具有梅斯的菌丝菌丝菌丝菌群菌丝菌群; 2）通过分类和分化与脐带血和骨髓的表型定义种群的分类和分化，确定特异性产生B1细胞而不是B2细胞的最早祖细胞；和3）表征通过特定转录物的单细胞PCR评估内源基因表达的鉴定祖细胞，并与定义的淋巴细胞阶段的谱进行比较，并评估祖细胞生成的成熟B1细胞的特征，以及对B1细胞对B1细胞的外源性巨细胞影响的检查。了解人类B1细胞的起源，直到最近才在正常和患者种群中鉴定出来，对于理解B1细胞发育以及B1细胞生理和病理生理学至关重要，这可能导致对B1细胞数量和功能的治疗性操纵的新策略，以防止感染性和其他疾病。 公共卫生相关性：称为B1细胞的B淋巴细胞的专业人群产生所谓的“天然”抗体，可预防微生物感染，但与自身免疫有关。尽管在动物中描述了很好的描述，但B1细胞直到最近才通过确定这些免疫细胞的表型或地址的申请人实验室在人类中鉴定出来。现在，我们建议鉴定人类B1细胞祖细胞，该细胞是B1细胞的干细胞，并引起该专业人群。人B1细胞祖细胞的鉴定和特征将使设计B1细胞指导的疗法以增加保护性天然抗体或减少自身免疫反应。