Human B1 Lymphopoiesis

人类 B1 淋巴细胞生成

基本信息

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
项目类别：
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

项目摘要

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）：该项目涉及鉴定产生 B1 细胞（B 细胞的一种特殊亚群）的造血祖细胞。 B1 细胞负责产生所谓的“天然”抗体，这些抗体可以在适应性免疫出现之前防止微生物感染，并且似乎在以下方面发挥保护作用：一些退行性疾病。 B1 细胞在许多其他重要方面与传统 B 细胞不同，包括刺激 T 细胞、产生免疫抑制性 IL-10 以及偏向促炎性 T 细胞分化。在小鼠中，B1 细胞构成独特的淋巴细胞谱系它是由独特的淋巴细胞祖细胞产生的，与产生传统 B2 细胞的祖细胞是分开的。申请实验室现已发现人类 B1 细胞的表型特征，如其他地方更详细的描述。掌握了人类 B1 细胞的真实性质，本应用的目的是确定人类 B1 细胞的特定造血/淋巴细胞起源，并支持或反驳这样的假设：人类 B1 细胞与小鼠对应细胞一样，源自独特的祖先。鉴定和表征 B1 细胞祖细胞有望操纵成熟 B1 细胞的发育，从而调节成熟 B1 细胞的数量和/或功能，以增强或减弱特殊的天然抗体以及对 T 细胞的特殊作用，由 B1 细胞通过特定的 B1 祖细胞定向疗法在健康和疾病中产生。为了实现这一目标，将追求几个具体目标：1）建立淋巴细胞生成模型系统，通过过继转移至免疫功能低下的动物，并辅以体外培养，促进脐带血和/或骨髓造血干细胞发育成B1细胞。研究造血干细胞与间充质细胞共培养的 B1 细胞发育； 2) 通过对脐带血和骨髓中表型定义的群体进行分选纯化和分化，鉴定特异性产生 B1 细胞而不是 B2 细胞的最早祖细胞； 3) 通过特定转录本的单细胞 PCR 评估内源基因表达，并与确定的淋巴细胞生成阶段的概况进行比较，同时评估祖细胞生成的成熟 B1 细胞的特征，从而表征产生人类 B1 细胞的已鉴定祖细胞，以及检查外源细胞因子对 B1 细胞发育的影响。了解人类 B1 细胞的起源（最近才在正常人和患者群体中发现）对于了解 B1 细胞发育和 B1 细胞生理学和病理生理学至关重要，这可以导致治疗操纵 B1 细胞数量和功能的新策略预防传染病和其他疾病。公共健康相关性：B 淋巴细胞的特殊群体（称为 B1 细胞）可产生所谓的“天然”抗体，可防止微生物感染，但与自身免疫有关。尽管在动物中得到了很好的描述，但申请人实验室最近才在人体中鉴定出 B1 细胞，并确定了这些免疫细胞的表型或地址。我们现在建议鉴定人类 B1 细胞祖细胞，它是 B1 细胞的干细胞，并产生这个特殊的群体；人类 B1 细胞祖细胞的鉴定和表征将使设计 B1 细胞定向疗法以增加保护性天然抗体或减少自身免疫反应成为可能。