IL-7 in Human B1 and B2 Lymphocyte Differentiation

IL-7 在人 B1 和 B2 淋巴细胞分化中的作用

• 批准号: 7291203
• 负责人: KIMBERLY J PAYNE
• 金额: $ 2.2万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291203
• 关键词: B lymphocyte; SCID mouse; bioluminescence; blocking antibody; bone marrow; cell differentiation; cell population study; clinical research; cord blood; cytokine receptors; gene expression; human subject; human tissue; immune response; immunologic assay /test; interleukin 7; microarray technology; patient oriented research; phenotype; receptor binding; receptor expression; severe combined immunodeficiency; stem cell transplantation; stem cells; tissue /cell culture; xenotransplantation

DESCRIPTION (provided by applicant): The goal of the proposed project is to characterize differences in human B1 and B2 lymphocyte differentiation and to determine if IL-7/IL-7R interactions play a role in B2 versus B1 cell fate determination. B1 and B2 lymphocytes perform complementary roles in immune function and predominate at different points in ontogeny. B1 cells predominate early in life and generate polyreactive antibodies that provide protection from common bacterial pathogens. B1 cells are associated with autoimmune diseases and have been implicated as critical regulators of autoimmune responses. Several functional and phenotypic differences between B1 and B2 lymphocytes have been identified in the mouse, however, human B1 cells are poorly characterized. Mice defective in IL-7 production have a complete block in B2 differentiation, but normal numbers of B1 cells. However, the mechanism that determines B1 versus B2 differentiation is controversial. Preliminary studies support a model of B2 versus B1 differentiation that incorporates aspects of both historical models. Preliminary studies suggest that cord blood (CB) contains an IL-7R-B cell differentiation pathway that is absent in adult bone marrow (BM). The following hypotheses are proposed: 1) human B1 and B2 cells arise from distinct progenitors that predominate at different points in ontogeny, 2)expression of the IL-7R distinguishes human B2 from B1 lymphocyte progenitor populations, and 3) events downstream of IL7/IL-7R interactions promote human B2 versus B1 differentiation. Hypotheses will be tested using three experimental approaches. First, phenotypic and functional characteristics that distinguish mature human B1 and B2 cells will be determined. Second, B1 and B2 differentiation from human CB and BM progenitor populations will be studied in vitro, in the immunodeficient mouse xenograft model, and by examining B1 and B2 cell recovery in stem cell transplant patients. Third, the role of IL-7/IL-TR interactions in B1 and B2 differentiation will be examined by using IL-7 blocking antibodies in B cell differentiation assays and by characterizing B cells from patients defective in IL-7R signaling. Through the proposed project the applicant will gain knowledge of immune function and training in a variety of cellular and molecular techniques that will be applied as an independent investigator to understanding the role of the immune system in disease states.

描述（由申请人提供）： 拟议项目的目的是表征人B1和B2淋巴细胞分化的差异，并确定IL-7/IL-7R相互作用是否在B2与B1细胞命运确定中起作用。 B1和B2淋巴细胞在免疫功能中发挥互补作用，并在个体发育中的不同点占主导地位。 B1细胞在生命的早期占主导地位，并产生可保护常见细菌病原体的多反应性抗体。 B1细胞与自身免疫性疾病有关，并被认为是自身免疫反应的关键调节剂。在小鼠中已经发现了B1和B2淋巴细胞之间的几种功能和表型差异，但是，人B1细胞的特征很差。 IL-7产生中有缺陷的小鼠在B2分化中具有完整的障碍，但正常数的B1细胞。但是，决定B1与B2分化的机制是有争议的。初步研究支持B2与B1分化的模型，该模型结合了两个历史模型的各个方面。初步研究表明，脐带血（CB）包含成人骨髓（BM）中不存在的IL-7R-B细胞分化途径。提出了以下假设：1）人类B1和B2细胞源于在个体发育的不同点上占主导地位的不同祖细胞，2）IL-7R的表达将人B2与B1淋巴细胞祖细胞群体区分开，而3）事件下游IL7/IL-7R相互作用的事件可促进人类B2 b2 vesus b1 vesus b1的不同。假设将使用三种实验方法进行检验。首先，将确定区分成熟人B1和B2细胞的表型和功能特征。其次，将在免疫缺陷的小鼠异种移植模型中研究与人CB和BM祖细胞种群的B1和B2分化，并通过检查干细胞移植患者中的B1和B2细胞恢复。第三，通过在B细胞分化测定中使用IL-7阻断抗体以及表征IL-7R信号传导中有缺陷的患者的B细胞中IL-7阻断抗体，将检查IL-7/IL-TR相互作用在B1和B2分化中的作用。通过拟议的项目，申请人将在各种细胞和分子技术中获得有关免疫功能和训练的知识，这些技术将被用作独立研究者，以了解免疫系统在疾病状态中的作用。