Mechanisms of age related changes in B cell homeostasis

年龄相关 B 细胞稳态变化的机制

• 批准号: 7226694
• 负责人: PAMELA L. WITTE
• 金额: $ 29.56万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226694
• 关键词: Acute; Address; Adoptive Transfer; Affect; Age; Aging; Animals; Appearance; Architecture; B-Lymphocytes; Back; Bone Marrow; CXCL12 gene; CXCL13 gene; Cell Aging; Cell Count; Cell Lineage; Defect; Development; Equilibrium; Follicular Dendritic Cells; Funding; Home environment; Homeostasis; Homing; Immune; Individual; Kinetics; Life; Longevity; Lymphocyte; Lymphoid; Lymphoid Tissue; Lymphopoiesis; Marrow; Mature B-Lymphocyte; Mesenchymal Stem Cells; Mus; Numbers; Pattern; Peripheral; Plasma Cells; Population; Production; Rate; Reporting; Research Personnel; Role; Spleen; Stromal Cells; Testing; Tissues; age related; aged; cell age; cell motility; chemokine; day; immune function; juvenile animal; lymph nodes; mature animal; migration; programs; repaired; response; young adult

DESCRIPTION (provided by applicant): In the past funding period, we focused on the production of new, immature B-cells in aged mice by assessing kinetics of production, number of cells produced/day, and population turnover in the bone marrow and spleen. We found that B-lineage precursors decline with age, but newly-made B cells are generated in the bone marrow of aged animals at about the same rate as that observed in young animals. In spite of ongoing formation of new B-cells in the aged, few of these newly-made B-cells become part of the transitional or mature B-cell pools in the spleens. Kinetic studies indicate that splenic B-cells turn over very slowly and are long-lived in aged mice. We and others have concluded that B-cell homeostasis differs in aged mice from the well described homeostatic patterns of young mice. Furthermore, our results imply that a major defect is the inability of immature B-cells to join the peripheral B cell compartments. Adoptive transfer studies show that even young immature B-cells cannot home effectively to an aged spleen, suggesting a deficiency in the aged tissue microenvironment. In contrast, immature B-cells from aged mice are equally able to home to spleen compared to those from young mice. The tissue architecture of aged spleen and lymph nodes is disrupted in appearance and chemokine production is reduced, which likely alters lymphocyte migration and homeostasis. Thus, our results emphasize the acute need to know more about how immune homeostasis changes with age. Two general premises are addressed in this renewal application: (1) We hypothesize that B-cell homeostasis changes because the marrow and splenic microenvironments are altered during aging. (2) We propose that alterations in the microenvironments are modulated by changes in the types of B-cells populating the marrow and secondary tissues. Aim I will define the deficiencies of the aged lymphoid microenvironment that affect B-cell homeostasis and the homing and retention of newly-made B-cells. Aim II addresses the hypothesis that the long-lived, mature B-cells found in the spleens of aged mice are insufficient to maintain chemokine production and normal lymphoid compartmentalization. Aim III proposes that mature and effector B-cell populations (plasma cells), which are retained in bone marrow in increasing numbers with age, actually alter the ability of marrow stromal cells to function in B-lymphopoiesis. We believe that changes in B-cell homeostasis may predict poor immune function in the aged.

描述（由申请人提供）：在过去的资金期间，我们通过评估生产动力学，生产/天的细胞数量以及骨髓和脾脏中的人口转移来重点介绍新老鼠的新的，未成熟的B细胞。我们发现B-Linege前体随着年龄的增长而下降，但是在老年动物的骨髓中产生了新制作的B细胞，其速率与年轻动物中观察到的速率大致相同。尽管在老年中持续形成了新的B细胞，但这些新制作的B细胞中很少有脾脏中过渡或成熟的B细胞池的一部分。动力学研究表明，脾脏B细胞非常缓慢地翻转，并且在老年小鼠中长期存在。我们和其他人得出的结论是，老年小鼠的老年小鼠的B细胞稳态不同。此外，我们的结果表明，主要缺陷是未成熟的B细胞无法连接外围B细胞室。收养转移研究表明，即使是年轻的未成熟B细胞也无法有效地回家到老年脾脏，这表明老化的组织微环境缺乏。相反，与年轻小鼠相比，来自老年小鼠的未成熟B细胞同样能够回家脾脏。老化脾脏和淋巴结的组织结构在外观上被破坏，趋化因子产生降低，这可能会改变淋巴细胞迁移和稳态。因此，我们的结果强调了急性需要更多地了解免疫稳态如何随着年龄的变化而变化。在此续签应用中解决了两个一般的前提：（1）我们假设B细胞稳态发生了变化，因为骨髓和脾脏微环境在衰老过程中发生了变化。 （2）我们提出，微环境的改变是由填充骨髓和二级组织的B细胞类型的变化来调节的。目的我将定义影响B细胞稳态的老化淋巴微环境的缺陷以及新制作的B细胞的归巢和保留。 AIM II解决了以下假设：在老年小鼠的脾脏中发现的长期成熟的B细胞不足以维持趋化因子的产生和正常的淋巴样分区化。 AIM III提出成熟和效应B细胞种群（浆细胞）保留在骨髓中的数量随着年龄的增长，实际上改变了骨髓基质细胞在B淋巴结中起作用的能力。我们认为，B细胞稳态的变化可能预测年龄的免疫功能不良。