Maintaining B cell immunity with aged B lymphocytes

用老化的 B 淋巴细胞维持 B 细胞免疫

• 批准号: 7878421
• 负责人: Katherine L. Knight
• 金额: $ 4.74万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878421
• 关键词: Adoptive Transfer; Adult; Age; Age-Months; Antibodies; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Birth; Bone Marrow; Bromodeoxyuridine; Cell Culture Techniques; Cell Lineage; Cells; Data; Dose; Elderly; Elements; Extracellular Matrix; Extracellular Matrix Proteins; Face; Generations; Goals; Grant; Gut associated lymphoid tissue; Homeostasis; Human; Immune response; Immune system; Immunity; In Vitro; Infection; Interleukin-7; Lead; Left; Life; Lymphocyte; Lymphoid Tissue; Lymphopoiesis; Maintenance; Modeling; Mus; Oryctolagus cuniculus; Peripheral; Population; Process; Production; RNA Splicing; Radiation; Research; Research Personnel; Seeds; Solutions; Staging; Stromal Cells; Testing; Therapeutic Intervention; Time; Vaccination; Variant; Work; aged; bone; in vivo; inhibitor/antagonist; irradiation; microorganism; middle age; notch protein; periostin; progenitor; receptor; research study

DESCRIPTION (provided by applicant): B cells provide us with antibodies against a multitude of infectious microorganisms. In humans, B cells are produced in the bone marrow throughout life in a process called B lymphopoiesis. Even so, in human, B cell immunity declines with age leaving the elderly more susceptible to infections and autoimmune diseases, and less responsive to vaccinations. In rabbits, B lymphopoiesis occurs for only a few weeks after birth, and yet, they maintain robust B cell immunity throughout life. In this grant, we will study the mechanism by which B lymphopoiesis is developmentally-terminated in rabbits; whether gut-associated lymphoid tissues (GALT) contribute to maintenance of B cell homeostasis throughout the rabbit's life in the absence of ongoing B lymphopoiesis; and how B lymphopoiesis can be reinitiated. In Aim 1, we will identify and characterize the stage of differentiation at which B lymphopoiesis is arrested in bone marrow by using in vitro cultures and adoptive transfer of putative lymphocyte progenitors. In Aim 2, we will determine the turnover rate of B cells in GALT by incorporation of BrdU, and determine the rate at which GALT B cells seed other peripheral lymphoid tissues. Further, we will assess the contribution of GALT to maintenance of B cell immunity by surgically removing all organized GALT from adult rabbits and testing for the first time in any species, whether GALT serves as a reservoir of B cells for other lymphoid tissues throughout life. In Aim 3, we will use antibodies and in vivo expression of decoy soluble receptors or extracellular matrix molecules to test if one or more of three candidate molecules, activated Notch-1, a splice variant of IL-7, or an extracellular matrix protein, has the capacity to reinitiate B lymphopoiesis. Data from these experiments will provide an understanding of the mechanism by which B lymphopoiesis declines, and how B cell immunity can be maintained in the absence of de novo development of B cells. These results should provide potential solutions for maintaining robust immune responses in the elderly as B cell immunity declines. The research proposed in this grant is significant because by the year 2030, 20% of the US population is expected to be age 65 or older and have diminished B cell immune systems. This work has the potential to identify targets for therapeutic interventions that will allow the elderly to maintain a healthy immune system.

描述（由申请人提供）：B细胞为我们提供针对多种传染性微生物的抗体。在人类中，在一个称为B淋巴细胞的过程中，在骨髓中产生B细胞。即便如此，在人类的B细胞免疫力下降，随着年龄的增长，老年人更容易感染和自身免疫性疾病，对疫苗接种的反应较小。在兔子中，B淋巴细胞发生在出生后的几周后，但它们一生都保持了强大的B细胞免疫力。在这笔赠款中，我们将研究B淋巴管在兔子中终止的B淋巴细胞的机制。肠道相关的淋巴组织（GALT）是否有助于在没有持续的B淋巴细胞中的整个兔子的生命中维持B细胞稳态；以及如何重新促进B淋巴细胞。在AIM 1中，我们将通过使用体外培养物和假定的淋巴细胞祖细胞的过继转移来识别并表征在骨髓中停止B淋巴管的分化阶段。在AIM 2中，我们将通过掺入BRDU来确定GALT中B细胞的周转率，并确定Galt B细胞在哪些其他外周淋巴组织中播种的速率。此外，我们将通过手术从成年兔子中去除所有有组织的galt并在任何物种中首次进行测试来评估Galt对维持B细胞免疫的贡献，无论Galt是否可以用作B细胞的储层，以便在整个生命中作为其他淋巴组织。在AIM 3中，我们将使用诱饵可溶性受体或细胞外基质分子的抗体和体内表达来测试三个或多个候选分子中的一个或多个，即激活的Notch-1，IL-7的剪接变体，或一个细胞外基质蛋白的剪接变体，具有重新启动B淋巴瘤的能力。来自这些实验的数据将提供对B淋巴管下降的机制的理解，以及在没有B细胞的从头发展的情况下如何保持B细胞免疫。这些结果应提供潜在的解决方案，以维持老年人的稳健免疫反应，因为B细胞免疫力下降。该赠款中提出的研究很重要，因为到2030年，美国人口的20％预计将年龄在65岁或以上，并减少了B细胞免疫系统。这项工作有可能确定治疗干预措施的靶标，这将使老年人保持健康的免疫系统。