Maintaining B cell immunity with aged B lymphocytes

描述(申请人提供)：老龄化与适应性免疫力下降有关，这会使老年人对疫苗的反应降低，并增加对感染性病原体疾病的易感性。大部分下降是在免疫反应的B细胞臂中发现的，这使得老年人的抗体反应不佳，对疾病的易感性增加。兔在出生几周后B淋巴细胞数量急剧下降，到2-4个月龄时，B淋巴细胞量很少或根本没有，因此为研究B淋巴细胞量的下降提供了一个有用的模型。B淋巴细胞的减少可能是由于早期B淋巴细胞前体的内在变化、骨髓基质环境的改变或外周B细胞的反馈调节所致。BM变得高度脂肪，人类BM也是如此，我们最近发现，人和兔脂肪细胞都分泌一种分子，抑制CLP到前B细胞阶段的B淋巴细胞生成。这项资助的目的是阐明B淋巴细胞生成抑制的机制，并发现一种在体内重新启动新B细胞产生的方法。在目标1中，我们将比较幼兔和成年兔骨髓中早期B细胞前体细胞的B淋巴细胞造血能力以及成骨细胞支持早期B细胞系细胞分化的能力。在目标2中，我们将分离和鉴定脂肪细胞分泌的抑制物，并确定脂肪细胞衍生因子抑制B淋巴细胞生成的机制。我们将确定该抑制剂是作用于早期的B细胞前体细胞还是作用于基质细胞，并研究该抑制剂诱导的基因表达的变化。在目标3中，我们将专注于通过他汀类药物抑制脂肪生成，通过甲状旁腺激素促进MSC和成骨细胞的生成，以及通过耗尽外周B细胞来重新启动B淋巴细胞的生成。我们将对骨髓移植患者进行一项回顾性研究，以确定接受他汀类药物移植的患者是否比年龄匹配的对照组更成功。这项提议中的研究结果将导致未来在人体上进行实验，以确定导致老年人适应性免疫下降的机制，以及一种可以逆转这种情况的方法，从而提高对疫苗的反应。

DESCRIPTION (provided by applicant): Aging is associated with a decline in adaptive immunity that leaves senior citizens with decreased responses to vaccines and increased vulnerability to disease from infectious agents. Much of the decline is found in the B cell arm of immune responses, leaving the elderly with a suboptimal antibody response and increased vulnerability to disease. Rabbits provide a useful model for studying the decline in B lymphopoiesis because it declines precipitously a few weeks after birth, and by 2 to 4 months of age, little or no B lymphopoiesis occurs. The decline in B lymphopoiesis could be due to intrinsic changes in early B lymphocyte precursors, to changes in the bone marrow (BM) stromal environment, or to feed-back regulation by peripheral B cells. The BM becomes highly adipose as does human BM and we recently discovered that both human and rabbit adipocytes secrete a molecule that inhibits B-lymphopoiesis at the CLP to pre-pro-B cell stage. The goal of this grant is to elucidate the mechanism by which B lymphopoiesis arrests and discover a means to re-initiate production of new B cells in vivo. In Aim 1, we will compare the B-lymphopoietic capacity of early B-cell progenitors in BM of young and adult rabbits as well as the capacity of osteoblasts to support the differentiation of early B-lineage cells. In Aim 2, we will isolate and characterize the inhibitor secreted by adipocytes and also determine the mechanism by which the adipocyte-derived factor inhibits B-lymphopoiesis. We will determine if the inhibitor acts on early B cell progenitors or on the stromal cells and investigate changes in gene expression induced by the inhibitor. In Aim 3, we will focus on re-initiating B lymphopoiesis by inhibiting adipogenesis with statins, by promoting generation of MSC and osteoblasts with parathyroid hormone, and by depleting peripheral B cells. We will perform a retrospective study of BM transplant patients to determine if patients on statins engraft more successfully than age-match controls. Results from studies in this proposal will lead to future experiments in humans to identify mechanisms that contribute to the decline in adaptive immunity in the elderly, as well as a means by which this can be reversed, leading to improved responses to vaccines.