Maintaining B cell immunity with aged B lymphocytes

描述（由申请人提供）：老龄化与适应性免疫的下降有关，这使得老年人对疫苗的反应降低，对传染性疾病的易感性增加。大部分下降发生在免疫反应的B细胞部分，这使得老年人的抗体反应不佳，对疾病的抵抗力增加。兔子在出生后几周内急剧下降，到2 ~ 4个月时，很少或根本没有B淋巴生成，这为研究B淋巴生成的下降提供了一个有用的模型。B淋巴生成的减少可能是由于早期B淋巴细胞前体的内在改变，骨髓基质环境的改变，或外周B细胞的反馈调节。骨髓变得高度脂肪化，人和人骨髓一样，我们最近发现人和兔的脂肪细胞都分泌一种分子，在CLP到前-前b细胞阶段抑制b淋巴生成。这项资助的目的是阐明B淋巴生成被阻止的机制，并发现一种在体内重新启动新B细胞生产的方法。在目的1中，我们将比较幼年兔和成年兔BM中早期b细胞祖细胞的b淋巴生成能力，以及成骨细胞支持早期b系细胞分化的能力。在Aim 2中，我们将分离和表征脂肪细胞分泌的抑制剂，并确定脂肪细胞衍生因子抑制b淋巴生成的机制。我们将确定抑制剂是作用于早期B细胞祖细胞还是作用于基质细胞，并研究抑制剂诱导的基因表达变化。在Aim 3中，我们将重点关注通过他汀类药物抑制脂肪生成，通过甲状旁腺激素促进间充质干细胞和成骨细胞的生成，以及通过消耗外周B细胞来重新启动B淋巴细胞生成。我们将对骨髓移植患者进行回顾性研究，以确定他汀类药物移植患者是否比年龄匹配的对照组更成功。本提案中的研究结果将导致未来的人体实验，以确定导致老年人适应性免疫力下降的机制，以及一种可以逆转这种情况的方法，从而改善对疫苗的反应。

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.