Decline of B lymphopoiesis with Age: Adipocytes and Myeloid Suppressor Cells

描述（由申请方提供）：老年人对感染的易感性增加，对疫苗接种的反应较差。这是由于免疫系统的缺陷随着年龄的增长而积累。一个缺陷是随着年龄的增长，淋巴细胞生成减少，这导致可用于对新感染作出反应的幼稚B细胞和T细胞减少。老年人、小鼠和兔子的B淋巴细胞生成减少。在兔中，B细胞发育的丧失发生在2月龄时，并且与骨髓中脂肪组织的增加相关。老年人在骨髓中积累脂肪组织，使兔子成为研究骨髓随年龄变化的良好体内模型。我们还发现脂肪细胞衍生因子在体外抑制人、小鼠和兔B淋巴细胞生成。虽然脂肪细胞衍生因子抑制B淋巴细胞生成的机制尚不清楚，但通过体外共培养研究脂肪细胞衍生可溶性因子对B细胞发育的影响，我们有初步数据表明脂肪细胞衍生可溶性因子促进CD 11 B + Gr 1+抑制细胞的积累，然后抑制B细胞发育。这些CD11b+ Gr1+抑制细胞类似于髓源性抑制细胞（MDSC）。因为几乎没有数据支持MDSC影响B谱系细胞的观点，我们将确定通过用脂肪细胞来源的可溶性因子处理产生的抑制细胞是否是已知抑制T细胞的经典MDSC。此外，我们将确定CD 11 B + Gr 1+抑制细胞抑制B细胞发育的机制。我们还将阐明这些MDSC样细胞发育的机制，并确定MDSC的耗竭是否可以恢复不再产生新B细胞的兔骨髓中的B淋巴细胞生成。这些研究将提供有价值的信息，增加脂肪组织对造血功能的影响，在老年人。揭示脂肪细胞导致B细胞发育下降的机制将导致旨在恢复老年人B淋巴细胞生成的疗法。

DESCRIPTION (provided by applicant): Aged individuals exhibit increased susceptibility to infection and respond poorly to vaccination. This is due to defects in the immune system that accumulate with age. One defect is the decline in lymphopoiesis with increased age, which results in fewer naive B cells and T cells available to respond to new infections. Aged humans, mice, and rabbits have decreased B lymphopoiesis. In rabbits the loss of B cell development occurs by 2 months of age, and correlates with increased adipose tissue in the bone marrow. Aged humans accumulate adipose tissue in the bone marrow, making rabbit a good in vivo model to study the changes that occur in the bone marrow with age. We also discovered that adipocyte-derived factors inhibit human, mouse, and rabbit B lymphopoiesis in vitro. Although the mechanism by which adipocyte-derived factors inhibit B lymphopoiesis is unknown, by using in vitro co-cultures to study the impact of adipocyte-derived soluble factors on B cell development, we have preliminary data suggesting that adipocyte-derived soluble factors promote the accumulation of CD11b+ Gr1+ suppressor cells, which then inhibit B cell development. These CD11b+ Gr1+ suppressor cells resemble myeloid-derived suppressor cells (MDSCs). Because there is little to no data supporting the idea that MDSCs affect B lineage cells, we will determine if suppressor cells generated by treatment with adipocyte-derived soluble factors are classical MDSCs that are known to suppress T cells. Further, we will determine the mechanism by which CD11b+ Gr1+ suppressor cells inhibit B cell development. We will also elucidate the mechanism by which these MDSC-like cells develop, and determine if depletion of MDSCs can restore B lymphopoiesis in the bone marrow of rabbits that no longer generate new B cells. These studies will provide valuable information on the impact of increased adipose tissue on hematopoiesis in aged individuals. Uncovering the mechanisms by which adipocytes lead to the decline of B cell development will lead to therapies aimed at restoring B lymphopoiesis in aged individuals.