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

B 淋巴细胞生成随着年龄的增长而下降：脂肪细胞和骨髓抑制细胞

• 批准号: 8718740
• 负责人: Domenick Edward Kennedy
• 金额: $ 2.94万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718740
• 关键词: Adipocytes; Adipose tissue; Affect; Age; Age-Months; B-Cell Development; B-Lymphocytes; Bone Marrow; Cell Aging; Cell Lineage; Cells; Coculture Techniques; Common Lymphoid Progenitor; Conditioned Culture Media; Data; Defect; Exhibits; Foundations; Goals; Hematopoiesis; Human; ITGAM gene; Immune system; In Vitro; Individual; Infection; Lead; Lymphopoiesis; Mus; Myelogenous; Myeloid Cells; Oryctolagus cuniculus; Predisposition; Staging; Suppressor-Effector T-Lymphocytes; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Vaccination; aged; cell age; cell type; in vivo; in vivo Model; progenitor; public health relevance

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.

描述（由申请人提供）：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，淋巴系统的生成能力会下降，这导致能够对新感染做出反应的幼稚B细胞和T细胞减少。老年人类、小鼠和家兔的B淋巴生成减少。在家兔中，B细胞发育的丧失发生在2个月大时，并与骨髓中脂肪组织的增加有关。老年人在骨髓中积累脂肪组织，使家兔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、小鼠和家兔的B淋巴生成。尽管脂肪源性因子抑制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源性可溶性因子对B细胞发育的影响，我们有初步的数据表明，脂肪源性可溶性因子促进CD11b+ Gr1+抑制细胞的积累，从而抑制B细胞的发育。这些CD11b+ Gr1+抑制细胞类似于髓源性抑制细胞（MDSCs）。由于几乎没有数据支持MDSCs影响B系细胞的观点，我们将确定通过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MDSCs。此外，我们将确定CD11b+ Gr1+抑制细胞抑制B细胞发育的机制。我们还将阐明这些MDSCs样细胞发育的机制，并确定MDSCs的消耗是否可以恢复兔骨髓中不再产生新B细胞的B淋巴生成。这些研究将为老年人脂肪组织增加对造血的影响提供有价值的信息。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淋巴细胞生成的治疗。