Immunology of aging and immunotherapy of aging-associated diseases

衰老免疫学和衰老相关疾病的免疫治疗

• 批准号: 10007358
• 负责人: Arya Biragyn
• 金额: $ 63.74万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10007358
• 关键词: Age; Aging; Anaerobic Bacteria; Antibiotics; Antibodies; B-Lymphocytes; Blood; Blood Circulation; Butyrates; CD8-Positive T-Lymphocytes; CD86 gene; Cells; Clinical; Disease; Elderly; Endotoxins; Epithelial; Extravasation; Generations; Granzyme; Growth; Health; Human; Hyperglycemia; Immune; Immunology; Immunotherapy; Impairment; Inflammatory; Insulin; Insulin Resistance; Journals; Macaca; Membrane; Microbe; Mus; Myeloid Cell Activation; Myeloid Cells; Omentum; Pathologic; Pathology; Pathway interactions; Personal Satisfaction; Primates; Publishing; Reporting; Science; Signal Transduction; Supplementation; TNF gene; TNFSF5 gene; Testing; aged; commensal bacteria; gut microbiome; inhibitor/antagonist; insight; microbiome; monocyte; novel; response; vaccine response

We recently reported that aged humans, primates, and mice accumulate a unique type of activated B cells, termed 4BL cells (Lee-Chang et al., Blood, 2014). Contrary to widely believed assumption that innate B cells do not change upon aging, we showed that these cells are derived from innate B1a cells (Lee-Chang et al., J. Immunol., 2016). Mechanistically, aging activates myeloid cells, such as upregulated 4-1BB and CD40L, to convert B1a cells into 4BL cells expressing 4-1BBL, HLA-I, IFNR1, CD86 and membrane TNF. Functionally, this enables 4BL cells to induce expression of granzyme B in CD8+T cells. Here, we explored the mechanism/cause of activation of myeloid cells and their cell subset which convert 4BL cells; and the clinical consequence of the accumulation of 4BL cells in aging. We report that the main cause of aging-associated activation of myeloid cells is gut microbiome. We found that aging changes their composition, such as accumulates potentially pro-inflammatory microbes while decreases beneficial commensal bacteria. Aging gut was markedly decreased in Akkermansia muciniphila, an anaerobic bacterium which protects epithelial integrity of the gut and supports growth of butyrate-producing beneficial commensals. Mechanistically, the loss of A. muciniphila increased leakage of bacterial products such as endotoxin into the circulation and decreased levels of butyrate, an inhibitor of TLR signaling. Thus, the leakage of endotoxin activates CCR2+ monocytes (MO) when butyrate is decreased. Then, activated MO convert innate B1a cells into 4BL cells in the omentum. The clinical consequence of this pathway is that 4BL cells increase hyperglycemia, insulin resistance (IR) in aged hosts via 4-1BBL axis. We show also that this pathway and IR are reversible, as supplementation with A. muciniphila alone or antibiotic enrofloxacin, which increases its abundance, restores normal insulin response in aged mice and macaques. Additionally, treatment with butyrate or antibodies that eliminate CCR2+ MO or 4BL cells have the same effect on IR. These results underscore the previously unknown pathological function of B1a cells, suggesting that the microbiome-MO-4BL cell axis can be targeted to reverse IR and possibly other age-associated pathologies. The results of this study we recently published in high-impact scientific journal (Bodogai et al., Science Transl. Med., 2018). Overall, the project is progressing well as planned. It continues generating novel insights with significant scientific and clinical implications.

我们最近报道，老年人、灵长类动物和小鼠积累了一种独特类型的活化B细胞，称为4 BL细胞（Lee-Chang et al.，Blood，2014）。与普遍认为的先天性B细胞在衰老时不改变的假设相反，我们表明这些细胞来源于先天性B1 a细胞（Lee-Chang et al.，免疫学杂志，2016年）。从机制上讲，衰老激活骨髓细胞，如上调的4-1BB和CD 40 L，将B1 a细胞转化为表达4-1BBL、HLA-I、IFNR 1、CD 86和膜TNF的4 BL细胞。在功能上，这使得4 BL细胞能够诱导颗粒酶B在CD 8 +T细胞中的表达。 在这里，我们探索了骨髓细胞及其转化4 BL细胞的细胞亚群活化的机制/原因;以及衰老中4 BL细胞积累的临床后果。 我们报告说，与衰老相关的骨髓细胞活化的主要原因是肠道微生物组。我们发现，衰老改变了它们的组成，例如积累潜在的促炎微生物，同时减少有益的肠道细菌。嗜粘蛋白阿克曼氏菌（Akkermansia muciniphila）的老化肠道显著减少，这是一种厌氧细菌，可保护肠道上皮完整性并支持产生丁酸盐的有益微生物的生长。机械地，A的损失。嗜粘蛋白菌增加了细菌产物如内毒素向循环中的渗漏，并降低了丁酸盐（TLR信号传导的抑制剂）的水平。因此，当丁酸盐减少时，内毒素的泄漏激活CCR 2+单核细胞（MO）。然后，激活的MO将先天B1 a细胞转化为网膜中的4 BL细胞。 这一通路的临床结果是4 BL细胞通过4-1BBL轴增加老年宿主的高血糖、胰岛素抵抗（IR）。我们还表明，这一途径和IR是可逆的，补充A。单独的嗜粘蛋白体或增加其丰度的抗生素恩诺沙星恢复了老年小鼠和猕猴的正常胰岛素反应。此外，用丁酸盐或消除CCR 2 + MO或4 BL细胞的抗体治疗对IR具有相同的效果。这些结果强调了B1 a细胞先前未知的病理功能，表明微生物组-MO-4 BL细胞轴可以靶向逆转IR和可能的其他年龄相关的病理。这项研究的结果，我们最近发表在高影响力的科学杂志（Bodogai等人，科学翻译医学、2018年）。 总体而言，该项目正在按计划顺利进行。它继续产生具有重大科学和临床意义的新见解。