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Interleukin-3 producing IRA B cells as mediators of acute and delayed immune responses during inflammation

产生 IRA B 细胞的 Interleukin-3 作为炎症期间急性和延迟免疫反应的介质

基本信息

批准号：
316129653
负责人：
Professor Dr. Georg Weber
金额：
--
依托单位：
Chirurgische Klinik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/316129653?language=en
关键词：
Interleukin producing IRA cells mediators

项目摘要

The immune system consists of innate and adaptive components that operate in close proximity to protect the host against infections. During infection the host can be at risk due to overwhelming or diminished immune responses. A major therapeutic goal, then, is to establish a balance between controlling infection and controlling inflammation. One promising strategy is to harness the endogenous immune system to augment processes that are beneficial and curb processes that cause harm. Such strategies, however, require an in-depth, mechanistic understanding of the diseases pathophysiology. Recently, we discovered a new cell named the innate response activator (IRA) B cell. Infection of the peritoneal cavity activates innate like B1a B cells via TLR4/MyD88 signalling. As a consequence, activated B1a B cells migrate out of the peritoneum, accumulate in lymphoid organs, and differentiate to granulocyte/macrophages-colony stimulating factor (GM-CSF) and interleukin-3 (IL-3) producing IRA B cells.The function of IRA B cell produced GM-CSF during acute inflammation has been investigated recently. However, the role of the hematopoietic cytokine IL-3 in acute/innate and delayed/adaptive immune responses is still rudimentary understood. We hypothesise that IRA B cells - via the production of IL-3 -are master regulators of acute and delayed immune responses by promoting the generation of monocytes, neutrophils and plasmacytoid dendritic cells (pDCs). Our hypothesis is based on several own published and unpublished data: (i) IRA B cells are a major source of IL-3 in a mouse model of acute inflammation and compared to controls, IL-3 knockout mice (ii) do not succumb to sepsis, a well known model for acute inflammation; (iii) do not produce Ly-6Chigh monocytes in acute inflammation; (iv) do not produce IL-1beta, IL-6, and TNFalpha; and (v) fail to produce pDCs in a model of secondary pulmonary infection.We will test the hypothesis using gene-knockout animal models, sophisticated surgical techniques, and classical molecular and cell biology tools. The project is important because it is based on a strong phenotype and has clear translational potential: IL-3 may be considered as a therapeutic target for the treatment of acute inflammation and sepsis. The project is innovative because it explores the biology of a newly-discovered cell and will identify new functions for IL-3 in both, acute/innate and delayed/adaptive immune responses.

免疫系统由先天性和适应性组成，它们在很近的距离内起作用，以保护宿主免受感染。在感染过程中，宿主可能由于压倒性或减弱的免疫反应而处于危险之中。因此，一个主要的治疗目标是在控制感染和控制炎症之间建立平衡。一个有希望的策略是利用内源性免疫系统来增强有益的过程并抑制造成伤害的过程。然而，这种策略需要对疾病的病理生理学有深入的、机械的理解。最近，我们发现了一种新的细胞命名为先天性反应激活（伊拉）B细胞。腹膜腔感染通过TLR 4/MyD 88信号传导激活先天性类B1 a B细胞。因此，活化的B1 a B细胞可迁移出腹膜，聚集在淋巴器官中，并分化为产生粒细胞/巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-3（IL-3）的伊拉B细胞。然而，造血细胞因子IL-3在急性/先天性和延迟/适应性免疫应答中的作用仍然是初步了解的。我们假设伊拉B细胞-通过产生IL-3 -是通过促进单核细胞、嗜中性粒细胞和浆细胞样树突状细胞（pDC）的产生的急性和延迟免疫应答的主要调节者。我们的假设是基于几个自己发表和未发表的数据：（i）伊拉B细胞是急性炎症小鼠模型中IL-3的主要来源，与对照组相比，IL-3敲除小鼠（ii）不死于脓毒症，这是一种众所周知的急性炎症模型;（iii）在急性炎症中不产生Ly-6Chigh单核细胞;（iv）不产生IL-1 β、IL-6和TNF α;以及（v）在继发性肺部感染模型中不能产生pDCs。我们将使用基因敲除动物模型、复杂的外科技术以及经典的分子和细胞生物学工具来检验这一假设。该项目很重要，因为它基于强大的表型并具有明确的翻译潜力：IL-3可被视为治疗急性炎症和脓毒症的治疗靶点。该项目具有创新性，因为它探索了新发现的细胞的生物学，并将确定IL-3在急性/先天性和延迟/适应性免疫反应中的新功能。