Mechanisms of Leukocyte Recruitment During IPS After BMT

BMT 后 IPS 期间白细胞募集机制

• 批准号: 6908137
• 负责人: KENNETH R COOKE
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-11 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908137
• 关键词: chemokine; chemokine receptor; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; hematopoietic tissue transplantation; inflammation; isoantigen; laboratory mouse; leukocyte activation /transformation; macrophage; neutrophil; pathologic process; pneumonia; stem cell transplantation

DESCRIPTION (provided by applicant): Pulmonary dysfunction remains a frequent and potentially fatal complication following allogeneic hematopoietic stem cell transplantation (SCT). Almost half of the pneumonias that occur in this setting are non-infectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). We have developed mouse models of IPS in order to examine the pathophysiologic mechanisms responsible for this process. Significant progress has been made in identifying roles for donor derived T cells and accessory cells (monocytes/macrophages/neutrophils) in the development of IPS These findings are significant because they support a paradigm shift away from identifying IPS solely as a clinical syndrome and toward understanding IPS as a process in which the lung is a target of two distinct, but inter-related pathways of immune mediated injury. However, the mechanisms by which leukocytes traffic to the lung during IPS have not been explored. Initial studies demonstrate that chemokine ligands and receptors that are responsible for leukocyte migration to inflamed tissue are associated with IPS, but a mechanistic relationship between chemokines and recruitment of cells to the lung during IPS remains to be determined. Extensive preliminary data support a central hypothesis that links enhanced chemokine expression and leukocyte infiltration to the lung with systemic inflammation that occurs after allogeneic SCT and proposes that the sequential influx of cells is causally rather than temporally related; modification of the local chemokine milieu by infiltrating leukocytes will directly contribute to the recruitment of subsequent effector populations. Preliminary data will confirm that donor lymphocyte effectors are recruited to the lung first and are followed by donor accessory cell subsets. This sequential influx of cells follows, and then correlates with, increased expression of corresponding chemokine ligands and receptors respectively. This proposal will use established mouse SCT models to test this hypothesis. The specific aims of this proposal will investigate the following chemokine receptor:ligand pairs and their contribution to the recruitment of lymphocytes, macrophages and neutrophils to the lung during the development of IPS: SA1: CCR5 / RANTES (CCL5) and MIP-1alpha (CCL3) --> Th1 lymphocytes --> days 7-21 SA2: CXCR3 / IP-10 (CXCL10) and Mig (CXCL9) SA3: CCR2: / MCP-1 (CCL2) --> monocytes/macrophages --> days 14-28 SA4:CXCR2 / KC and MIP-2 (CXCL1) --> neutrophils --> days 21 to 42

描述（由申请人提供）： 肺功能障碍仍然是异基因造血干细胞移植（SCT）后常见且可能致命的并发症。在这种情况下发生的肺炎几乎一半是非传染性的，被称为特发性肺炎综合征（IPS）。我们开发了 IPS 小鼠模型，以研究导致这一过程的病理生理机制。在确定供体来源的 T 细胞和辅助细胞（单核细胞/巨噬细胞/中性粒细胞）在 IPS 发展中的作用方面已取得重大进展。这些发现意义重大，因为它们支持从仅将 IPS 识别为临床综合征转向理解的范式转变IPS 作为一个过程，其中肺部是免疫介导损伤的两种不同但相互关联的途径的目标。然而，IPS 期间白细胞运输至肺部的机制尚未被探索。初步研究表明，负责白细胞迁移至发炎组织的趋化因子配体和受体与 IPS 相关，但趋化因子与 IPS 期间细胞募集至肺部之间的机制关系仍有待确定。大量的初步数据支持一个中心假设，即趋化因子表达增强和白细胞浸润肺部与同种异体 SCT 后发生的全身炎症有关，并提出细胞的顺序流入是因果关系而不是时间关系；通过浸润白细胞改变局部趋化因子环境将直接有助于随后效应细胞群的招募。初步数据将证实供体淋巴细胞效应细胞首先被招募到肺部，然后是供体辅助细胞亚群。细胞的这种顺序流入跟随相应趋化因子配体和受体的表达增加，然后分别与相应趋化因子配体和受体的表达增加相关。该提案将使用已建立的小鼠 SCT 模型来检验这一假设。该提案的具体目标将研究以下趋化因子受体：配体对及其在 IPS 发育过程中对肺部淋巴细胞、巨噬细胞和中性粒细胞募集的贡献： SA1：CCR5 / RANTES (CCL5) 和 MIP-1alpha (CCL3) --> Th1 淋巴细胞 --> 第 7-21 天 SA2：CXCR3 / IP-10 (CXCL10) 和 Mig (CXCL9) SA3: CCR2: / MCP-1 (CCL2) --> 单核细胞/巨噬细胞 --> 第 14-28 天 SA4:CXCR2 / KC 和 MIP-2 (CXCL1) --> 中性粒细胞 --> 第 21 至 42 天