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）： 同种异体造血干细胞移植（SCT）后，肺功能障碍仍然是常见且潜在的致命并发症。在这种情况下发生的几乎一半的肺炎是非感染性的，被称为特发性肺炎综合征（IPS）。我们开发了IP的小鼠模型，以检查负责此过程的病理生理机制。在确定供体衍生的T细胞和辅助细胞（单核细胞/巨噬细胞/中性粒细胞）中，取得了重大进展，这些发现很重要，因为它们支持范式从完全识别IPS的临床综合征和理解IPS的过程中，而将IPS视为肺部的肺部，而肺则是两种差异的靶标，但不受影响，但不受其跨性别的影响。但是，尚未探索白细胞在IPS期间向肺部流动的机制。最初的研究表明，负责白细胞迁移到发炎组织的趋化因子配体和受体与IPS有关，但是在IPS期间，趋化因子与细胞对肺的募集之间的机械关系尚待确定。广泛的初步数据支持了一个中心假设，该假设将增强的趋化因子表达和白细胞浸润与肺部与同种异体SCT后发生的全身性炎症联系在一起，并提出细胞的顺序流入是因果关系而非时间相关的；通过浸润白细胞对局部趋化因子环境的修饰将直接有助于募集随后的效应人群。初步数据将确认供体淋巴细胞效应子首先募集到肺部，然后是供体辅助细胞子集。细胞的顺序流入遵循，然后与相应的趋化因子配体和受体的表达增加相关。该建议将使用已建立的鼠标SCT模型来检验该假设。该提案的具体目的将研究以下趋化因子受体：配体对及其对淋巴细胞，巨噬细胞和嗜中性粒细胞在IPS发育过程中的贡献： 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 - > 21至42天