Mechanisms of Leukocyte Recruitment During IPS After BMT

描述（由申请人提供）： 肺功能不全仍然是异基因造血干细胞移植（SCT）后常见且潜在致命的并发症。在这种情况下发生的肺炎几乎有一半是非感染性的，被称为特发性肺炎综合征（IPS）。我们已经开发了小鼠模型的IPS，以检查负责这一过程的病理生理机制。在鉴定供体来源的T细胞和辅助细胞（单核细胞/巨噬细胞/嗜中性粒细胞）在IPS发展中的作用方面已经取得了重大进展。这些发现是重要的，因为它们支持了从将IPS仅鉴定为临床综合征到将IPS理解为其中肺是两种不同但相互关联的免疫介导的损伤途径的靶点的过程的范式转变。然而，IPS期间白细胞向肺运输的机制尚未探索。初步研究表明，负责白细胞迁移到发炎组织的趋化因子配体和受体与IPS相关，但IPS期间趋化因子与细胞向肺募集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的假设，即连接增强的趋化因子表达和白细胞浸润到肺部与全身炎症发生后，异基因SCT，并提出细胞的顺序流入是因果关系，而不是时间相关的;局部趋化因子环境的修改浸润白细胞将直接有助于随后的效应群体的招聘。初步数据将证实供体淋巴细胞效应物首先被募集到肺，然后是供体辅助细胞亚群。细胞的这种顺序流入分别跟随相应趋化因子配体和受体的表达增加，然后与相应趋化因子配体和受体的表达增加相关。本提案将使用已建立的小鼠SCT模型来检验这一假设。本提案的具体目的将研究以下趋化因子受体：配体对及其在IPS发展期间对淋巴细胞、巨噬细胞和中性粒细胞向肺募集的贡献： SA 1：CCR 5/ RANTES（CCL 5）和MIP-1 α（CCL 3）-> Th 1淋巴细胞->第7-21天SA 2：CXCR 3/ IP-10（CXCL 10）和Mig（CXCL 9） SA 3：CCR 2：/ MCP-1（CCL 2）-->单核细胞/巨噬细胞-->第14-28天 SA 4：CXCR 2/ KC和MIP-2（CXCL 1）-->中性粒细胞-->第21 - 42天

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