Kamei Akinobu, Gao Geli, Neale Geoffrey, Loh Lip Nam, Vogel Peter, Thomas Paul G, Tuomanen Elaine I, Murray Peter J
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105; Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan;
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105.
Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6153-E6161. doi: 10.1073/pnas.1607787113. Epub 2016 Sep 26.
Infection is the single greatest threat to survival during cancer chemotherapy because of depletion of bone marrow-derived immune cells. Phagocytes, especially neutrophils, are key effectors in immunity to extracellular pathogens, which has limited the development of new approaches to protect patients with cancer and chemotherapy-induced neutropenia. Using a model of vaccine-induced protection against lethal Pseudomonas aeruginosa pneumonia in the setting of chemotherapy-induced neutropenia, we found a population of resident lung macrophages in the immunized lung that mediated protection in the absence of neutrophils, bone marrow-derived monocytes, or antibodies. These vaccine-induced macrophages (ViMs) expanded after immunization, locally proliferated, and were closely related to alveolar macrophages (AMs) by surface phenotype and gene expression profiles. By contrast to AMs, numbers of ViMs were stable through chemotherapy, showed enhanced phagocytic activity, and prolonged survival of neutropenic mice from lethal P. aeruginosa pneumonia upon intratracheal adoptive transfer. Thus, induction of ViMs by tissue macrophage remodeling may become a framework for new strategies to activate immune-mediated reserves against infection in immunocompromised hosts.
由于骨髓来源的免疫细胞耗竭，感染是癌症化疗期间生存的最大单一威胁。吞噬细胞，尤其是中性粒细胞，是抵御细胞外病原体免疫的关键效应细胞，这限制了保护癌症患者和化疗诱导的中性粒细胞减少症患者的新方法的开发。利用在化疗诱导的中性粒细胞减少症背景下疫苗诱导的针对致死性铜绿假单胞菌肺炎的保护模型，我们在免疫的肺中发现了一群驻留肺巨噬细胞，它们在没有中性粒细胞、骨髓来源的单核细胞或抗体的情况下介导保护作用。这些疫苗诱导的巨噬细胞（ViM）在免疫后扩增，在局部增殖，并且通过表面表型和基因表达谱与肺泡巨噬细胞（AM）密切相关。与AM不同，ViM的数量在化疗过程中保持稳定，表现出增强的吞噬活性，并且在气管内过继转移后延长了中性粒细胞减少小鼠死于致死性铜绿假单胞菌肺炎的存活时间。因此，通过组织巨噬细胞重塑诱导ViM可能成为激活免疫介导的储备以抵抗免疫受损宿主感染的新策略的框架。
