Inducible epithelial resistance protects mice against leukemia-associated pneumonia
Inducible epithelial resistance protects mice against leukemia-associated pneumonia
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DOI：
10.1182/blood-2016-03-708511
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发表时间：
2016-08-18
期刊：
影响因子：
20.3
通讯作者：
Evans, Scott E.
中科院分区：
文献类型：
--
作者：
Leiva-Juarez, Miguel M.;Ware, Hayden H.;Evans, Scott E.
尽管广泛的感染预防工作，肺炎仍然是急性白血病患者死亡的主要原因，这是由于复杂的疾病和治疗依赖性免疫缺陷。我们已经报道了Toll样受体2/6（TLR 2/6）和TLR 9激动剂（Pam 2-ODN）的协同组合的单次吸入治疗诱导小鼠对广泛的病原体的保护性粘膜防御。由于Pam 2-ODN诱导的保护作用持续存在，尽管几个白细胞群体的耗竭，我们测试了它是否可以预防急性髓性白血病（AML）缓解诱导治疗的小鼠模型中的肺炎。当小鼠大量移植白血病细胞、具有严重的化疗诱导的中性粒细胞减少症或两者兼有时，Pam 2-ODN防止了由于铜绿假单胞菌、肺炎链球菌和烟曲霉引起的肺炎而导致的死亡。Pam 2-ODN还延长了移植有原代人AML细胞的NSG小鼠中肺炎的存活。保护作用与感染时肺部快速杀灭病原体和观察结束时远处病原体负荷减少有关。病原体的杀伤是直接从分离的肺上皮细胞诱导，并没有废除的白血病细胞或细胞毒性药物的存在。Pam 2-ODN在体外或体内对小鼠或人白血病细胞的复制率、总肿瘤群体或化疗杀伤均无明显影响。总之，我们报告说，治疗刺激肺上皮防御有力地防止其他致命的肺炎，尽管深刻的免疫功能障碍与急性白血病及其治疗。这些研究结果可能表明，有机会在脆弱性高峰期保护这一群体。
Despite widespread infection prevention efforts, pneumonia remains the leading cause of death among patients with acute leukemia, due to complex disease-and treatment-dependent immune defects. We have reported that a single inhaled treatment with a synergistic combination of Toll-like receptor 2/6 (TLR 2/6) and TLR9 agonists (Pam2-ODN) induces protective mucosal defenses in mice against a broad range of pathogens. As Pam2-ODN-induced protection persists despite depletion of several leukocyte populations, we tested whether it could prevent pneumonia in a mouse model of acute myeloid leukemia (AML) remission induction therapy. Pam2-ODN prevented death due to pneumonia caused by Pseudomonas aeruginosa, Streptococcus pneumoniae, and Aspergillus fumigatus when mice were heavily engrafted with leukemia cells, had severe chemotherapy-induced neutropenia or both. Pam2-ODN also extended survival of pneumonia in NSG mice engrafted with primary human AML cells. Protection was associated with rapid pathogen killing in the lungs at the time of infection and with reduced pathogen burdens at distant sites at the end of observation. Pathogen killing was inducible directly from isolated lung epithelial cells and was not abrogated by the presence of leukemia cells or cytotoxic agents. Pam2-ODN had no discernible effect on replication rate, total tumor population, or killing by chemotherapy of mouse or human leukemia cells, either in vitro or in vivo. Taken together, we report that therapeutic stimulation of lung epithelial defenses robustly protects against otherwise lethal pneumonias despite the profound immune dysfunction associated with acute leukemia and its treatment. These findings may suggest an opportunity to protect this population during periods of peak vulnerability.