Wu Christina C N, Crain Brian, Yao Shiyin, Sabet Mojgan, Lao Fitzgerald S, Tawatao Rommel I, Chan Michael, Smee Donald F, Julander Justin G, Cottam Howard B, Guiney Donald G, Corr Maripat, Carson Dennis A, Hayashi Tomoko
Rebecca and John Moores UCSD Cancer Center, University of California San Diego, La Jolla, Calif., USA.
J Innate Immun. 2014;6(3):315-24. doi: 10.1159/000355217. Epub 2013 Nov 1.
Pulmonary administration of Toll-like receptor (TLR) ligands protects hosts from inhaled pathogens. However, systemic side effects induced by TLR stimulation limit clinical development. Here, a small-molecule TLR7 ligand conjugated with phospholipid, 1V270 (also designated TMX201), was tested for innate immune activation and its ability to prevent pulmonary infection in mice. We hypothesized that phospholipid conjugation would increase internalization by immune cells and localize the compound in the lungs, thus avoiding side effects due to systemic cytokine release. Pulmonary 1V270 administration increased innate cytokines and chemokines in bronchial alveolar lavage fluids, but neither caused systemic induction of cytokines nor B cell proliferation in distant lymphoid organs. 1V270 activated pulmonary CD11c+ dendritic cells, which migrated to local lymph nodes. However, there was minimal cell infiltration into the pulmonary parenchyma. Prophylactic administration of 1V270 significantly protected mice from lethal infection with Bacillus anthracis, Venezuelan equine encephalitis virus and H1N1 influenza virus. The maximum tolerated dose of 1V270 by pulmonary administration was 75 times the effective therapeutic dose. Therefore, pulmonary 1V270 treatment can protect the host from different infectious agents by stimulating local innate immune responses while exhibiting an excellent safety profile.
经肺部给予Toll样受体（TLR）配体可保护宿主免受吸入病原体的侵害。然而，TLR刺激引起的全身副作用限制了其临床开发。在此，对一种与磷脂偶联的小分子TLR7配体1V270（也称为TMX201）进行了先天免疫激活及其预防小鼠肺部感染能力的测试。我们假设磷脂偶联会增加免疫细胞的内化作用，并使该化合物在肺部定位，从而避免因全身细胞因子释放而产生的副作用。经肺部给予1V270可增加支气管肺泡灌洗液中的先天细胞因子和趋化因子，但既不会引起细胞因子的全身诱导，也不会导致远处淋巴器官中的B细胞增殖。1V270激活了肺部的CD11c+树突状细胞，这些细胞迁移至局部淋巴结。然而，肺实质中的细胞浸润极少。预防性给予1V270可显著保护小鼠免受炭疽芽孢杆菌、委内瑞拉马脑炎病毒和H1N1流感病毒的致死性感染。经肺部给予1V270的最大耐受剂量是有效治疗剂量的75倍。因此，经肺部给予1V270治疗可通过刺激局部先天免疫反应来保护宿主免受不同病原体的感染，同时展现出优异的安全性。
