Ito Ichiaki, Bhopale Kamlesh K, Nishiguchi Tomoki, Lee Jong O, Herndon David N, Suzuki Sumihiro, Sowers Lawrence C, Suzuki Fujio, Kobayashi Makiko
1 Department of Internal Medicine, The University of Texas Medical Branch , Galveston, Texas.
2 Shriners Hospitals for Children , Galveston, Texas.
Nucleic Acid Ther. 2016 Oct;26(5):269-276. doi: 10.1089/nat.2016.0617. Epub 2016 Aug 22.
M2b macrophages (Mφ) play a major role in the increased susceptibility of subacutely burned patients, to sepsis stemming from enterococcal translocation. Certain opportunistic infections in severely burned mice have been controlled by murine CCL1 antisense oligodeoxynucleotide (ODN), a specific polarizer of mouse M2bMφ. In the present study, we have screened CCL1 antisense ODN, which is active against human M2bMφ. Among the 20 CCL1 antisense ODNs synthesized in our laboratory, HCA-11 was shown to be the most active polarizer for human CCL1CD163CD14 cells. Burn patient CCL1CD163CD14 cells (3 × 10 cells/mL) switched to quiescent CCL1CD163CD14 cells within 48 h in cultures supplemented with 100 μg/mL of HCA-11. After treatment with a 25 μg/chimera dose of HCA-11, the bacterial growth was not observed in various organs of patient chimeras (γNSG mice inoculated with burn patient WBCs) infected with a lethal dose of Methicillin-resistant Staphylococcus aureus. The host antibacterial defenses against certain opportunistic pathogens should be improved in severely burned patients treated with a human CCL1 antisense ODN, HCA-11.
M2b巨噬细胞(Mφ)在亚急性烧伤患者对肠球菌易位引起的败血症易感性增加中起主要作用。严重烧伤小鼠中的某些机会性感染已通过鼠CCL1反义寡脱氧核苷酸(ODN)得到控制,鼠CCL1反义寡脱氧核苷酸是小鼠M2bMφ的一种特异性极化剂。在本研究中,我们筛选了对人M2bMφ有活性的CCL1反义ODN。在我们实验室合成的20种CCL1反义ODN中,HCA-11被证明是对人CCL1CD163CD14细胞最具活性的极化剂。在补充有100μg/mL HCA-11的培养物中,烧伤患者的CCL1CD163CD14细胞(3×10个细胞/mL)在48小时内转变为静止的CCL1CD163CD14细胞。用25μg/嵌合体剂量的HCA-11处理后,在接种了致死剂量耐甲氧西林金黄色葡萄球菌的患者嵌合体(接种烧伤患者白细胞的γNSG小鼠)的各个器官中未观察到细菌生长。在用人类CCL1反义ODN HCA-11治疗的严重烧伤患者中,宿主对某些机会性病原体的抗菌防御应得到改善。