苯丁酸钠和维生素 D 作为宿主定向治疗药物敏感肺结核的免疫反应。
Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D as host directed therapy.
机构信息
Infectious Diseases Division, icddr,b, 68 Shaheed Tajuddin Ahmed Sarani, Dhaka, 1212, Bangladesh.
Department of Laboratory Medicine, Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
出版信息
BMC Infect Dis. 2018 Jul 4;18(1):303. doi: 10.1186/s12879-018-3203-9.
BACKGROUND
We have previously shown that 8 weeks' treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D (vitD) (5000 IU/day) as host-directed therapy (HDT) accelerated clinical recovery, sputum culture conversion and increased expression of cathelicidin LL-37 by immune cells in a randomized, placebo-controlled trial in adults with pulmonary tuberculosis (TB). In this study we further aimed to examine whether HDT with PBA and vitD promoted clinically beneficial immunomodulation to improve treatment outcomes in TB patients.
METHODS
Cytokine concentration was measured in supernatants of peripheral blood mononuclear cells (PBMC) from patients (n = 31/group). Endoplasmic reticulum stress-related genes (GADD34 and XBP1spl) and human beta-defensin-1 (HBD1) gene expression were studied in monocyte-derived-macrophages (MDM) (n = 18/group) from PBMC of patients. Autophagy in MDM (n = 6/group) was evaluated using LC3 expression by confocal microscopy.
RESULTS
A significant decline in the concentration of cytokines/chemokines was noted from week 0 to 8 in the PBA-group [TNF-α (β = - 0.34, 95% CI = - 0.68, - 0.003; p = 0.04), CCL11 (β = - 0.19, 95% CI = - 0.36, - 0.03; p = 0.02) and CCL5 (β = - 0.08, 95% CI = - 0.16, 0.002; p = 0.05)] and vitD-group [(CCL11 (β = - 0.17, 95% CI = - 0.34, - 0.001; p = 0.04), CXCL10 (β = - 0.38, 95% CI = - 0.77, 0.003; p = 0.05) and PDGF-β (β = - 0.16, 95% CI = - 0.31, 0.002; p = 0.05)] compared to placebo. Both PBA- and vitD-groups showed a decline in XBP1spl mRNA on week 8 (p < 0.03). All treatment groups demonstrated increased LC3 expression in MDM compared to placebo over time (p < 0.037).
CONCLUSION
The use of PBA and vitD as adjunct therapy to standard TB treatment promoted favorable immunomodulation to improve treatment outcomes.
TRIALS REGISTRATION
This trial was retrospectively registered in clinicaltrials.gov, under identifier NCT01580007 .
背景
我们之前的研究表明，在一项随机、安慰剂对照试验中，使用苯丁酸钠（PBA）（500mgx2/天）联合或不联合维生素 D（vitD）（5000IU/天）作为宿主定向治疗（HDT）治疗 8 周，可加速成人肺结核（TB）患者的临床康复、痰培养转化，并增加免疫细胞中 cathelicidin LL-37 的表达。在这项研究中，我们进一步旨在研究 PBA 和 vitD 的 HDT 是否促进了有益的临床免疫调节，以改善 TB 患者的治疗结果。
方法
测量了 31 名患者/组外周血单核细胞（PBMC）上清液中的细胞因子浓度。研究了患者 PBMC 来源的单核细胞衍生巨噬细胞（MDM）中内质网应激相关基因（GADD34 和 XBP1spl）和人β-防御素-1（HBD1）基因的表达（n=18/组）。使用共聚焦显微镜评估 MDM 中的自噬（n=6/组），并用 LC3 表达进行评估。
结果
与安慰剂组相比，PBA 组（TNF-α（β=-0.34，95%CI=-0.68，-0.003；p=0.04）、CCL11（β=-0.19，95%CI=-0.36，-0.03；p=0.02）和 CCL5（β=-0.08，95%CI=-0.16，0.002；p=0.05））和 vitD 组（CCL11（β=-0.17，95%CI=-0.34，-0.001；p=0.04）、CXCL10（β=-0.38，95%CI=-0.77，0.003；p=0.05）和 PDGF-β（β=-0.16，95%CI=-0.31，0.002；p=0.05））从第 0 周到第 8 周细胞因子/趋化因子浓度显著下降。与安慰剂相比，PBA 和 vitD 组第 8 周时 XBP1spl mRNA 下降（p<0.03）。所有治疗组与安慰剂相比，MDM 中的 LC3 表达随时间增加（p<0.037）。
结论
苯丁酸钠和维生素 D 作为标准结核病治疗的辅助治疗，可促进有利的免疫调节，改善治疗结果。
试验注册
该试验在 clinicaltrials.gov 中进行了回顾性注册，标识符为 NCT01580007。
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