Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D 3 as host directed therapy.

Autor: Rekha RS; 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., Mily A; 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., Sultana T; Infectious Diseases Division, icddr,b, 68 Shaheed Tajuddin Ahmed Sarani, Dhaka, 1212, Bangladesh., Haq A; Infectious Diseases Division, icddr,b, 68 Shaheed Tajuddin Ahmed Sarani, Dhaka, 1212, Bangladesh., Ahmed S; 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., Mostafa Kamal SM; National Institute of the Diseases of the Chest and Hospital, Mohakhali, Dhaka, Bangladesh., van Schadewijk A; Department of Pulmonology, Leiden University Medical Centre, Leiden, the Netherlands., Hiemstra PS; Department of Pulmonology, Leiden University Medical Centre, Leiden, the Netherlands., Gudmundsson GH; Biomedical Center, University of Iceland, Reykjavik, Iceland., Agerberth B; Department of Laboratory Medicine, Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Raqib R; Infectious Diseases Division, icddr,b, 68 Shaheed Tajuddin Ahmed Sarani, Dhaka, 1212, Bangladesh. rubhana@icddrb.org.
Jazyk: angličtina
Zdroj: BMC infectious diseases [BMC Infect Dis] 2018 Jul 04; Vol. 18 (1), pp. 303. Date of Electronic Publication: 2018 Jul 04.
DOI: 10.1186/s12879-018-3203-9
Abstrakt: Background: We have previously shown that 8 weeks' treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D 3 (vitD 3 ) (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 3 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 3 -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 3 -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 3 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 .
Databáze: MEDLINE
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