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BMC Infectious Diseases
Published in: BMC Infectious Diseases 1/2018

Open Access 01-12-2018 | Research article

Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy

Authors: Rokeya Sultana Rekha, Akhirunnesa Mily, Tajnin Sultana, Ahsanul Haq, Sultan Ahmed, S. M. Mostafa Kamal, Annemarie van Schadewijk, Pieter S. Hiemstra, Gudmundur H. Gudmundsson, Birgitta Agerberth, Rubhana Raqib

Published in: BMC Infectious Diseases | Issue 1/2018

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Abstract

Background

We have previously shown that 8 weeks’ treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D3 (vitD3) (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 vitD3 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 vitD3-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 vitD3-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 vitD3 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.
Appendix
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Metadata
Title
Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy
Authors
Rokeya Sultana Rekha
Akhirunnesa Mily
Tajnin Sultana
Ahsanul Haq
Sultan Ahmed
S. M. Mostafa Kamal
Annemarie van Schadewijk
Pieter S. Hiemstra
Gudmundur H. Gudmundsson
Birgitta Agerberth
Rubhana Raqib
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2018
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-018-3203-9

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