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Table 1 List of immunomodulatory agents for the treatment of multidrug-resistant tuberculosis

From: Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis

Immunomodulatory agent

Host target

Currently licensed indication(s)

Biological activity

Ref.

Small molecules

    

Metformin

AMPK activator

Diabetes

Augments mitochondrial reactive oxygen species-mediated intracellular MDR M. tb killing and reduction of lung bacterial burden and pathology in mice likely via increased mitochondrial turnover; enhances CD8 T cell responses, possibly by increasing FAO with AMPK involvement in memory cells. Shown to promote anti-tumour CD8 T cell memory generation in engrafted TNF receptor associated factors knockout mice via FAO restoration

[41, 43, 120]

Zileuton

5-lipoxygenase inhibitor

Asthma

Inhibits 5-lipoxygenase and subsequent formation of leukotrienes; promotes reduced lung M. tb burden and pathology in mice by increasing PGE2 levels and augmenting IL-1β-mediated anti-TB immune control

[29, 30]

Ibuprofen

COX inhibitor

Pain and fever relief

Inhibits COX2 and suppresses prostaglandin H2 and thromboxane production; inhibits COX1; reduces lung pathology and M. tb load in a highly-susceptible TB mouse model

[27]

Aspirin (acetylsalicylic acid)

COX inhibitor

Pain and fever relief

Inhibits COX1 to suppress prostaglandin and thromboxane production to dampen TNF-α-induced overt inflammation; aids tissue repair and control of M. tb burden

[121]

Valproic acid

Histone deacetylase inhibitor

Epilepsy and bipolar disorder

Inhibits HDAC I, II and IV to block histone deacetylation and enhance gene transcription; activates latent HIV reservoirs and increases ART efficacy as well as increased CD8 T cell activity; can induce autophagy and apoptosis

[61, 122, 123]

Carbamazepine

GABA receptor agonist and sodium channel stabiliser

Epilepsy and neuropathic pain

Induces autophagy via inositol depletion in macrophages, potentiating killing of intracellular M. tb; reduces lung pathology and improves overall immune responses in a mouse model of TB

[124]

Vorinostat

Histone deacetylase inhibitor

Cutaneous T cell lymphoma

Inhibits HDAC I, II and IV to block histone deacetylation and enhance gene transcription; induces reactivation of latent HIV in CD4 T cells and improves CD8 T cell responses as well as ART efficacy – presently in clinical trials in HIV-infected individuals; can induce autophagy and apoptosis; shown to dampen neuroinflammation in a mouse model of West Nile virus infection, adjunctively to an experimental antiviral drug candidate

[62, 69, 125–127]

Phenylbutyrate

Histone deacetylase inhibitor, chemical chaperone

Urea cycle disorders

Inhibits HDAC I to block histone deacetylation and enhance gene transcription; induces autophagy by activating expression of antimicrobial peptides by macrophages to kill intracellular M. tb in combination with vitamin D3; shown to be very beneficial as short-course therapy (with vitamin D3) in a clinical study involving patients with pulmonary TB

[70, 71, 127, 128]

Cyclophosphamide

DNA alkylating agent

Lymphomas and pre-transplant preconditioning

Forms lethal phosphoramide mustard following activation specifically in low producers of aldehyde dehydrogenase (largely Tregs); activity shown to potentiate renal cell carcinoma clinical vaccine candidate; Treg depletion may imply clinically beneficial immune responses in severe pulmonary TB

[49, 51, 82, 85, 129]

Etoposide

Topoisomerase inhibitor

Various cancer types

Inhibits DNA topoisomerase I activity to abrogate cell proliferation; depletion of pathogenic inflammatory T cells in influenza-induced hemophagocytic lymphohistiocytosis shown to be beneficial

[130]

Imatinib mesylate

Tyrosine kinase inhibitor

Leukaemias and gastrointestinal stromal tumours

Inhibits mutant BCR-ABL tyrosine kinases in cells; reduces colony forming unit load and pathology in lungs of M. tb-infected mice; induces myelopoiesis

[44, 45]

Niraparib

PARP inhibitor

Ovarian and breast cancers

Inhibits PARP1/2 to cause double strand DNA breaks in cells, abrogating proliferation; niraparib has been shown to restore mitochondrial respiration in human muscle fibres, likely by improving FAO, thus promoting maintenance of anti-TB memory CD8 T cells

[131]

Prednisone

Glucocorticoid receptor agonist

Immunosuppressant used in cancer and inflammatory diseases

Activated downstream signalling of the GC receptor; has pleiotropic outcomes, including anti-inflammatory effects; use in community-acquired pneumonia showed improved survival among patients; results in TB patients inconclusive and requires further validation

[20, 22, 132]

Nutraceuticals

    

Resveratrol

Sirtuin agonist

Over-the-counter antioxidant

Increases cellular mitochondrial turnover, thus increased respiratory capacity; may promote maintenance of anti-TB memory CD8 T cells via FAO increase; alternatively, may also induce apoptosis of activated T cells during severe inflammation

[120, 133]

Vitamin D3

Innate immune response activator

Dietary supplement

Kills intracellular M. tb; activates innate immune responses in macrophages, thus improving ensuing T cell responses in combination with phenylbutyrate; also augments IL-32 and IL-15-mediated immune responses in clinical TB

[70, 71, 85, 86, 88, 128, 134]

Biologicals

    

Interleukin 15

Involved in CD8 memory T cells maintenance

In clinical trials for various cancers

Signals via IL-15Rβ and the common chain to activate STAT3 and STAT5; increases mitochondrial mass and fatty acid oxidation in memory CD8 T cells to prolong survival and maintenance; augments IFN-γ and vitamin D3-mediated immune responses in human TB

[86, 135, 136], NCT01727076

Nivolumab/pembrolizumab (anti-PD-1)

Immune checkpoint inhibitor

Melanoma; in clinical trials for various other cancers

Inhibits PD-1 expressed on T cells, and abrogates interaction with PD-L1 on tumour cells and myeloid cells to reverse T cell exhaustion increases tumour-specific CD8 T cell activity and tumour regression in metastatic melanoma patients; highly expressed on Tregs isolated from peripheral blood of MDR-TB patients; in vitro blockade of PD-1 on T cells from TB patients potentiated M. tb antigen-dependent IFN-γ secretion; anti-TB treatment success is commensurate with lower PD-1 expression in patients

[137–140]

Ipilimumab (anti-CTLA-4)

Immune checkpoint inhibitor

Melanoma; in clinical trials for various other cancers

Inhibits CTLA-4 expressed on T cells, abrogates interaction with CD80 and/or CD86 on tumour cells and myeloid cells to reverse T cell exhaustion; increases CD8 T cell activity and tumour regression in melanoma patients; highly expressed on Tregs isolated from peripheral blood of MDR-TB patients; may potentiate cellular immune responses in clinical TB

[141]

Anti-LAG3

Immune checkpoint inhibitor

In clinical trials for various cancers

Inhibits LAG3 expression; blockade of LAG3 can prevent T1DM development in mice, potentiate CD8 T cell activity of a prostate cancer vaccine candidate and enhance antimalarial immune responses; in non-human primate models of TB, LAG3 expression on CD4 T cells has been shown to correlate with poor anti-TB immune function; blocking LAG3 may contribute to successful containment of TB infection by T cells

NCT02460224, NCT02061761, [106]

Adalimumab (anti-TNF-α)

Cytokine neutralisation

Rheumatoid arthritis

Removes excess TNF-α from systemic circulation and target organs; successfully used as salvage therapy in a patient with severe pulmonary TB

[72]

Siltuximab (anti-IL-6)

Cytokine neutralisation

Juvenile arthritis, Castleman’s disease

Removes excess IL-6 from systemic circulation and target organs; use in MDR-TB patients co-infected with HIV may aid in management of ART-induced TB-IRIS

[6, 74, 142, 143]

Tocilizumab (anti-IL-6R)

Cytokine signalling blockade

Arthritis, Castleman’s disease

Prevents IL-6 from binding to its receptor on cell surfaces to reduce pro-inflammatory signalling; use in MDR-TB patients infected with HIV may aid in management of ART-induced TB-IRIS

[6, 74, 142, 143]

Bevacizumab (anti-VEGF)

Angiogenesis inhibitor

Various cancer types (mostly solid tumours)

Inhibits binding of VEGF-A to its receptor to block signalling and subsequent formation of new blood vessels; bevacizumab inhibited neovascularisation and improved lung pathology in a rabbit model of TB; may also facilitate drug penetration into granulomas and increased oxygenation, with implications for enhancing anti-TB drug efficacy

[79, 144]

Cellular therapy

    

Bone marrow-derived mesenchymal stromal cells

Reduction of inflammation and improved tissue regeneration

In clinical trials for various inflammatory indications

Successful phase 1 safety study of mesenchymal stromal cell reinfusion into patients with MDR/extensively drug resistant-TB in Belarus; showed improved lung radiographic findings, pulmonary function (57 % cure); promoted fine-tuning of T cell responses to specific M. tb antigens in recipients; trial is currently being repeated in Durban, South Africa

[112, 114, 145]

Antigen-specific T cells

Targeted killing of M. tb-infected host cells

Cancer and viral infections

Currently used in cancer immunotherapy; successfully used in treating post-transplantation opportunistic viral infections, i.e. cytomegalovirus, Epstein–Barr virus

[111–113, 115, 116, 118, 146]

  1. ART antiretroviral therapy, IRIS immune reconstitution inflammatory syndrome, FAO fatty acid oxidation, HDAC, Histone deacetylase inhibitors, MDR multidrug resistant; M. tb Mycobacterium tuberculosis, TB tuberculosis