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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, 125127]
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 [137140]
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 [111113, 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