Table 1.
List of immunomodulatory agents for the treatment of 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] |
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