Table 2.
The role of cytokines in TB disease and evidence to support their therapeutic intervention and outcome as TB HDT strategies.
| Cytokine | Role in TB disease | Therapeutic intervention and outcome in TB disease | Reference |
|---|---|---|---|
| INF-γ | Activates macrophages and DCs, promotes cell proliferation, apoptosis, cell adhesion and bacterial killing (through phagocytosis and reactive nitrogen and oxygen intermediates). | Aerosol administration of INF-γ improved bacillary clearance and improved clinical condition. Aerosol administration of INF-γ in conjunction with anti-TB drugs cured MDR-TB. Nebulized INF-γ1b and subcutaneous injections of INF-γ1b alleviated disease symptoms, although culture showed that nebulized administration increased the likelihood of negative smears at 4 weeks. Supplementation of recombinant INF-γ improves response to anti-TB drugs in cavitary TB patients. | 75,174–177 |
| TNF-α | Controls Mtb infection and replication by formation and maintenance of the granuloma; by regulating macrophage activation, phagocytosis, and nitrogen and oxygen intermediates. | TNFα inhibition causes granuloma disruption and bacillus reactivation to increase Mtb susceptibility to standard TB drugs; results in rapid clearance of Mtb from the lung and altered inflammatory responses to benefit the host in TB/HIV-1 co-infected individuals. | 178,179 |
| GM-CSF | Induces granulocyte and macrophage proliferation and differentiation, stimulates macrophage phagocytosis, increases cytotoxicity and reactive nitrogen and oxygen intermediates. | Administration of GM-CSF resulted in negative sputum culture conversion after 8 weeks. | |
| TGF-β* | Immunosuppressive cytokine, inhibits the Th1 response during chronic infection. | Suppression of TGF-β enhances resolution of local Mtbinfection and associated inflammatory responses, while decreasing bacillary load in mouse models. | 180 |
| VEGF* | Angiogenic cytokine that promotes hypoxic microenvironment. | Neutralization or inhibition increases efficiency of TB treatment regimens by disrupting the granuloma thus promoting drug penetration and Mtb killing in human, rabbit and zebrafish models. | 181,182 |
| IL-2 | Aids proliferation of antigen-specific CD4+ and CD8+ T, activates the JAK-STAT signalling pathway for gene transcription of cell growth and survival genes. | Recombinant IL-2 supplementation with anti-TB drugs improved immunity status and promoted sputum smear conversion to negative, with reduced INF-γ production and low skin response to Mtb antigens (response is likely mediated by regulatory T cells). | 183 |
| IL-4* | Downregulates INF-γ production and mediates cytotoxicity and fibrosis. | Genetically deficient IL-4−/− mice successfully eradicated Mtb infection following reconstruction with recombinant IL-4, and has the potential to be adjunctive to standard TB regimens. | 184,185 |
| IL-7* | Enhances T-cell memory, upregulates IL-17 production, downregulates TGF-β, aids in DC activation. | Mtb mouse models demonstrated increased survival and bacilli clearance when administered in conjunction with BCG vaccine. | 186,187 |
| IL-10* | Immunoregulatory cytokine with Th2-modulatory effects. | Inhibition of IL-10 in conjunction with anti-TB drugs effectively improved disease outcome and drug efficiency. | 188 |
| IL-12* | Strong inducer of INF-γ production in antigen-stimulated CD4+ T cells, essential for protective immune response to intracellular pathogens. | Administration to Mtb-infected mice decreased viable bacilli load in lymphoid organs. One case study provided evidence of successful response to anti-TB drugs only following treatment with IL-12 for 3 months in a patient that was previously refractory to anti-TB treatment. | 189,190 |
| IL-15* | Aids proliferation and survival of CD8+ T cells, strengthens immune memory. | BCG-vaccinated IL-15 transgenic mice displayed resistance against Mtb infection, thus acting as an immune adjuvant to increase efficiency when administered with BCG vaccination. | 186,191 |
| IL-23* | Inducer of INF-γ production and proliferation of activated memory T cells. | Vector-mediated intratracheal delivery in mice reduced bacilli load and inflammation. | 192 |
| IL-24* | Activated CD8+ T cells, increases INF-γ production, activates neutrophils and increases IL-12 production | Mtb mouse models demonstrate protective response upon administration of exogenous IL-24. | 193 |
| IL-37* | Antiinflammatory cytokine, broadly suppresses innate and adaptive immunity. | BCG-infected transgenic IL-37 mice displayed reduced bacilli load and tissue damage in the lung, with reduced frequencies of regulatory T cells and Th17 cells. | 194 |
| Cytokine modulators | |||
| RhIL-2 | Cytokine adjunctive therapy is thought to restore the immune response and modulate the immunologic status in favour of the host by promoting CD4+ and CD8+ T-cell proliferation, and by activating gene transcription pathways of cell growth and cell survival genes. | Study of adjunctive recombinant human interleukin-2 therapy in patients with MDR-TB | 74,183,195,196 |
| Pascolizumab | The IL-4 cytokine is known as an immunosuppressant molecule which impairs the immune system’s ability to clear Mtb infection. Thus, pascolizumab, an anti-IL-4 monoclonal antibody is thought to strengthen the immune response and benefit the host’s ability to clear infection. | Safety and Efficacy of Blocking IL-4 with Pascolizumab in Patients Receiving Standard Therapy for Pulmonary Tuberculosis | 185,197 |
INF-γ interferon-γ, TNF-α tumor necrosis factor-α, GM-CSF granulocyte/macrophage-colony stimulating factor, VEGF vascular endothelial growth factor, Ang angiopoietin, IL interleukin, DCs dendritic cells, CD cluster of differentiation, JAK-STAT Janus tyrosine kinase-signal transducer and activator of transcription, TGF-β transforming growth factor-β; BCG = Bacille Calmette Guerin, CFU colony-forming units, MGIT Mycobacteria Growth Indicator Tube
aNo clinical trial data as evidence for therapeutic intervention potential and outcome in TB disease