Table 2.
Potential immunotherapeutic agents that have been studied in murine or human models for the treatment of TB
| Agent | Mechanism | Comment |
|---|---|---|
| Immunoregulatory agents | ||
| Mycobacterium vaccae | Drives Th1 and CD8+ CTL but downregulates Th2 through CD4+CD45+Rblow regulatory cells | Single-dose M. vaccae not effective in clinical trials but full results of multiple-dose studies are awaited (reduced TB incidence shown in HIV-positive subjects in the DARDAR study). Used in China to treat MDR-TB |
| Mycobacterium w | Drives a Th1 response in mice but mechanism of action is unknown. Licensed in India as a immunomodulator for use in leprosy | Preliminary data suggest a beneficial effect in a murine model and one small human study |
| High-dose IVIG | Unknown but may involve pathways implicating sialic acid residues on IgG | Effective in a murine model. No human trials undertaken |
| HE2000 | Modified form of DHEA (an adrenal steroid). Mode of action is unknown | Therapeutic in a murine model of TB. Reduced coinfection with TB shown in a cohort of HIV-infected individuals |
| DNA vaccine encoding HSP65 from M. leprae | Enhances CD8+ CTL activity and downregulates Th2 | Effective in a mouse model but there are conflicting data. Phase 1 studies are planned |
| Fragmented lipid-depleted M. tuberculosis delivered in liposomes (RUTI) | Liposomal preparation of the M. tuberculosis cell wall skeleton. Suggested as an adjunct to eradicate long-term persisters | Accelerates bacterial clearance in a mouse model. Phase 1 studies underway |
| Immunoxel (Dzherelo) | Combination of plant extracts used in the Ukraine. Mechanism of action is unknown | Striking effects in small uncontrolled studies of M and XDR-TB patients. Larger controlled studies are warranted |
| SCV-07 SciCLone | Unknown | Results from one murine study |
| Anti-IL-4 | Reduced macrophage apoptosis, enhanced macrophage function, reduced TGF-β, drives expansion of CD8+ CTL etc. | Therapeutic effect in mouse models. Humanized monoclonal IL-4 has been produced by Glaxo Smith Kline but no human studies have been performed |
| Supplemental effector cytokines | ||
| Recombinant IFN-γ | Theoretically upregulate Th1-mediated macrophage killing | Two controlled trials showed minimal effects and their results have never been published |
| Recombinant IL-2 | Promotes T-cell proliferation and granuloma formation | No beneficial effects found in an RCT (in fact reduced culture conversion was observed in the IL-2 arm) |
| IL-12 | Drives a Th1 response | Beneficial in a murine model |
| Recombinant GM-CSF | Reduced M. tuberculosis replication in macrophages and DC | Trend to faster sputum conversion in one human study |
| Immunosuppressive agents | ||
| Thalidomide, newer thalidomide analogues and TNF blockers e.g. etanercept | Disruption of immunopathological environment in which M. tuberculosis resides with replication upon exposure of bacteria to drugs. Newer analogues are PDE4 inhibitors | Murine and human studies have been undertaken. Newer thalidomide analogues show enhanced killing in murine models. Etanercept showed enhanced culture conversion in a clinical trial |
| High-dose prednisolone | Attenuates TNF-α production | Large controlled trial showed a dramatic effect on enhanced sputum culture conversion. Two other prospective studies showed a beneficial effect on sputum conversion |
These agents, their mechanisms of actions and evidence for their utility have recently been reviewed in detail elsewhere116,125,126 and this table should be read in conjunction with Churchyard et al.125
CTL, cytolytic T lymphocyte; DARDAR, Dartmouth and Dar es Salaam; DC, dendritic cell; DHEA, Dehydroepiandrosterone; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; MDR-TB, multi-drug-resistant tuberculosis; RCT, randomized controlled trial; TB, tuberculosis; TGF, transforming growth factor; TNF, tumour necrosis factor; XDR-TB; extensively drug-resistant tuberculosis.