Role of Immunomodulators in Multi Drug Resistant Tuberculosis

Role of Immunomodulators in Multi Drug Resistant Tuberculosis

Over the past several years, extensive preclinical and clinical studies have revealed a myriad of immunological pathways and biomarkers that either influence the outcome of M. tuberculosis infection or indicate the state of disease, respectively.

These pathways include

• cytokine-mediated signalling,
• intracellular antimicrobial processes, and
• establishment of long-term immunological memory as well as physiological homeostasis.

The use of immunomodulatory agents as Host Directed Therapies (HDTs) for tuberculosis (TB) treatment has therefore garnered great interest as a means of improving clinical outcome of therapy, based on previous experience with other infectious diseases and cancer.

Immunomodulatory drugs: Several non-antibiotic drugs with immunomodulatory properties have already shown clinical efficacy in ameliorating infection-induced pathology.

For example, interventional use of glucocorticoid receptor agonists, i.e., prednisone and dexamethasone, has mortality-reducing effects in community-acquired pneumonia, concomitant with lowering of pro-inflammatory cytokine release.

1. Zileuton – inhibiting 5-Lipooxygenase(5-LO) activity
2. Metformin – acts by affecting the mitochondrial respiratory chain
3. Imatinib mesylate- inhibits the Bcr-Abl tyrosine kinase
4. Cyclophosphamide- anti-proliferative cancer drug.
5. Vitamin D₃ – immunological control of TB à orchestration of IFN-γ, IL-32 and IL-15 signalling.
6. Cellular therapy: re-infusion of bone marrow-derived mesenchymal stromal cells

Zileuton

• anti-inflammatory drug currently licensed for the treatment of asthma
• inhibiting 5-Lipooxygenase(5-LO) activity.
• As opposed to NSAIDs, zileuton blocks LO-mediated leukotriene production, facilitating COX₂ activation and PGE₂ synthesis.
• In a mouse model of TB, zileuton was shown to dramatically abate IFN-α/β levels in the lung to improve lung pathology, in addition to reducing M. tuberculosis load.
• Combination therapy comprising zileuton and PGE² augmented interleukin 1 beta (IL-1β)-mediated control of M. tuberculosis growth.
• Furthermore, patients with latent TB infection who successfully contained infection and did not develop active pulmonary TB appear to maintain balanced serum levels of PGE₂ and LXA₄.

Metformin (MET)

• essential drug used in the treatment of T2DM,
• acts by affecting the mitochondrial respiratory chain.
• Recent preclinical study à MET was evaluated as an adjunct therapeutic for drug-susceptible (DS)-TB and MDR-TB.
• MET treatment induced superoxide anion production in macrophages infected with DS or MDR M. tuberculosis in an-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner.
• MET therapy potentiated the activity of the first-line anti-TB drugs isoniazid and ethionamide in a mouse model of TB, commensurate with improved anti-TB CD8 T cell responses, reduced concentrations of inflammatory cytokines and lung pathology.

Imatinib mesylate,

• highly specific and successful drug that inhibits the Bcr-Abl tyrosine kinase in chronic myelogenous leukaemia has also been evaluated in TB;
• treatment of M. marinum-infected mice with imatinib resulted in enhanced myelopoiesis in the bone marrow.
• Furthermore, an early influx of neutrophils into the lungs of infected mice helped reduce the bacterial burden.
• Imatinib in combination with rifampicin greatly reduced liver pathology in mice infected with M. marinum, while reducing lung bacterial load also in M. tb-infected animals.

Cyclophosphamide (CP)

• potent anti-proliferative cancer drug and pre-conditioning agent metabolised by cytochrome P450 to produce reactive metabolites that crosslink with guanine residues.
• Cell types expressing low amounts of aldehyde dehydrogenase are most susceptible to CP treatment since its enzymatic activity neutralises drug-derived cytotoxicity.
• Regulatory T cells (Tregs) express high cellular levels of ATP-binding cassette B1, which binds CP, thus making these cells especially vulnerable to the drug.
• Conversely, aldehyde dehydrogenase overexpression can promote resistance to CP toxicity.
• Prior CP administration to patients participating in a clinical trial of a renal cell cancer vaccine candidate (IMA901) led to Treg decline in peripheral blood of the participants, afforded better CD8 T cells priming and improved overall survival.
• CP treatment may remove Treg cells as well as pathological lymphocytosis in patients with MDR-TB.

Vitamin D₃ (VD₃):

• important for host resistance to TB; pulmonary TB patients with VD₃ deficiency are not able to mount adequate control of primary M. tuberculosis infection in the lung.
• Further, VD₃ has been implicated in immunological control of TB in humans involving orchestration of IFN-γ, IL-32 and IL-15 signalling.
• Recent evaluation of the therapeutic potential of VD3 in combination with PBA has shown improved anti-mycobacterial effects and faster conversion to AFB-negative sputum by the participating TB patients.
• In vitro evaluation of M. tb-infected macrophages treated with VD₃ resulted in upregulation of a collage of anti-inflammatory (IL-10, ARG1) and pro-inflammatory (IL1B, TNF) genes over a 72-hour exposure period – this profile was relatively unchanged with PBA co-treatment.

Cellular therapy:

• isolated from patients with MDR/extensively drug resistant-TB was shown to be safe
• a phase 2 trial is underway in Durban, South Africa, to evaluate their efficacy in improving treatment outcomes and effects on immune responses.
• Mesenchymal stromal cell treatment also re-programmed anti-TB T cell responses, with focus on specific M. tuberculosis antigens.
• Infusion of M. tuberculosis -specific T cells has yet to be clinically evaluated in TB patients, although in vitro evidence for feasibility, comprising subsets of CD8 T cells, NK T cells and TCR γδ T cells, has been established.