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.

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