{"id":757,"date":"2020-02-17T22:02:29","date_gmt":"2020-02-17T16:32:29","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=757"},"modified":"2020-02-17T22:02:29","modified_gmt":"2020-02-17T16:32:29","slug":"role-of-immunomodulators-in-multi-drug-resistant-tuberculosis","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/role-of-immunomodulators-in-multi-drug-resistant-tuberculosis\/","title":{"rendered":"Role of Immunomodulators in Multi Drug Resistant Tuberculosis"},"content":{"rendered":"\n<p><strong><u>Role of Immunomodulators in Multi Drug Resistant Tuberculosis<\/u><\/strong><\/p>\n\n\n\n<p>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.<\/p>\n\n\n\n<p>These pathways include<\/p>\n\n\n\n<ul><li>cytokine-mediated signalling,<\/li><li>intracellular antimicrobial processes, and<\/li><li>establishment of long-term immunological memory as well as physiological homeostasis.<\/li><\/ul>\n\n\n\n<p>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.<\/p>\n\n\n\n<p><strong>Immunomodulatory drugs<\/strong>: Several non-antibiotic drugs with immunomodulatory properties have already shown clinical efficacy in <strong>ameliorating infection-induced pathology<\/strong>.<\/p>\n\n\n\n<p>For example, interventional use of <strong>glucocorticoid receptor agonists, i.e., prednisone and dexamethasone<\/strong>, has <strong>mortality-reducing effects in community-acquired pneumonia<\/strong>, concomitant with lowering of pro-inflammatory cytokine release.<\/p>\n\n\n\n<ol type=\"1\"><li><strong><u>Zileuton<\/u><\/strong> &#8211; inhibiting 5-Lipooxygenase(5-LO) activity<\/li><li><strong><u>Metformin &#8211; <\/u><\/strong>acts by affecting the mitochondrial respiratory chain<\/li><li><strong><u>Imatinib mesylate- <\/u><\/strong>inhibits the Bcr-Abl tyrosine kinase<\/li><li><strong><u>Cyclophosphamide- <\/u><\/strong>anti-proliferative cancer drug.<\/li><li><strong><u>Vitamin D<sub>3 <\/sub><\/u><\/strong>&#8211; immunological control of TB \u00e0 orchestration of IFN-\u03b3, IL-32 and IL-15 signalling.<\/li><li>Cellular therapy: re-infusion of bone marrow-derived mesenchymal stromal cells<\/li><\/ol>\n\n\n\n<p><strong><u>Zileuton<\/u><\/strong><\/p>\n\n\n\n<ul><li>anti-inflammatory drug currently licensed for the treatment of asthma<\/li><li>inhibiting 5-Lipooxygenase(5-LO) activity.<\/li><li>As opposed to NSAIDs, zileuton blocks LO-mediated leukotriene production, facilitating COX<sub>2<\/sub> activation and PGE<sub>2<\/sub> synthesis.<\/li><li>In a mouse model of TB, zileuton was shown to dramatically abate IFN-\u03b1\/\u03b2 levels in the lung to improve lung pathology, in addition to reducing <em>M. tuberculosis<\/em> load.<\/li><li>Combination therapy comprising zileuton and PGE<sup>2<\/sup> augmented interleukin 1 beta (IL-1\u03b2)-mediated control of <em>M. tuberculosis<\/em> growth.<\/li><li>Furthermore, <strong>patients with latent TB infection<\/strong> who successfully contained infection and <strong>did not develop active pulmonary TB<\/strong> appear to maintain balanced serum levels of PGE<sub>2<\/sub> and LXA<sub>4<\/sub>.<\/li><\/ul>\n\n\n\n<p><strong><u>Metformin (MET)<\/u><\/strong><\/p>\n\n\n\n<ul><li>essential drug used in the treatment of T2DM,<\/li><li>acts by affecting the mitochondrial respiratory chain.<\/li><li>Recent preclinical study \u00e0 MET was evaluated as an adjunct therapeutic for drug-susceptible (DS)-TB and MDR-TB.<\/li><li>MET treatment <strong>induced superoxide anion production in macrophages<\/strong> infected with DS or MDR <em>M. tuberculosis<\/em> in an-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner.<\/li><li>MET therapy <strong>potentiated the activity of the first-line anti-TB drugs<\/strong> 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.<\/li><\/ul>\n\n\n\n<p><strong><u>Imatinib mesylate<\/u><\/strong>,<\/p>\n\n\n\n<ul><li>highly specific and successful drug that <strong>inhibits the Bcr-Abl tyrosine kinase in chronic myelogenous leukaemia<\/strong> has also been evaluated in TB;<\/li><li>treatment of M. marinum-infected mice with imatinib resulted in <strong>enhanced myelopoiesis in the bone marrow.<\/strong><\/li><li>Furthermore, an <strong>early influx of neutrophils into the lungs<\/strong> of infected mice<strong> helped reduce the bacterial burden.<\/strong><\/li><li>Imatinib in combination with rifampicin <strong>greatly reduced liver pathology<\/strong> in mice infected with M. marinum, while reducing lung bacterial load also in M. tb-infected animals.<\/li><\/ul>\n\n\n\n<p><strong><u>Cyclophosphamide (CP)<\/u><\/strong><\/p>\n\n\n\n<ul><li>potent <strong>anti-proliferative cancer drug<\/strong> and pre-conditioning agent metabolised by cytochrome P450 to <strong>produce reactive metabolites that crosslink with guanine residues<\/strong>.<\/li><li><strong>Cell types expressing low amounts of aldehyde dehydrogenase are most susceptible to CP treatment<\/strong> since its enzymatic activity neutralises drug-derived cytotoxicity.<\/li><li>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.<\/li><li>Conversely, aldehyde dehydrogenase overexpression can promote resistance to CP toxicity.<\/li><li>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.<\/li><li>CP treatment <strong>may remove Treg cells as well as pathological lymphocytosis <\/strong>in patients with MDR-TB.<\/li><\/ul>\n\n\n\n<p><strong><u>Vitamin D<sub>3<\/sub> <\/u><\/strong><strong><u>(VD<sub>3<\/sub>)<\/u><\/strong>:<\/p>\n\n\n\n<ul><li>important for host resistance to TB; <strong>pulmonary TB patients with VD<sub>3<\/sub> deficiency are not able to mount adequate control of primary <em>M. tuberculosis<\/em> infection<\/strong> in the lung.<\/li><li>Further, <strong>VD<sub>3<\/sub> has been implicated in immunological control of TB<\/strong> in humans involving orchestration of <strong>IFN-\u03b3, IL-32 and IL-15 signalling.<\/strong><\/li><li>Recent evaluation of the therapeutic potential <strong>of VD3 in combination with PBA has shown improved anti-mycobacterial effects and faster conversion to AFB-negative sputum by the participating TB patients<\/strong>.<\/li><li>In vitro evaluation of M. tb-infected macrophages treated with VD<sub>3<\/sub> resulted in <strong>upregulation of a collage of anti-inflammatory (IL-10, ARG1)<\/strong> and pro-inflammatory (IL1B, TNF) genes over a 72-hour exposure period \u2013 this profile was relatively unchanged with PBA co-treatment.<\/li><\/ul>\n\n\n\n<p><strong><u>Cellular therapy<\/u><\/strong>:<\/p>\n\n\n\n<ul><li>isolated from patients with MDR\/extensively drug resistant-TB was shown to be safe<\/li><li>a phase 2 trial is underway in Durban, South Africa, to evaluate their efficacy in improving treatment outcomes and effects on immune responses.<\/li><li>Mesenchymal stromal cell treatment also <strong>re-programmed anti-TB T cell responses, with focus on specific <em>M. tuberculosis<\/em> antigens.<\/strong><\/li><li>Infusion of <em>M. tuberculosis<\/em> -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 \u03b3\u03b4 T cells, has been established.<\/li><\/ul>\n","protected":false},"excerpt":{"rendered":"<p>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[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/757"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=757"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/757\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=757"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=757"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=757"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}