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  • jak stat inhibitor Recent approaches toward more efficacious

    2018-10-23

    Recent approaches toward more efficacious interventions against TB, including shortening the length of the chemotherapy, include host-directed therapy (HDT) (). HDTs that focus on modulation of jak stat inhibitor comprise strategies to release immune suppression and enhance anti-microbial mechanisms, or alternatively, reduce inflammatory responses. Corticosteroids, TNF blockers, statins, thalidomide analogues and inhibitors of phosphodiesterases, cyclooxygenases and leukotrienes have been singled out as potentially adjunctive to canonical chemotherapy (). Reduction of inflammation promotes bacillary replication and destabilizes granulomas, thereby enhancing the tissue penetrability of drugs effective against metabolically active bacteria. The rationale for dampening inflammation has been informed by the efficacy of most anti-mycobacterial drugs against actively replicating and their limited activity against dormant bacilli. Tofacitinib inhibits JAK3- and to a lesser extent JAK-2-mediated phosphorylation of activated cytokine receptors and subsequently limits responsiveness to pro-inflammatory cytokines (). Tofacitinib is licensed for therapy of rheumatoid arthritis and ulcerative colitis. Moreover, similar to usage of TNF blockers, TB reactivation has been reported jak stat inhibitor for this JAK inhibitor in cases of latent TB infection () and in a mouse model of chronic paucibacillary TB (). Pursuing observations that Tofacitinib interferes with containment of TB () and based on pharmacokinetic studies, Maiga et al. evaluated efficacy of Tofacitinib as HDT for standard TB chemotherapy in different mouse models (). The authors showed that addition of Tofacitinib to standard chemotherapy profoundly shortened time to lung sterility in a chronic TB mouse model. Importantly, treatment did not lead to isoniazid resistance and did not alter the time required to achieve relapse-free TB cure, which together are critical for the design of novel, more efficacious treatment regimens. These findings strengthen the concept that strategies promoting “awakening” of dormant are favorable for TB patients when applied concomitantly with chemotherapy. Many anti-inflammatory drugs are clinically approved, and as such are a rationale choice for accelerating the transition of preclinical findings to clinical trials. Design of novel therapies based on repurposing drugs is particularly appealing for protracted disease courses that require lengthy therapy, such as TB. Furthermore, the authors provide proof of principle for successful JAK-centered HDT of TB as an adjunct to standard TB chemotherapy. Ideal for translational work, the therapy regimen used in murine studies by Maiga et al. encompasses first-line drugs as recommended for canonical TB treatment. Advancing HDT to the arena of human clinical research requires the addition of immunomodulatory compounds to standard TB treatment. Refinement of JAK inhibitors according to enzyme specificities and pharmacological profiles could further enhance efficacy of a JAK-centered HDT in TB. Moreover, compounds with immunomodulatory activity similar to Tofacitinib could exhibit more pronounced adjunctive effects in TB therapy. Preclinical validation of Tofacitinib as adjunct to canonical chemotherapy effectively consolidates a framework of anti-inflammatory HDT for TB. Some questions remain, however. Shortening the length of treatment was observed for the Balb/c mouse model, a commonly used mouse strain for studies investigating efficiency of anti-mycobacterial drugs. Tofacitinib administration to -infected C3HeB/FeJ mice did not show therapeutic effectiveness as observed in Balb/c animals. Notably, C3HeB/FeJ mice developed lung lesions resembling human TB granulomas, including hypoxia, necrosis and caseation (). Discrepant chemotherapeutical outcomes could reflect differences in inflammatory patterns and lung pathology in the mouse models under investigation. Future studies will clarify the mechanisms underlying divergent therapeutic outcomes. Further elaboration of disease diversity and how efficacy of medication is affected accordingly, will advance anti-TB therapy and contribute to our understanding of the complexity of TB pathophysiology.