Reply to Levis and Rendini

Reply to Levis and Rendini—We appreciate the comments by Levis et al. on our work documenting the potential utility of clofazimine for the treatment of tuberculosis. We support their view on the efficacy of clofazimine in leprosy, both as an antibacterial and an anti-inflammatory agent. In addition to mycobacterial infections, the vast majority of infectious diseases and cancers involve pathology induced by inflammation. Although inflammatory responses play a central role in inducing protective immune responses, profound inflammation can exacerbate pathology. Thus, the addition of anti-inflammatory agents to the treatment regimens for certain infections and cancers might be beneficial. Consistent with this notion, corticosteroids enhance the efficacy of tuberculosis treatment regimens [1]. However, corticosteroids also suppress host immunity, which might have deleterious effects on the host, such as the risk for disease relapse and reinfection. Clofazimine, an inhibitor of the voltage-gated K⁺ channel Kv1.3, has antimicrobial and anti-inflammatory activities and is beneficial for the treatment of infectious diseases such as leprosy [2] and tuberculosis [3]. Interestingly, effector memory T (T_EM) cells abundantly express Kv1.3. We have recently shown that inhibition of Kv1.3 by clofazimine promotes the induction of long-lived, antigen-specific central memory T (T_CM) cells, which are crucially important for the efficacy of vaccines [4]. Therefore, clofazimine may be effective as an adjunct to a variety of therapies and vaccines:

Tuberculosis therapy: Tuberculosis is associated with potent inflammatory responses; consequently, corticosteroids can curb such responses [1]. Clofazimine exhibits immunosuppressive effects and inhibits T_EM cells, which are associated with inflammation and pathology [3]. The addition of clofazimine to antibiotic regimens yields improved treatment efficacy and simultaneously enhances Mycobacterium tuberculosis–specific T_CM responses that protect the host against future reinfection, a property we have termed “self-propelled vaccination” [4].

Tuberculosis vaccine: The only approved vaccine for tuberculosis, bacillus Calmette Guérin (BCG), is efficacious for meningitic and disseminated tuberculosis in children but lacks efficacy in adult pulmonary tuberculosis [4]. Although the exact cause of BCG failure is unclear, optimal vaccine efficacy against tuberculosis requires both T helper 1 (Th1) and T helper 17 (Th17) immune responses [5]. Therefore, the addition of clofazimine to BCG may provide improved vaccine efficacy, as was recently confirmed in our studies with a mouse model of M. tuberculosis infection [4].

Cancer: Cancer is associated with inflammation and dysfunction of tumor-infiltrating antigen-specific T cells. It is well known that tumor-infiltrating T cells become dysfunctional in the tumor microenvironment where they adopt a regulatory phenotype [6]. Therefore, overcoming the tolerance of these cells may enhance antitumor immunity. BCG has been employed in bladder cancer, where it promotes T-cell functions, likely because of its capacity to induce interleukin 6 (IL-6) [7]. BCG-induced IL-6 together with transforming growth factor-β, which is readily available in the tumor microenvironment, induce Th17 cell responses with potent antitumor activities. Thus, clofazimine might be able to promote tumor antigen–specific, Th17-type T_CM cells, acting as a “self-propelled vaccine.”Numerous studies have shown direct killing of cancer cells by modulating the extracellular/intracellular and mitochondrial K⁺ ion balance [8]. Furthermore, by inhibiting T_EM cells, clofazimine might be effective in curbing inflammation and preventing T cell immune suppression (via tolerance, exhaustion, or anergy) during tumor progression. Additionally, the enhancement of T_CM-cell differentiation by clofazimine should be effective in preventing tumor metastasis. Such T_CM responses are expected to impart long-term protection against tumor relapses, while avoiding the development of autoimmunity, a common side effect of cancer immunotherapy.

Human immunodeficiency virus/AIDS: Levis et al. also suggested the potential utility of clofazimine in human immunodeficiency virus (HIV)/AIDS, owing to the well-documented neurotoxicity of HIV proteins (eg, trans-activator of transcription [Tat], envelope glycoprotein 120 [gp120]) against microglia [9]. This neurotoxicity was abrogated by pharmacological or genetic inhibition of Kv1.3 [9]. Clofazimine should also provide benefits by enhancing T-cell–mediated immunity against HIV. Additionally, clofazimine might influence immune reconstitution following antiretroviral therapy (ART). ART treatment of patients with advanced immunosuppression may cause immune reconstitution inflammatory syndrome (IRIS), with delayed restoration of host immunity [10]. Clofazimine might be able to prevent IRIS, while preserving the integrity of HIV-specific effector T-cell responses.

In summary, clofazimine shows promise for prophylactic and therapeutic intervention in a variety of diseases and their comorbidities, including infections, autoimmunity, and cancer.

Notes

Financial support. This work was supported by the Department of Biotechnology (DBT) grant no. BT/PR6312/MED/29/605/2012; Government of India, New Delhi and ICGEB core research grant.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.