16α‐Bromoepiandrosterone Restores T Helper Cell Type 1 Activity and Accelerates Chemotherapy‐Induced Bacterial Clearance in a Model of Progressive Pulmonary Tuberculosis

Abstract

BALB/c mice with pulmonary tuberculosis develop a T helper cell type 1 response that peaks at 3 weeks, temporarily controlling bacterial growth. Then bacterial proliferation recommences, accompanied by increasing interleukin (IL)-4 levels and decreasing interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase (iNOS) levels. These changes mimic those in the human disease. In a previous study, administration of dehydroepiandrosterone (DHEA) beginning on day 60 after infection reversed these changes and protected the mice. However, DHEA is suboptimal for human use, partly because it is readily metabolized into sex steroids. 16alpha-Bromoepiandrosterone (EpiBr; 16alpha -bromo-5alpha -androstan-3beta-ol-17-one) is a synthetic adrenal steroid derivative that does not enter sex steroid pathways. In the present study, when tuberculous BALB/c mice were treated with EpiBr 3 times/week beginning on day 60, inhibition of bacterial proliferation and increased expression of TNF-alpha, IFN-gamma, and iNOS were observed, although decreased expression of IL-4 was also observed. Moreover, when given as an adjunct to conventional chemotherapy, EpiBr enhanced bacterial clearance. Trials for the use of EpiBr in the treatment of human tuberculosis are now justified.

The curative effect of fucoidan on visceral leishmaniasis is mediated by activation of MAP kinases through specific protein kinase C isoforms

“…28 In this context, natural dietary components are gaining immense importance as potent immunomodulators with multifarious roles and targets, as they not only boost the immune system to produce microbicidal molecules such as NO and ROS, but also modulate the Th1/Th2 cytokine balance in favor of the host. 30,31 Although the mouse model of VL suffers from several limitations as it differs from symptomatic human VL, it remains a good experimental model for early infection of L. donovani. The present study has exploited the use of a mouse model of VL up to 6 weeks, a time frame for which it closely mimics human VL, and can be used for further development of fucoidan as a therapeutic target against L. donovani.…”

HIV–TB coinfection impairs CD8+ T‐cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses

“…Among hormonal effects on the immune response, glucocorticoids can promote a Th2 cytokine acquisition profile [14], facilitating Th2 activities, whereas its natural antagonist dehydroepiandrosterone (DHEA) is able to favor Th1 cytokine production and interfere with Th2 cytokine synthesis [15]. In fact, the synthetic DHEA derivative, 16 α-bromoepiandrosterone, exerts beneficial effects in clinical and experimental TB and in HIV patients [16][17][18]. We have previously demonstrated that in vitro treatment of PBMCs from HIV-TB patients with DHEA increased Mtb-specific IFN-γ responses and decreased FoxP3 expression in regulatory T cells, thus inducing a bias toward a protective antitubercular immune response [19].…”

Safety and Activity of the Immune Modulator HE2000 on the Incidence of Tuberculosis and Other Opportunistic Infections in AIDS Patients

“…HE2000 is clinically active in clearing malarial parasites in patients with uncomplicated malaria (7). It is also active against feline immunodeficiency virus, rodent tuberculosis, and rodent malaria (1,6,8,12).…”