The use of immunotherapy for the treatment of tuberculosis

Ramos-Espinosa, Octavio; Islas-Weinstein, León; Peralta-Álvarez, Marco Polo; López-Torres, Manuel Othoniel; Hernández-Pando, Rogelio

doi:10.1080/17476348.2018.1457439

Cited by 15 publications

(15 citation statements)

References 125 publications

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“…In the 𝐹 δ × 𝐹 α 1 diagram, a synergistic effect was found when both parameters rise simultaneously, taking almost half the recruitment needed to lead the system to bacterial clearance when 𝐹 𝛿 is raised by two units, lowering the risk of an excessive inflammation. An immunotherapy that rises IFN-γ [43] and block IL-4 and IL-10 cytokines [47] will rise 𝐹 𝛿 and keep 𝐹 α 1 from dropping which will result in an efficient nontoxic therapy. Phagocytosis and recruitment synergy also showed to work even in scenarios where 𝑃𝑇𝑓 rises.…”

Section: Discussionmentioning

confidence: 99%

Bifurcation analysis of a tuberculosis progression model for drug target identification

Flores-Garza,

Hernández-Pando,

García-Zárate

et al. 2023

Preprint

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Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. The emergence and rapid spread of drug-resistant M. tuberculosis strains urge us to develop novel treatments. Experimental assays are restricted by lab capacity, insufficient funds, low numbers of laboratory animals and obsolete technology. Systems-level approaches to quantitatively study TB can overcome these limitations. Previously, we proposed a mathematical model describing the key regulatory mechanisms underlying the pathological progression of TB. Here, we systematically explore the effect of parameter variations on disease outcome. We find five bifurcation parameters that steer the clinical outcome of TB: number of bacteria phagocytized per macrophage, macrophages death, macrophage killing by bacteria, macrophage recruitment, and phagocytosis of bacteria. The corresponding bifurcation diagrams show all-or-nothing dose-response curves with parameter regions mapping onto bacterial clearance, persistent infection, or history-dependent clearance or infection. Importantly, pathogenic stage strongly affects the host’s sensitivity to these parameter variations. We identify parameter values corresponding to a latent-infection model of TB, where disease progression occurs significantly slower than in progressive TB. Two-dimensional bifurcation analyses uncovered synergistic parameter pairs which could act as efficient compound therapeutic approaches. Through bifurcation analysis, we reveal how modulating specific regulatory mechanisms could steer the clinical outcome of TB.

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Section: Discussionmentioning

confidence: 99%

Bifurcation analysis of a tuberculosis progression model for drug target identification

Flores-Garza,

Hernández-Pando,

García-Zárate

et al. 2023

Preprint

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“…Moreover, when given as an adjunct to conventional chemotherapy, BEA enhances bacterial clearance (38). Interestingly, this synthetic hormone showed therapeutic benefit in patients with TB, malaria (23,39) and in the acquired immune deficiency syndrome (AIDS) (40).…”

Section: Discussionmentioning

confidence: 99%

“…However, the anabolic effects of DHEA prevents its pharmacological use in the treatment of these diseases. 16α-bromoepiandrosterone (BEA) is a synthetic analog of DHEA that modulates immune and metabolic responses (22,23). Compared to DHEA, BEA does not display anabolic activities, which makes it a feasible candidate drug for T2D and TB.…”

Section: Introductionmentioning

confidence: 99%

16α-Bromoepiandrosterone as a new candidate for experimental diabetes–tuberculosis co-morbidity treatment

López-Torres

Marquina‐Castillo

Ramos-Espinosa

et al. 2021

Clinical and Experimental Immunology

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Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-β-hydroxysteroid dehydrogenase type 1 (11-βHSD1).11-βHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-β-hydroxysteroid dehydrogenase type 2 (11-βHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-βHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv.Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-βHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-βHSD1 expression while increasing 11-βHSD2 expression. These molecular | 233

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“…Cytokine-based therapies, such as interleukin-2 (IL-2), IL-7 and IL-15, stimulate the growth and activation of T cells and help restore their function. To treat T cell exhaustion in TB, various approaches are also being developed, including immunomodulatory drugs, such as interferongamma (IFN-g), and immune checkpoint inhibitors (62)(63)(64). Additionally, combination therapies, such as the use of antibiotics and immunotherapy, are being explored as a way to restore T cell function and improve treatment outcomes (65, 66).…”

Section: The T Cell-mediated Response To Mtb Infectionmentioning

confidence: 99%

Maintenance and recall of memory T cell populations against tuberculosis: Implications for vaccine design

Liu

et al. 2023

Front. Immunol.

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Despite the widespread use of standardised drug regimens, advanced diagnostics, and Mycobacterium bovis Bacille-Calmette-Guérin (BCG) vaccines, the global tuberculosis (TB) epidemic remains uncontrollable. To address this challenge, improved vaccines are urgently required that can elicit persistent immunologic memory, the hallmark of successful vaccines. Nonetheless, the processes underlying the induction and maintenance of immunologic memory are not entirely understood. Clarifying how memory T cells (Tm cells) are created and survive long term may be a crucial step towards the development of effective T cell–targeted vaccines. Here, we review research findings on the memory T cell response, which involves mobilization of several distinct Tm cell subsets that are required for efficient host suppression of M. tuberculosis (Mtb) activity. We also summaries current knowledge related to the T cell response-based host barrier against Mtb infection and discuss advantages and disadvantages of novel TB vaccine candidates.

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The use of immunotherapy for the treatment of tuberculosis

Cited by 15 publications

References 125 publications

Bifurcation analysis of a tuberculosis progression model for drug target identification

Bifurcation analysis of a tuberculosis progression model for drug target identification

16α-Bromoepiandrosterone as a new candidate for experimental diabetes–tuberculosis co-morbidity treatment

Maintenance and recall of memory T cell populations against tuberculosis: Implications for vaccine design

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