“…14 In another study, Kumar et al reported lower Th1 and Th2 responses to mycobacteria antigens in meningitis opposed to pulmonary infection during the course of TB disease. 15 Unlike Kumar study, only a reduction of Th2 responses to M.tb antigens was observed in the most severe forms of TB infection in our study. Th2 responses to pathogens and vaccines are favored in early age as reviewed in a recent meeting report 52 and a bias toward Th2 responses as a mechanism involved in TB severity in children has been questioned.…”
Section: Discussioncontrasting
confidence: 76%
“…13 The duration of antigen stimulation may also be involved. 15 Other potential confounders rely to the study population with regard to disease severity and treatment. As an example, Dlugovitzky et al reported that in vitro M.tb-induced IFN-g production in patients with moderate TB lesions was significantly higher than in advanced cases.…”
“…14 In another study, Kumar et al reported lower Th1 and Th2 responses to mycobacteria antigens in meningitis opposed to pulmonary infection during the course of TB disease. 15 Unlike Kumar study, only a reduction of Th2 responses to M.tb antigens was observed in the most severe forms of TB infection in our study. Th2 responses to pathogens and vaccines are favored in early age as reviewed in a recent meeting report 52 and a bias toward Th2 responses as a mechanism involved in TB severity in children has been questioned.…”
Section: Discussioncontrasting
confidence: 76%
“…13 The duration of antigen stimulation may also be involved. 15 Other potential confounders rely to the study population with regard to disease severity and treatment. As an example, Dlugovitzky et al reported that in vitro M.tb-induced IFN-g production in patients with moderate TB lesions was significantly higher than in advanced cases.…”
“…In the present study, our results demonstrate that anti-IFN-γ antibody inhibits the expression of IFN-γ in Th1 cells and inhibits the cell proliferation and expression of OPG, promotes the expression and secretion of RANKL, TNF-α, MCP-1 and SDF-1 and expression of NF-κB and TRAF6. Consistently, the increase in actin ring formation, The Mycobacterium tuberculosis is mainly present in macrophages, and causes pathological changes in the body by stimulating the peripheral blood T lymphocytes [27]. Tuberculosis of bone refers to the Mycobacterium tuberculosis invading the bones or joints [28].…”
Background/Aims: Tuberculosis induces bone loss and activates Th1 cells that play an important role in the host defense of Bacille Calmette-Guérin tuberculosis vaccine. However, the role of tuberculosis-activated Th1 cells in differentiation of osteoclast precursors to osteoclasts is unclear. As secretion of IFN-γ in Th1 cells is induced by tuberculosis, we aimed to investigate the role of anti-IFN-γ antibody on the differentiation and activation of osteoclasts in bone marrow monocyte-derived macrophages (BMMs). Methods: BMMs were isolated and co-cultured with CD4+T helper 1 cells (Th1 cells), pretreated with anti-IFN-γ antibody. Then, cell proliferation, expression and release of cytokines, formation of actin ring, differentiation of osteoclasts and bone resorption function were measured by CCK8 assay, qRT-PCR/Western blot/flow cytometry, ELISA, immunofluorescence, tartrate-resistant acidic phosphatase (TRAP) staining and bone absorbance assay, respectively. Results: Anti-IFN-γ antibody inhibited the cell viability of BMMs, and induced the expressions of RANKL, TNF-α, NF-κB and TRAF6 in BMMs. In addition, it led to increased expression levels of RANK on cell surfaces, and increased production of RANKL, TNF-α, MCP-1 and SDF-1. Anti-IFN-γ antibody also induced the expression of osteoclast differentiation factor and actin ring formation, but inhibited the expression of osteoprotegerin. TRAP staining and bone resorption assays showed that anti-IFN-γ antibody induced an increase in osteoclast formation and bone resorption. Conclusion: The anti-IFN-γ antibody induced osteoclast formation, and is probably mediated by RANKL-induced activation of NF-κB, that induces TRAF6 in the RANKL-RANK signaling pathway. Our data suggest an inhibitory role for IFN-γ in osteoclast formation induced by tuberculosis.
“…), virulence of the infecting organism and the immunology of the child [1, 7–9]. Cases of immunosuppression greatly increase this risk, such as age [1, 10–12], malnutrition [13, 14], diabetes, tobacco and alcohol use, or human immunodeficiency virus (HIV)[15]. As stated before, TB remains a very real threat primarily in third-world countries and is in part due to these risk enhancers.…”
Section: The Global Tuberculosis Epidemic: a Focus On Pediatricsmentioning
confidence: 99%
“…In addition, the DOTS strategy largely neglects children, as the primary means of detection is sputum smear-positive, which pediatrics often don’t display [10, 14, 24]. Other factors contribute to the delicate disease state of pediatric TB infections including altered immune response [11, 12], difficulties in proper dosing (both amounts and formulation)[34], and the rapid progression to severe disease state. We will discuss the future of small molecule M.tb therapeutics, specifically how it pertains to the pediatric population, as well as alterations in screening and target validation strategies that are proving helpful in the identification of lead candidates to be advanced to the clinic.…”
Section: The Global Tuberculosis Epidemic: a Focus On Pediatricsmentioning
Pediatric tuberculosis is an underappreciated global epidemic estimated to afflict around half a million children worldwide. This problem has historically been overlooked, due in part to their low social status and the difficulty in diagnosis of tuberculosis in children. Children are more susceptible to tuberculosis infection and disease progression, including rapid dissemination into extra-pulmonary infection sites. Treatment of pediatric tuberculosis infections has been traditionally built around agents used to treat the adult disease, but the disease pathology, drug pharmacokinetics and the safety window in children differs from the adult disease. This produces additional concerns for drug discovery and development of new agents. This review examines: (i) the safety concerns for current front and second line agents used to treat complex drug resistant infections and how this knowledge can be used to identify, prioritize and dose agents that may be better tolerated in pediatric populations; (ii) the chemistry and suitability of new drugs in the clinical development pipeline for tuberculosis for the treatment of pediatric infections indicating several new agents may offer significant improvements for the treatment of multi-drug resistant tuberculosis in children.
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