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      Effect of Standard Tuberculosis Treatment on Plasma Cytokine Levels in Patients with Active Pulmonary Tuberculosis

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          Abstract

          Background

          Sputum Mycobacterium tuberculosis (Mtb) culture is commonly used to assess response to antibiotic treatment in individuals with pulmonary tuberculosis (TB). Such techniques are constrained by the slow growth rate of Mtb, and more sensitive methods to monitor Mtb clearance are needed. The goal of this study was to evaluate changes in plasma cytokines in patients undergoing treatment for TB as a means of identifying candidate host markers associated with microbiologic response to therapy.

          Methods

          Twenty-four plasma cytokines/chemokines were measured in 42 individuals diagnosed with active pulmonary TB, 52% were HIV co-infected. Individuals, undergoing a 26-week standard TB treatment, were followed longitudinally over 18 months and measurements were associated with HIV status and rates of sputum culture conversion.

          Results

          Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status. By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02). Moreover, in HIV negative patients, plasma VEGF concentrations, measured as early as 2-weeks post TB treatment initiation, positively correlated with the time of sputum conversion (p = 0.0017). No significant changes were observed in other studied immune mediators.

          Conclusions

          These data suggest that VEGF plasma concentration, measured during early TB treatment, could represent a surrogate marker to monitor sputum culture conversion in HIV uninfected individuals.

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          Most cited references47

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          IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge.

          Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.
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            Signal transduction by vascular endothelial growth factor receptors.

            VEGFs (vascular endothelial growth factors) control vascular development during embryogenesis and the function of blood vessels and lymphatic vessels in the adult. There are five related mammalian ligands, which act through three receptor tyrosine kinases. Signalling is modulated through neuropilins, which act as VEGF co-receptors. Heparan sulfate and integrins are also important modulators of VEGF signalling. Therapeutic agents that interfere with VEGF signalling have been developed with the aim of decreasing angiogenesis in diseases that involve tissue growth and inflammation, such as cancer. The present review will outline the current understanding and consequent biology of VEGF receptor signalling.
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              Angiogenesis and chronic inflammation: cause or consequence?

              Evidence has been gathered regarding the association between angiogenesis and inflammation in pathological situations. These two phenomena have long been coupled together in many chronic inflammatory disorders with distinct etiopathogenic origin, including psoriasis, rheumatoid arthritis, Crohn's disease, diabetes, and cancer. Lately, this concept has further been substantiated by the finding that several previously established non-inflammatory disorders, such as osteoarthritis and obesity, display both inflammation and angiogenesis in an exacerbated manner. In addition, the interplay between inflammatory cells, endothelial cells and fibroblasts in chronic inflammation sites, together with the fact that inflammation and angiogenesis can actually be triggered by the same molecular events, further strengthen this association. Therefore, elucidating the underlying cellular and molecular mechanisms that gather together the two processes is mandatory in order to understand their synergistic effect, and to develop new therapeutic approaches for the management of these disorders that cause a great deal of discomfort, disability, and in some cases death.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                14 May 2012
                : 7
                : 5
                : e36886
                Affiliations
                [1 ]Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IIDMM), Clinical Laboratory Sciences, University of Cape Town, Cape Town, Western Cape, South Africa
                [2 ]Laboratory of Mycobacterial Immunity and Pathogenesis and the TB Research Unit (TBRU), Public Health Research Institute at the University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, United States of America
                [3 ]Division of Medical Virology, Institute of Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town, Cape Town, Western Cape, South Africa
                [4 ]Department of Biomedical Sciences, Department of Science and Technology/National Research Foundation (DST/NRF) Center of Excellence for TB Research, Stellenbosch University, Cape Town, Western Cape, South Africa
                [5 ]Tuberculosis Research Unit - Clinical and Biomedical, Medical Research Council, Durban, KwaZulu-Natal, South Africa
                National Institute for Infectious Diseases (L. Spallanzani), Italy
                Author notes

                Conceived and designed the experiments: DF CG GK. Performed the experiments: BPP CM. Analyzed the data: CR LR KR. Contributed reagents/materials/analysis tools: RR TM. Wrote the paper: CR LR GW CG GK.

                Article
                PONE-D-12-01330
                10.1371/journal.pone.0036886
                3351475
                22606304
                197b0123-f999-442b-8ad9-ed525cea99f5
                Riou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 12 January 2012
                : 9 April 2012
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Immunology
                Immune System
                Cytokines
                Immune Response
                Medicine
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Infectious Diseases
                Bacterial Diseases
                Tuberculosis
                Tropical Diseases (Non-Neglected)
                Tuberculosis
                Viral Diseases
                HIV

                Uncategorized
                Uncategorized

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