Evaluation of profile and functionality of memory T cells in pulmonary tuberculosis

Tonaco, Marcela M.; Moreira, Jôsimar Dornelas; Nunes, Fernanda Freire Campos; Loures, Cristina de Mello Gomide; Souza, Larissa R.; Martins, Janaina M.; Silva, Henrique R.; Porto, Arthur Henrique R.; Toledo, Vicente de Paulo Coelho Peixoto de; Miranda, Silvana Spíndola de; Guimarães, Talita Antunes

doi:10.1016/j.imlet.2017.10.014

Cited by 16 publications

(10 citation statements)

References 40 publications

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“…At later timepoints following infection (weeks 16 and 22), therapeutic immunization induced a significantly higher frequency of CD4 + T cells producing CD154, GM-CSF, IFN-γ, IL-2, and TNF-α at 16 and 22 weeks post infection compared to RHZ-treated mice with ex vivo ID93 antigen stimulation ( Figure 2 ). Immunized mice also induced higher levels of CD4 + IL-17A + T cells by our final time point of 22 weeks post infection ( Figure 2 ), similar to findings in human clinical studies [ 25 ]. This delay in antigen-specific responses suggest that the three-immunization regimen is critical to mounting this strong TH1 phenotype in the therapeutic schedule used here.…”

Section: Resultssupporting

confidence: 86%

Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment

et al. 2018

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It is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). This astounding statistic, in combination with costly and lengthy treatment regimens make the development of therapeutic vaccines paramount for controlling the global burden of tuberculosis. Unlike prophylactic vaccination, therapeutic immunization relies on the natural pulmonary infection with Mtb as the mucosal prime that directs boost responses back to the lung. The purpose of this work was to determine the protection and safety profile over time following therapeutic administration of our lead Mtb vaccine candidate, ID93 with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion (GLA-SE)), in combination with rifampicin, isoniazid, and pyrazinamide (RHZ) drug treatment. We assessed the host inflammatory immune responses and lung pathology 7–22 weeks post infection, and determined the therapeutic efficacy of combined treatment by enumeration of the bacterial load and survival in the SWR/J mouse model. We show that drug treatment alone, or with immunotherapy, tempered the inflammatory responses measured in brochoalveolar lavage fluid and plasma compared to untreated cohorts. RHZ combined with therapeutic immunizations significantly enhanced TH1-type cytokine responses in the lung over time, corresponding to decreased pulmonary pathology evidenced by a significant decrease in the percentage of lung lesions and destructive lung inflammation. These data suggest that bacterial burden assessment alone may miss important correlates of lung architecture that directly contribute to therapeutic vaccine efficacy in the preclinical mouse model. We also confirmed our previous finding that in combination with antibiotics therapeutic immunizations provide an additive survival advantage. Moreover, therapeutic immunizations with ID93/GLA-SE induced differential T cell immune responses over the course of infection that correlated with periods of enhanced bacterial control over that of drug treatment alone. Here we advance the immunotherapy model and investigate reliable correlates of protection and Mtb control.

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Section: Resultssupporting

confidence: 86%

Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment

et al. 2018

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“…2) and CD8+ ( Fig. 3) T cells (Appay et al, 2008;Tonaco et al, 2017). The gating strategy is illustrated in Fig.…”

Section: B Cell Depletion Increases the Ratio Of Naïve To Memory T Cellsmentioning

confidence: 99%

B cell depletion with ublituximab reshapes the T cell profile in multiple sclerosis patients

Lovett-Racke

Gormley

Liu

et al. 2019

Journal of Neuroimmunology

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Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, thought to be mediated by myelin-specific CD4+ T cells. However, B cell depletion has proven to be an effective therapy for MS, but the mechanism is not well understood. This study was designed to determine how B cell depletion changes lymphocyte profiles. During a phase IIa clinical trial with ublituximab, a novel CD20 antibody, blood was collected from 48 MS patients at 11 time points over 24 weeks and the lymphocyte profiles were analyzed by flow cytometry. The percentage of naïve CD4+ and CD8+ T cells increased, while the percentage of both effector and central memory T cells declined. CD4+ Th1 effector cells decreased, while there was a significant increase in CD4+ regulatory T cells. The depletion of B cells had a favorable shift in the lymphocyte landscape, reducing the number of naïve T cells becoming activated and transitioning to memory T cells. The ratio of Th1 cells to CD4+ regulatory T cells declined, suggesting that immune regulation was being restored. These data suggest that loss of B cells as antigen presenting cells is a major mechanism of action for the beneficial effects of CD20 antibody therapy in MS.

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“…Several subsets of memory T cells exist, including stem cell memory (T-SCM), central memory (T-CM), transitional memory (T-TM) and effector memory (T-EM). Development of memory CD4 + T-cells is critical for protection against TB disease [ 46 ] and yet, the impact of undernutrition and parasitic infections on the responsiveness of Mtb antigen-specific T-cells has not been fully explored. In this study, we will characterize Mtb antigen-specific memory T-cell phenotypes and functionality, to broaden understanding of the impact of undernutrition and parasitic infections on these cells, beyond that of IFNγ expression.…”

Section: Methodsmentioning

confidence: 99%

Tuberculosis—Learning the Impact of Nutrition (TB LION): protocol for an interventional study to decrease TB risk in household contacts

et al. 2021

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Background Comorbidities such as undernutrition and parasitic infections are widespread in India and other tuberculosis (TB)-endemic countries. This study examines how these conditions as well as food supplementation and parasite treatment might alter immune responses to Mycobacterium tuberculosis (Mtb) infection and risk of progression to TB disease. Methods This is a 5-year prospective clinical trial at Jawaharlal Institute of Post Graduate Medical Education and Research in Puducherry, Tamil Nadu, India. We aim to enroll 760 household contacts (HHC) of adults with active TB in order to identify 120 who are followed prospectively for 2 years: Thirty QuantiFERON-TB Gold Plus (QFT-Plus) positive HHCs ≥ 18 years of age in four proposed groups: (1) undernourished (body mass index [BMI] < 18.5 kg/m2); (2) participants with a BMI ≥ 18.5 kg/m2 who have a parasitic infection (3) undernourished participants with a parasitic infection and (4) controls—participants with BMI ≥ 18.5 kg/m2 and without parasitic infection. We assess immune response at baseline and after food supplementation (for participants with BMI < 18.5 kg/m2) and parasite treatment (for participants with parasites). Detailed nutritional assessments, anthropometry, and parasite testing through polymerase chain reaction (PCR) and microscopy are performed. In addition, at serial time points, these samples will be further analyzed using flow cytometry and whole blood transcriptomics to elucidate the immune mechanisms involved in disease progression. Conclusions This study will help determine whether undernutrition and parasite infection are associated with gene signatures that predict risk of TB and whether providing nutritional supplementation and/or treating parasitic infections improves immune response towards this infection. This study transcends individual level care and presents the opportunity to benefit the population at large by analyzing factors that affect disease progression potentially reducing the overall burden of people who progress to TB disease. Trial registration ClinicalTrials.gov; NCT03598842; Registered on July 26, 2018; https://clinicaltrials.gov/ct2/show/NCT03598842

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Evaluation of profile and functionality of memory T cells in pulmonary tuberculosis

Cited by 16 publications

References 40 publications

Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment

Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment

B cell depletion with ublituximab reshapes the T cell profile in multiple sclerosis patients

Tuberculosis—Learning the Impact of Nutrition (TB LION): protocol for an interventional study to decrease TB risk in household contacts

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