Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining

Smith, Steven G.; Lalor, Maeve K.; Gorak‐Stolinska, Patricia; Blitz, Rose; Beveridge, Natalie E. R.; Worth, Andrew; McShane, Helen; Dockrell, Hazel M.

doi:10.1186/1471-2172-11-35

Cited by 40 publications

(39 citation statements)

References 35 publications

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“…Similar levels of CD8 1 T-cell activation with PPD have been reported, but the mechanism of this finding is unclear (10,35). In contrast, up-regulation of CD8…”

Section: Original Articlementioning

confidence: 58%

Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Toward Better Risk Stratification

Escalante

Peikert

Keulen³

et al. 2015

Am J Respir Crit Care Med

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Rationale: Most immunocompetent patients diagnosed with latent tuberculosis infection (LTBI) will not progress to tuberculosis (TB) reactivation. However, current diagnostic tools cannot reliably distinguish nonprogressing from progressing patients a priori, and thus LTBI therapy must be prescribed with suboptimal patient specificity. We hypothesized that LTBI diagnostics could be improved by generating immunomarker profiles capable of categorizing distinct patient subsets by a combinatorial immunoassay approach.Objectives: A combinatorial immunoassay analysis was applied to identify potential immunomarker combinations that distinguish among unexposed subjects, untreated patients with LTBI, and treated patients with LTBI and to differentiate risk of reactivation.Methods: IFN-g release assay (IGRA) was combined with a flow cytometric assay that detects induction of CD25 1 CD134 1 coexpression on TB antigen-stimulated T cells from peripheral blood. The combinatorial immunoassay analysis was based on receiver operating characteristic curves, technical cut-offs, 95% bivariate normal density ellipse prediction, and statistical analysis. Risk of reactivation was estimated with a prediction formula.Measurements and Main Results: Sixty-five out of 150 subjects were included. The combinatorial immunoassay approach identified at least four different T-cell subsets. The representation of these immune phenotypes was more heterogeneous in untreated patients with LTBI than in treated patients with LTBI or unexposed groups. Patients with IGRA(1) CD41 CD25 1 CD134 1 T-cell phenotypes had the highest estimated reactivation risk (4.11 6 2.11%).Conclusions: These findings suggest that immune phenotypes defined by combinatorial assays may potentially have a role in identifying those at risk of developing TB; this potential role is supported by risk of reactivation modeling. Prospective studies will be needed to test this novel approach.

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“…Similar levels of CD8 1 T-cell activation with PPD have been reported, but the mechanism of this finding is unclear (10,35). In contrast, up-regulation of CD8…”

Section: Original Articlementioning

confidence: 58%

Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Toward Better Risk Stratification

Escalante

Peikert

Keulen³

et al. 2015

Am J Respir Crit Care Med

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“…The long-lasting effects of BCG vaccination are important 29,30 and will have to be taken into account if and when phase 3 trials will be initiated. In fact, the proper dose and frequency of BCG remain to be determined.…”

mentioning

confidence: 99%

Effects of Bacille Calmette-Guérin after the first demyelinating event in the CNS

et al. 2014

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Objective: To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS).Methods: In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-b-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months.Results: Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). Conclusions: Early BCG may benefit CIS and affect its long-term course.Classification of evidence: BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence). Neurology ® 2014;82:41-48 GLOSSARY BCG 5 Bacille Calmette-Guérin; CDMS 5 clinically definite multiple sclerosis; CI 5 confidence interval; CIS 5 clinically isolated syndrome; CSE 5 conventional spin-echo; DMT 5 disease-modifying therapy; EDSS 5 Expanded Disability Status Scale; Gd 5 gadolinium; IFN 5 interferon; MS 5 multiple sclerosis; RR 5 relative risk; T1W 5 T1-weighted; T2W 5 T2-weighted; TE 5 echo time; TR 5 repetition time.The majority of multiple sclerosis (MS) cases start with a first demyelinating episode (usually referred to as clinically isolated syndrome [CIS]) that is generally reversible. Approximately half of these cases convert to clinically definite MS (CDMS) within 2 years of the diagnosis and have substantial risk of disability, while about 10% of people with CIS remain free of further neurologic events, even in the presence of MRI compatible with MS.

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“…However, data on the induction of polyfunctional T cells by BCG vaccination in adults have been conflicting (16,17). In one report, the induction of polyfunctional CD4 ϩ T cells was similar in magnitude in BCG-vaccinated infants and adults; however, when induction was analyzed as the proportion of polyfunctional versus single-cytokine-producing T cells, the proportion of polyfunctional CD4 ϩ T cells was larger in children than in adults (16).…”

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confidence: 99%

Mycobacterium bovis BCG Vaccination Induces Divergent Proinflammatory or Regulatory T Cell Responses in Adults

Boer¹,

Prins²,

Meijgaarden³

et al. 2015

Clin. Vaccine Immunol.

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T uberculosis (TB), caused by Mycobacterium tuberculosis, is the second greatest infectious cause of death worldwide after HIV, accounting for 1.3 million deaths in 2012 (1). The only available vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), protects infants from disseminated forms of TB but has insufficient and inconsistent efficacy in protecting adults from pulmonary TB (1, 2). A vaccine preventing active pulmonary TB, the contagious form of the disease, would greatly impact the epidemic (3), and a better understanding of vaccine-induced mechanisms of protection is essential in developing new surrogate endpoints (4).Both CD4 ϩ Th1 (gamma interferon-positive [IFN-␥ ϩ ]) cells and CD8 ϩ T cells are critical for protection against TB (5). Specifically, CD4ϩ IFN-␥ ϩ interleukin 2-positive (IL-2 ϩ ) tumor necrosis factor ␣-positive (TNF-␣ ϩ ) polyfunctional T cells have been proposed as a correlate of vaccine-induced protective immunity in murine infection models (6). In infants, BCG vaccination induced specific cytokine expression in CD4 ϩ and CD8 ϩ T cells (7-9), including IFN-␥ ϩ IL-2 ϩ TNF-␣ ϩ polyfunctional CD4 ϩ T cells (10). However, there was no relation between the presence of such cells and the development of TB during follow-up (11).In adults, BCG vaccination induced CD4 ϩ IFN-␥ ϩ responses (12-14) as well as IFN-␥-and TNF-␣-secreting CD8 ϩ T cells with cytotoxic activity (15). However, data on the induction of polyfunctional T cells by BCG vaccination in adults have been conflicting (16,17). In one report, the induction of polyfunctional CD4 ϩ T cells was similar in magnitude in BCG-vaccinated infants and adults; however, when induction was analyzed as the proportion of polyfunctional versus single-cytokine-producing T cells, the proportion of polyfunctional CD4 ϩ T cells was larger in children than in adults (16). Further, studies on latent (controlled) versus active TB in adults yielded variable results on changes in monoand triple-cytokine-producing T cell subsets (18,19), such that it was suggested that polyfunctional T cells are also present in active TB disease and that these cells are not a surrogate marker of protection against TB in humans (19,20).Another explanation for the inconsistent protection induced by BCG against TB in adults is the induction of regulatory T cells (Tregs) by mycobacteria, which can dampen proinflammatory responses (21). In that context, we reported that live BCG triggers the specific activation of CD8 ϩ (but not CD4 ϩ ) Tregs from peripheral blood mononuclear cells (PBMCs) of mycobacterial purified protein derivative (PPD)-responsive adults (22), while others found that BCG vaccination induced CD4 ϩ Tregs in newborns (23) and adults (24). Here, in a small, well-defined cohort of pre-

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Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining

Cited by 40 publications

References 35 publications

Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Toward Better Risk Stratification

Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Toward Better Risk Stratification

Effects of Bacille Calmette-Guérin after the first demyelinating event in the CNS

Mycobacterium bovis BCG Vaccination Induces Divergent Proinflammatory or Regulatory T Cell Responses in Adults

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