Repeat tuberculin skin testing leads to desensitisation in naturally infected tuberculous cattle which is associated with elevated interleukin-10 and decreased interleukin-1 beta responses

Coad, Michael; Clifford, Derek; Rhodes, Shelley; Hewinson, R. Glyn; Vordermeier, H. Martin; Whelan, Adam O.

doi:10.1051/vetres/2009062

Cited by 74 publications

(77 citation statements)

References 33 publications

(48 reference statements)

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“…Several studies have shown that the skin test boosts serum antibody responses and consequently increases sensitivity (11)(12)(13)26). In contrast, IFN-␥ production is little affected by skin testing when the SICCT is used (7,9), although IFN-␥ responses have been shown to be boosted following the caudal fold tuberculin test (6,30). Therefore, further studies are needed to assess whether prior skin testing will affect sensitivity.…”

Section: Resultsmentioning

confidence: 99%

Performance of the Enferplex TB Assay with Cattle in Great Britain and Assessment of Its Suitability as a Test To Distinguish Infected and Vaccinated Animals

Whelan

Shuralev

et al. 2010

Clin Vaccine Immunol

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Rapid, simple, and accurate antemortem tests for tuberculosis (TB) in cattle need to be developed in order to augment the existing screening methods. In particular, as cattle vaccines are developed, such tests would allow the continuation of test-and-slaughter policies alongside vaccination. Therefore, the development of an assay that distinguishes infected from vaccinated animals (a DIVA test) is an urgent research requirement. In this study, we assessed the performance of a novel multiplex serological test with sera collected from 96 skin-tested animals with bovine tuberculosis, 93 TB-free animals, and 39 cattle vaccinated with Mycobacterium bovis BCG. Our results indicate that the test has a relative sensitivity range of 77.0% to 86.5% at corresponding specificity levels of 100.0% to 77.6%. Comparison with the Bovigam gamma interferon antemortem test revealed that this serology test was significantly more sensitive at specificities above 97.9%, while the Bovigam test was, on average, about 10% more sensitive when the test specificity was set below 97%. Importantly, this serological multiplex assay does not react with sera from BCG-vaccinated calves and is therefore suitable as a DIVA test alongside BCG-based vaccine strategies.Bovine tuberculosis (bTB) is a zoonotic disease caused by the bacterial pathogen Mycobacterium bovis. Although the main host is cattle, M. bovis can infect many species, including wildlife and humans. In developed countries where the control and eradication of bTB continue to be a problem, the impact of bTB on the farming community and government control agencies is primarily of economic significance (1, 20; http://www.defra.gov.uk/foodfarm/farmanimal/diseases/atoz/tb /documents/expenditure-stats.pdf). However, in the presence of wildlife reservoirs, such as the possum in New Zealand or the badger in Great Britain and Ireland, bTB has been difficult to eradicate. The primary bTB screening and control tool is the tuberculin skin test (TST), with the removal of animals found to be positive (reactors). The TST as applied in Great Britain and Ireland is called the single intradermal comparative cervical tuberculin test (SICCT) (14). It involves the injection of bovine tuberculin (a purified protein derivative [PPD] prepared from M. bovis strain AN5) and PPD tuberculin from Mycobacterium avium into the skin of the neck. Animals with bovine PPD (PPD-B)-biased responses are then removed.A widely used ancillary in vitro test for TB is a gamma interferon (IFN-␥) release assay (IGRA) that also employs avian and bovine tuberculin (Bovigam) (18,28,30). Both the TST and the Bovigam assay probe cell-mediated immune (CMI) responses (16). Questions have been raised with regard to both the sensitivity (proportion of true positives) and specificity (proportion of true negatives) of tuberculin-based tests, for example, for herds that are coinfected with Mycobacterium avium subsp. paratuberculosis (2, 3), or in the context of vaccine strategies under development that involve the use of M. bovis bacillus Ca...

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Section: Resultsmentioning

confidence: 99%

Performance of the Enferplex TB Assay with Cattle in Great Britain and Assessment of Its Suitability as a Test To Distinguish Infected and Vaccinated Animals

Whelan

Shuralev

et al. 2010

Clin Vaccine Immunol

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“…Simultaneous detection of IFN-␥, IL-1␤, IL-4, IL-10, IL-12, MIP-1␤, and TNF-␣ was performed as previously described (3). Briefly, multiplex 96-well plates were commercially prespotted (Meso Scale Discovery [MSD], Gaithersburg, MD) with the following capture antibodies: antibovine IFN-␥ (Mabtech, Stockholm, Sweden), anti-bovine IL-4 and TNF-␣ (Endogen, Rockford, IL), anti-bovine IL-10 and IL-12 (AbD Serotec, Oxford, United Kingdom), and anti-bovine IL-1␤ and cross-reactive anti-human MIP-1␤ (MSD).…”

Section: Methodsmentioning

confidence: 99%

Simultaneous Measurement of Antigen-Stimulated Interleukin-1β and Gamma Interferon Production Enhances Test Sensitivity for the Detection of Mycobacterium bovis Infection in Cattle

Pirson

Hewinson

et al. 2010

Clin Vaccine Immunol

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In order to identify cytokines that may be useful as candidates for inclusion in diagnostic tests for Mycobacterium bovis infection in cattle, we compared the levels of gamma interferon (IFN-␥), interleukin 1␤ (IL-1␤), IL-4, IL-10, IL-12, macrophage inflammatory protein 1␤ (MIP-1␤), and tumor necrosis factor alpha (TNF-␣) in whole-blood cultures from tuberculosis (TB) reactor animals or TB-free controls following stimulation with M. bovis-specific antigens (purified protein derivative from M. bovis [PPD-B] or ESAT-6/CFP-10). In addition to IFN-␥ responses, the production of IL-1␤ and TNF-␣ was also statistically significantly elevated in TB reactor cattle over that in uninfected controls following stimulation with PPD-B or ESAT-6/CFP-10 peptides. Thus, we evaluated whether the use of these two additional readouts could disclose further animals not detected by measuring IFN-␥ alone. To this end, receiver operating characteristic (ROC) analyses were performed to define diagnostic cutoffs for positivity for TNF-␣ and IL-1␤. These results revealed that for ESAT-6/CFP-10-induced responses, the use of all three readouts (IFN-␥, TNF-␣, and IL-1␤) in parallel increased the sensitivity of detection of M. bovis-infected animals by 11% but also resulted in a specificity decrease of 14%. However, applying only IFN-␥ and IL-1␤ in parallel resulted in a 5% increase in sensitivity without the corresponding loss of specificity. The results for PPD-B-induced responses were similar, although the loss of specificity was more pronounced, even when only IFN-␥ and IL-1␤ were used as readout systems.In conclusion, we have demonstrated that the use of an additional readout system, such as IL-1␤, can potentially complement IFN-␥ by increasing overall test sensitivity for the detection of M. bovis infection in cattle.

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“…Although, compared to the IFN-␥ test, the IL-2 test was not as sensitive in SICCT-negative animals compared to skin testpositive animals, identifying just 30.3% of all the IFN-␥ ϩ animals, and 37.8% of the IFN-␥ ϩ VL cattle. However, it is possible that future improvement in the sensitivity to detect IL-2, for example using enzyme-linked immunosorbent spot (ELISPOT) assay read-outs (as we are currently investigating in our laboratory [data not shown]) or a more sensitive system, such as Meso Scale Discovery technology (which we already use in our laboratory to detect other low-level cytokines, like IL-10 [22]) to quantify IL-2 in supernatants could enhance its overall test sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Use of Antigen-Specific Interleukin-2 To Differentiate between Cattle Vaccinated with Mycobacterium bovis BCG and Cattle Infected with M. bovis

Rhodes

McKinna

Steinbach

et al. 2013

Clin. Vaccine Immunol.

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bWe describe here the application of a novel bovine interleukin-2 (IL-2) enzyme-linked immunosorbent assay (ELISA) for the measurement of antigen-specific IL-2 in cattle naturally infected with Mycobacterium bovis and in cattle vaccinated with Mycobacterium bovis BCG and then experimentally challenged with pathogenic M. bovis. Supernatants from whole-blood cultures stimulated with mycobacterial antigen (bovine purified protein derivative [PPDB] or the peptide cocktail ESAT6-CFP10) were assessed using a sandwich ELISA consisting of a new recombinant monoclonal fragment capture antibody and a commercially available polyclonal anti-bovine-IL-2. The production of IL-2 was compared to the production of gamma interferon (IFN-␥) in the same antigen-stimulated whole-blood supernatants. The data show that cattle infected with M. bovis produced quantifiable levels of antigen-specific IL-2, while IL-2 levels in cattle vaccinated with M. bovis BCG did not. Furthermore, cattle vaccinated with M. bovis BCG and then challenged with pathogenic M. bovis displayed a more rapid induction of IL-2 but ultimately had lower levels of infection-induced IL-2 than did unvaccinated challenge control cattle. These data suggest that IL-2 responses are not detectable post-BCG vaccination and that these responses may require infection with virulent M. bovis to develop. This may be useful to differentiate infected cattle from uninfected or BCG-vaccinated cattle, although the overall sensitivity is relatively low, particularly in single intradermal comparative cervical tuberculin (SICCT)-negative infected animals. Furthermore, the strength of the IL-2 response may correlate with pathology, which poses interesting questions on the immunobiology of bovine tuberculosis in contrast to human tuberculosis, which is discussed.

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Repeat tuberculin skin testing leads to desensitisation in naturally infected tuberculous cattle which is associated with elevated interleukin-10 and decreased interleukin-1 beta responses

Cited by 74 publications

References 33 publications

Performance of the Enferplex TB Assay with Cattle in Great Britain and Assessment of Its Suitability as a Test To Distinguish Infected and Vaccinated Animals

Performance of the Enferplex TB Assay with Cattle in Great Britain and Assessment of Its Suitability as a Test To Distinguish Infected and Vaccinated Animals

Simultaneous Measurement of Antigen-Stimulated Interleukin-1β and Gamma Interferon Production Enhances Test Sensitivity for the Detection of Mycobacterium bovis Infection in Cattle

Use of Antigen-Specific Interleukin-2 To Differentiate between Cattle Vaccinated with Mycobacterium bovis BCG and Cattle Infected with M. bovis

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