https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)60359-5.pdf

Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice

http://www.mossmanassociates.com/TB%20Biomarker%20report%20Lancet_2010.pdf

Tuberculosis 4 Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice

The development of new tuberculosis (TB) vaccines will require the identification of correlates of human protection. This study examined the balance between immunity and virulence in a whole blood infection model in which intracellular mycobacterial survival was measured using BACTEC. In the blood of tuberculin-negative donors, counts of Mycobacterium tuberculosis H(37)Ra organisms fell by 0.14 log(10) CFU during 96 h of whole blood culture, whereas counts of Mycobacterium bovis BCG, M. tuberculosis H(37)Rv, and a clinical TB isolate's organisms increased by 0.13, 0.43, and 1.04 log(10) CFU, respectively (P < 0.001), consistent with their relative virulence. Inhibition of tumor necrosis factor alpha by the addition of methylprednisolone or pentoxifylline or removal of CD4(+) or CD8(+) T cells by magnetic beads had deleterious effects on immune control of intracellular growth only in the blood of tuberculin-positive donors. Repeated vaccination of eight tuberculin-negative volunteers with M. bovis BCG resulted in a 0.3 log (50%) reduction in BCG CFU counts in the model compared to baseline values (P < 0.05). Three of the volunteers responded only after the second vaccination. These experiments indicate that whole blood culture may be used to measure immunity to M. tuberculosis and that further studies of repeated BCG vaccination are warranted.

/pdf/bactericidal-activity-in-whole-blood-as-a-potential-2m3kx3tyyx.pdf

Bactericidal activity in whole blood as a potential surrogate marker of immunity after vaccination against tuberculosis

Tuberculosis (TB) remains a serious global health threat and an improved vaccine is urgently needed. New candidate TB vaccines are tested using preclinical animal models such as mice, guinea pigs, cattle and non-human primates. Animals are routinely infected with virulent Mycobacterium tuberculosis (Mtb) in challenge experiments to evaluate protective efficacy, raising ethical issues regarding the procedure of infection itself, symptoms of disease and humane end-points. We summarize the importance and limitations of animal models in TB vaccine research and review current alternatives and modifications in the context of the NC3Rs framework for replacing, reducing and refining the use of animals for scientific purposes.

/pdf/replacing-reducing-and-refining-the-use-of-animals-in-26xwm2xp4n.pdf

Replacing, reducing and refining the use of animals in tuberculosis vaccine research.

Research on the immunology of tuberculosis and leprosy in recent years has been inspired by the new laboratory techniques of molecular biology. However, as monoclonal antibodies and gene cloning dissect the mycobacterial and host components of the immune reaction, so our continuing ignorance of the ultimate killing ofthe mycobacteria is increasingly exposed. The simple idea that lymphocytes activate macrophages so that the macrophages kill the mycobacteria by phagocytosis, is appealing and may even be correct. There are many details now on the processes that might be involved in anti-mycobacterial mechanisms, (Lowrie & Andrew, 1988), but there has been no unequivocal demonstration of killing of virulent tubercle bacilli by human macrophages. Indeed, a different concept is also gaining ground, that active destruction ofmonocytes or macrophages containing mycobacteria may be of positive benefit and even crucial to the expression of protective immunity against tuberculosis and leprosy. Evidence for the involvement of both CD4+ (MHC class Il-restricted) and MHC non-restricted cytolytic T lymphocytes in protection from leprosy has recently been reported (Hancock, Cohn & Kaplan, 1989). Prominence of the same cytotoxic cells in the immune response to infected macrophages in tuberculosis is reported in an article in this issue (Kumararatne et al., 1990).

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.1990.tb03285.x

Is macrophage death on the field of battle essential to victory, or a tactical weakness in immunity against tuberculosis?

A blood sample was taken from children aged 13-15 years immediately before BCG vaccination and 8 weeks after. The children were tuberculin skin-test negative to PPD-S before vaccination and positive after. Mononuclear cells were separated from the blood, infected with Mycobacterium microti at a low bacterium/monocyte ratio and allowed to form monolayers in microtitre wells. The infected monolayers were rinsed daily and the change in number of live bacteria in monolayers and supernatants was monitored by colony counts on agar. The cells were bacteriostatic during the first day, thereafter growth accelerated in pre-vaccination monolayers. When monolayers received pulsed exposures to autologous lymphocytes that had been incubated with whole dead tubercle bacilli the growth rates of M. microti were increased. However, growth rates in lymphocyte-pulsed monolayers were significantly lower after vaccination than before. It is proposed that this difference reflects the protective effect of vaccination.

Demonstration of increased anti-mycobacterial activity in peripheral blood monocytes after BCG vaccination in British school children.

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Demonstration of increased anti-mycobacterial activity in peripheral blood monocytes after BCG vaccination in British school children.