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Experimental-animal models of tuberculosis began to emerge shortly after the discovery of the bacterium itself. If one is an optimist, one can argue that the animal models are fully validated because they predict that the only vaccine fully tested in humans, BCG, will have a positive effect and that this will be mediated via CD4 Th1 T-cell responses. The primary models that are currently used in the preclinical screening program for vaccine candidates are (i) the low-dose aerosol mouse model and (ii) the low-dose aerosol guinea pig model. The National Institutes of Health preclinical tuberculosis vaccine screening program was established to identify novel vaccines that will eventually be used throughout the world to combat tuberculosis. The presence of the infection in the lung tissues sets up a local inflammation, creating chemokine gradients and blood vessel adhesion molecule expression, which facilitate the influx of granulocytes (which are short-lived and therefore not sustained) and monocytes from the bloodstream. The purpose of vaccination is to establish a long-lived state of heightened resistance to challenge infection, which in practical terms means many recirculating memory T cells capable of rapidly entering sites of inflammation in the lungs. With the current enthusiasm for attenuated live vaccines based on BCG or M. tuberculosis itself, this is a serious issue that needs to be resolved. Fortunately, such environmental mycobacteria (EM) effects may be less important in interfering with other classes of vaccines including DNAs and subunit nonliving vaccines.
The BHRB building at Colorado State University (top left) is a biosafety level 3 facility in which much of our vaccine testing is performed. Mouse aerosol exposures are performed using a Middlebrook apparatus (top right), whereas guinea pigs are infected using an instrument manufactured by the University of Wisconsin at Madison (bottom).
Survival of guinea pigs following low-dose (ca. 20 bacilli) aerosol exposure. Animals injected with saline live about 25 weeks (♦), whereas those vaccinated with BCG live about a year on average (▄).
Some explanations of why certain mouse strains, such as CBA/J, are prone to reactivation or regrowth of pulmonary infection about 150 days after aerosol exposure. These include bronchial epithelial degeneration (top left), failure to upregulate the expression of adhesion molecules such as ICAM-1 on responding T cells (top right; open trace, CBA/J; filled trace, C57BL/6), and accumulation of large amounts of interleukin-10 (IL-10) in macrophages in lung lesions. C57BL/6 mice rendered transgenic (Tg) overexpressors of IL-10 behave like reactivation-prone strains in terms of the course of the infection (bottom).
CD4 cells in the lungs express an activated/effector phenotype even well into the chronic stage of the disease process.
The possible fates of antigen-specific T cells may be different for chronic infectious diseases such as tuberculosis in comparison to T cells induced into individual protein antigens.
Low-power (A, C, E, and G) and high-power (B, D, F, and H) photomicrographs of lung lesions in guinea pigs 10 (A and B), 20 (C and D), 30 (E and F), and 90 (G and H) days after aerosol exposure to M. tuberculosis. As described in the text, a “classical” granuloma develops over the first 30 days and then degenerates into a highly mineralized mass that erodes out through adjacent vessels. Reprinted from reference 72a.
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