The host protective response to Mycobacterium tuberculosis infection

The cell-mediated immune response to tuberculosis infection involves a complex network of leukocytes and a cascade of soluble immune mediators. Following exposure to Mycobacterium tuberculosis the majority of individuals mount an

1This chapter was presented at the symposium by Gilla Kaplan.

immune response that presumably prevents active disease manifestations (protective immune response; Fig. 1). However, some individuals (about 10%) develop active disease. Moreover, when individuals do develop active disease, there is a wide range in symptoms, rate of clinical deterioration and duration of survival. In individuals with active tuberculosis, the protective immune response may still be operative, although obviously unable to prevent development of disease. Alternatively, active disease may be due to the absence of any protective response in some infected individuals.

During therapy, even if the infecting organism is sensitive to antimycobacterial drugs, the cell-mediated immune response may be ineffective and consequently the infection may not resolve, which will lead to chronic active tuberculosis. When individuals are infected with multidrug-resistant strains of M. tuberculosis, the antibiotics cannot sterilize the infection even in the presence of an adequate cell-mediated immune response, which will result in progressive and often fatal disease.

Our studies have concentrated on the characterization of the cytokines that regulate the protective response to M. tuberculosis. Here, we describe an adjunctive immune therapeutic intervention that may enhance the immune response to infection, thereby improving clinical outcome in patients who are not responding adequately to conventional antituberculosis therapy.

The cells and cytokines of the host response to tuberculosis

When the host is infected with M. tuberculosis, the development of a protective immune response depends on the activation of T helper (Th)1 cells and cytotoxic

Exposure

Host response

Infection

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t

Protection

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f

Protection

X

FIG. 1. Infection and development of active disease following exposure to Mycobacterium tuberculosis.

FIG. 1. Infection and development of active disease following exposure to Mycobacterium tuberculosis.

FIG. 2. The cells and cytokines involved in the host immune response to Mycobacterium tuberculosis infection. Ag, antigen; DNT, double-negative T cells; IFN-y, y-interferon; IL, interleukin; LAK cell, lymphokine-activated killer cell; NK cell, natural killer cell; TGF-ß, transforming growth factor ß; TNF a, tumour necrosis factor a.

FIG. 2. The cells and cytokines involved in the host immune response to Mycobacterium tuberculosis infection. Ag, antigen; DNT, double-negative T cells; IFN-y, y-interferon; IL, interleukin; LAK cell, lymphokine-activated killer cell; NK cell, natural killer cell; TGF-ß, transforming growth factor ß; TNF a, tumour necrosis factor a.

effector cells (Fig. 2). Following exposure of these cells to mycobacteria and their antigens, tumour necrosis factor a (TNF-a) and interleukin (IL)-12 are produced predominantly by macrophages, whereas IL-2 is produced by T cells (Orme & Collins 1994, Boom etal 1992, Barnes etal 1993, Balaji etal 1995, Orme et al 1993).

IL-2 is a central regulator of the Th1 response, and it stimulates leukocyte proliferation and differentiation (Kaplan et al 1992; Fig. 2). This cytokine induces y-interferon (IFN-y) production by lymphoid cells, which in turn activates macrophages to better control the growth of intracellular mycobacteria. IL-2 can also be shown to act directly by inducing cytotoxic T cells specific for M. tuberculosis antigens (Hancock et al 1989). Thus, the presence of IL-2 at the site of a mycobacterial infection stimulates the appropriate effector cells and thus limits the course of the infection. The Th2 type cytokines, including IL-4 and IL-5, which are associated with an enhanced humoral immune response, do not appear to contribute significantly to the development of protective immunity against tuberculosis infection (Lin et al 1996).

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