Immunotherapy for Infectious Diseases

Tuberculosis and Other Mycobacterial Infections 285
Table 1
Effect of Cytokines and Other Mononuclear Cell Products on Macrophage
Activation for Inhibition of Intracellular Mycobacterial Growth
Activating Deactivating
IL-2 IL-1�
IL-4 IL-3
1,25(OH) 2-D3 IL-6
GM-CSF IL-10
TNF-� TGF-�
IFN-�
IL-12
IL-15
PGE2 Abbreviations: GM-CSF, granulocyte/macrophage colony-stimulating factor; IFN-�, interferon-�; IL,
interleukin; 1,25(OH) 2-D 3, 1,25 dihydroxy vitamin D 3; PGE 2,prostaglandin E 2; TGF-�, transforming
growth factor-�; TNF-�, tumor necrosis factor-�.
mycobacteria and, in combination with perforin, decreased the viability of intracellular
M. tuberculosis (54,55). However, cytotoxicity per se does not appear to be a major
factor in control of intracellular bacilli (56,57).
IMMUNOPATHOGENESIS OF TUBERCULOSIS
The specific genetic defects described above appear to account for only a small fraction
of human TB cases. Nonetheless, there is substantial evidence of immune dysregulation
in patients with active disease. Up to 25% have a negative tuberculin skin test on
initial evaluation (58); this percentage is increased in those with disseminated or miliary
disease (59). Up to 60% of patients demonstrate reduced responses to M. tuberculosis
purified protein derivative (PPD) in vitro in terms of T-cell blastogenesis, production of
IL-2 and IFN-�, and surface expression of IL-2 receptors (60,61). These abnormalities
are accompanied by increased levels of M. tuberculosis-reactive antibody and increased
capacity for production of the cytokines IL-1 and TNF-� by monocytes (14,15).
Several studies indicate that activation of suppressive mechanisms in blood monocytes
contributes to this process. Depletion of monocytes partially restores T-cell
responses and IL-2 production, although not completely so. Blood monocytes in TB
show increased expression of HLA-DR, IL-2 and TNF receptors, B7, and Fc�RI and
RIII (62,63). When stimulated in vitro, they produce increased quantities of IL-10,
transforming growth factor-� (TGF-�) and prostaglandin E2 (PGE2) (22,64–69). This
altered macrophage cytokine profile may be a consequence of intracellular infection.
Mycobacterial lipoarabinomannan, for example, blocks activation of macrophages by
IFN-� via production of PGE2 and TGF-� and also inhibits mitogen-induced T-cell
activation in a dose-dependent fashion (70–74). This hypothesis is supported by the
observation that the immunologic abnormalities are most pronounced in patients with
far advanced disease. The immunologic defects may thus be a consequence of the
advanced disease stage and high bacillary burden in these patients.
Mechanisms other than the production of immunosuppressive factors by monocytes
may also be involved in the reduced T-cell responses in peripheral blood in TB.