Immunotherapy for Infectious Diseases

INTRODUCTION
From: Immunotherapy for Infectious Diseases
Edited by: J. M. Jacobson © Humana Press Inc., Totowa, NJ
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Immunotherapy for Tuberculosis and Other
Mycobacterial Infections
Robert S. Wallis and John L. Johnson
At least one-fourth of the world’s population is infected with Mycobacterium tuberculosis,
resulting in nearly 4 million deaths worldwide each year, more than any other
single pathogen. In some areas, such as southern Africa and southeast Asia, tuberculosis
case rates have approached 200 cases per 100,000 persons/year, or nearly 0.2%
annually (1), despite vaccination with M. bovis bacille Calmette-Guérin (BCG) and
increased access to chemotherapy. In other regions, including eastern Europe and Russia,
multidrug-resistant (MDR) infection has emerged as a major threat to public health
(2). As a consequence, there is greater urgency to define the factors involved in host
resistance to mycobacterial infection and to evaluate their potential therapeutic application
in clinical trials.
Basic clinical observations have shaped our understanding of mycobacterial immunity.
The initial infection with M. tuberculosis is usually inapparent. It is followed by
acquisition of delayed-type hypersensitivity and partial immunity to exogenous reinfection.
Although active TB can arise shortly after exposure, most TB cases represent
reactivation disease, which is separated in both time and distance from the initial infection.
In a normal host, the risk of TB is approximately 5% during the first year after
initial infection, and 5% subsequently, distributed over as much as decades. The risk
of TB is increased in the very young and the elderly, owing to impaired cellular
immune function. The risk is greatest in individuals with advanced HIV-1 infection, in
whom the likelihood of progression to active TB may be increased by as much as 170fold
(3–6). These observations underscore the critical role of cell-mediated immunity
and, in particular, the importance of antigen-specific CD4� T-cells in mycobacterial
immunity.
CYTOKINE REGULATION OF MACROPHAGE ACTIVATION
As intracellular pathogens, mycobacteria possess the capacity to replicate within the
phagocytic cells that comprise the major effector arm of the cellular immune system.
Resting human monocytes and macrophages are relatively permissive of intracellular