Immunotherapy for Infectious Diseases

Tuberculosis and Other Mycobacterial Infections 289
Interferon-�
Because of its critical role in macrophage activation and host defenses against mycobacterial
diseases, adjunctive treatment with IFN-� has been studied in several small trials.
In lepromatous leprosy, intradermal therapy with low-dose IFN-� resulted in increased
local T-cell and monocyte infiltration, HLA-DR (Ia) antigen expression, and decreased
bacillary load (110). In another study, twice or thrice weekly therapy with 25–50 �g/m 2
of subcutaneous IFN-� was administered to seven HIV-noninfected patients with disseminated
M. avium complex infection who had failed to respond to antibiotic therapy
(111). Within 8 weeks of beginning IFN treatment, all seven patients had significant and
sustained clinical improvement. In contrast, IFN-� therapy was not found to be beneficial
in patients with advanced AIDS and disseminated M. avium complex infection (112).
IFN-� immunotherapy also has been studied in MDR TB, for which drug treatment
options are limited. In a case report, adjunctive treatment with IFN-� and GCSF was
successful in the treatment of a leukemic patient with intracerebral and spinal cord
MDR TB (113). High-dose systemic therapy with IFN-� has, however, been associated
with frequent side effects including fatigue, myalgias, and malaise. Treatment with
aerosolized IFN-� has been studied in an attempt to decrease these systemic side
effects and deliver therapy directly to the site of disease in the lung. In an open-label
study in five patients with MDR TB, aerosolized IFN-� 500 �g three times weekly for
1 month was well tolerated and resulted in decreased sputum bacillary burden and stable
or improved body weight (114). Further studies of aerosolized IFN-� are warranted
to determine the optimal dose and duration of therapy.
Interferon-�
Interferon-� is another immunomodulatory cytokine produced by mononuclear
phagocytes stimulated by bacteria and viruses. IFN-� modulates differentiation of
T-cells toward the Th1 phenotype, induces production of IFN-� and IL-2, and inhibits
proliferation of Th2 cells. Two small studies have examined a possible role for IFN-� in
TB treatment. A randomized open-label trial in 20 HIV-seronegative TB patients in Italy
studied the effects of aerosolized IFN-� 3 million units thrice weekly during the first
2 months of TB treatment (115). Patients treated with IFN-� had significantly earlier
improvement in fever, sputum bacillary burden by quantitative microscopy after 1 week
of treatment, and pulmonary consolidation after 2 months than patients receiving placebo.
No adverse effects were noted in the IFN-� treatment group. In another pilot study,
IFN-�2b (3 million units weekly) was administered subcutaneously for 3 months as an
adjunct to chemotherapy for five patients with chronic MDR TB (116). Two of the five
patients became consistently sputum culture-negative over a 30-month follow-up period.
Interleukin-12
IL-12 is a pivotal cytokine that enhances host responses to intracellular pathogens by
inducing IFN-� production and Th1 responses at sites of disease. Patients with congenital
abnormalities of IL-12 receptors are highly susceptible to serious mycobacterial and
salmonella infections (52,53). Administration of IL-12 to severe combined immunodeficient
(SCID) or CD4� T-cell-depleted mice infected with M. avium enhances
IFN-� production and had modest activity against M. avium (117). Recombinant IL-12
also has been shown to upregulate M. tuberculosis-induced IFN-� responses in human