Immunotherapy for Infectious Diseases

Fungal Infections 309
has activity against C. neoformans in experimental murine infection (28–30). Like
chloroquine, there is no information about its efficacy as an antifungal agent in humans,
but its activity in mice suggests possible usefulness against human infection.
NONSPECIFIC AUGMENTATIVE IMMUNE THERAPIES
Colony-Stimulating Factors
CSFs are natural proteins that stimulate the differentiation of bone marrow progenitor
cells to mature effector cells. Three types of CSFs have been identified, cloned,
and produced in forms suitable for clinical use: granulocyte, granulocyte/macrophage,
and macrophage (for reviews, see refs. 31–33). G-CSF and GM-CSF are licensed for
use in the United States, whereas M-CSF is available in Japan (31). These factors are
produced for clinical use in bacterial, yeast, or mammalian expression systems (32).
The availability of CSFs has improved the management of neutropenia associated with
chemotherapy and bone marrow transplantation by shortening the length of neutropenic
episodes. Since the major fungal infections in patients with cancer and/or bone marrow
transplantation are associated with neutropenic episodes, CSF administration is, in theory,
an important form of prophylactic antifungal immunotherapy. There is considerable
evidence from laboratory studies that CSFs can augment host immune function and the
efficacy of antifungal agents against a variety of fungal pathogens and these compounds
may have clinical use in a direct antifungal mode. G-CSF, GM-CSF, and M-CSF have
all been shown to have powerful in vitro and in vivo effects in potentiating effector cell
function against many fungal pathogens (Table 3). However, most studies to date have
produced no conclusive evidence that use of G-CSF or GM-CSF reduces the incidence
of fungal infections or improves survival in neutropenic patients (34).
G-CSF
G-CSF promotes proliferation and differentiation of PMN progenitor cells (reviewed
in refs. 31 and 32). Administration of G-CSF results in an increased number of peripheral
blood PMNs, including band forms (left shift). Neutrophils from individuals given
G-CSF have enhanced superoxide production. Neutrophils from patients with AIDS
have impaired activity against Candida albicans, which can be restored by incubation
in G-CSF (35). G-CSF is used clinically to promote bone marrow recovery after
chemotherapy and bone marrow transplantation and to treat chronic neutropenia,
myelodysplastic syndrome, and aplastic anemia (31). G-CSF administration is also useful
for treating AIDS-associated neutropenia and may reduce the incidence of infections
in patients with advanced HIV infection (36). G-CSF enhances PMN antifungal
activity against a variety of fungal pathogens (Table 3).
Administration of G-CSF to human volunteers results in significant augmentation of
PMN activity against C. albicans, Aspergillus fumigatus, and Rhizopus arrhizus (37).
The enhanced killing power of PMNs from G-CSF-treated individuals is attributed to
enhanced respiratory bursts and suggests that G-CSF administration produces qualitative
improvements in granulocyte function (37). Several anecdotal case reports suggest
that G-CSF is beneficial as an adjunct to other therapeutic modalities for fungal infections,
which are notoriously difficult to treat (Table 4). Furthermore, a randomized trial
of therapy with ceftazidime and amikacin alone versus the same antibiotics plus G-CSF
in neutropenic patients with presumed infection revealed a significant trend toward