Therapeutic Efficacy of Human Macrophage Colony-Stimulating Factor, Used Alone and in Combination with Antifungal Agents, in Mice with SystemicCandida albicansInfection

Abstract

We examined the in vivo activity of human macrophage colony-stimulating factor (hM-CSF) against lethal Candida albicans infection in mice. In C. albicans-infected mice which had been immunosuppressed with cyclophosphamide, treatment with hM-CSF at a daily dose of 8 ؋ 10 5 units/kg of body weight or greater slightly but significantly prolonged survival. Furthermore, the therapeutic efficacy of amphotericin B (AMPH-B) in infected mice was enhanced by its combined use with hM-CSF, while that of fluconazole (FLCZ) was not. The activities of peritoneal macrophages and neutrophils from mice administered hM-CSF plus AMPH-B in combination for inhibition of hyphal growth of C. albicans cells and intracellular phagocytosis and killing of the cells were greater than those of comparable phagocytic cells from control mice to which hM-CSF plus AMPH-B was not administered. These results suggest that intravenous administration of hM-CSF augments the efficacy of AMPH-B by enhancing the antifungal activities of macrophages and neutrophils. Therefore, it is expected that therapy with the combination AMPH-B and hM-CSF could improve the efficacy of AMPH-B and reduce the therapeutic dose of the antifungal drug that is required.

Granulocyte colony-stimulating factor, granulocyte–macrophage colony-stimulating factor, and other immunomodulatory therapies for the treatment of infectious diseases in solid organ transplant recipients

“…M-CSF augments the activity of monocytes/macrophages against P. marneffei in vitro and against C. albicans and S. aureus ex vivo [46,47]. M-CSF prolonged survival when given either prophylactically in a neutropenic rabbit model of pulmonary aspergillosis or with treatment intent in an immunosuppressed mouse model of candidemia [48,49].…”

Combination Treatment of Invasive Fungal Infections

“…Effective antifungal agents may act in collaboration with host effector cells at var- (29,30,213). Overall, various antifungals combined with immunomodulators against candidiasis have been shown to be generally more effective than monotherapy (30,38,112,149,232). Adjunctive immunotherapy using antibody-based therapies has been investigated for C. neoformans and A. fumigatus infections and generally shows enhanced activity with combination therapies (34,69,152,153,157,192,231).…”

Therapeutic Modulation of Cytokines in Chronic Infectious Diseases

“…M-CSF has also been shown to improve host resistance in murine models of candidiasis [120,121]. M-CSF has been shown to promote a slightly but significantly prolonged survival time in cyclophosphamide-immunosuppressed C3H/ HeN mice lethally infected with C. albicans [120].…”

“…M-CSF has been shown to promote a slightly but significantly prolonged survival time in cyclophosphamide-immunosuppressed C3H/ HeN mice lethally infected with C. albicans [120]. Moreover, the therapeutic efficacy of AMB has been shown to be markedly enhanced by its combined use with M-CSF, which was associated with increased antifungal activities of macrophages and neutrophils [120]. Administration of M-CSF also improved the therapeutic outcome in both acute and chronic murine models of candidiasis when used in combination with fluconazole [120].…”