Host immune reactivity determines the efficacy of combination immunotherapy and antifungal chemotherapy in candidiasis.
In immunocompetent mice with candidiasis, successful therapy with amphotericin B and fluconazole relies on the induction of protective, T helper (Th) type 1 responses, an effect potentiated by concomitant interleukin (IL)-4 neutralization. To assess the therapeutic efficacy of combined treatments with antifungals and immunomodulators in conditions of immunosuppression, leukopenic or neutropenic mice with disseminated candidiasis were treated with amphotericin B or fluconazole alone or in combination with soluble IL-4 receptor (sIL-4R) or recombinant (r) IL-12 or IL-10 neutralizing monoclonal antibodies. We found that (1) the synergistic effect of sIL-4R and antifungals is retained in immunocompromised mice; (2) synergism with amphotericin B was superior to that with fluconazole, particularly in leukopenic mice; (3) rIL-12 synergized with fluconazole in neutropenic mice; and (4) IL-10 neutralization was always of limited efficacy. This study indicates that the therapeutic efficacy of antifungals is differentially potentiated by cytokines or cytokine antagonists and is influenced by host immune reactivity.
Mencacci
A
A
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06122 Perugia, Italy.
Cenci
E
E
Bacci
A
A
Bistoni
F
F
Romani
L
L
D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D002176:Candida albicans / Q000276:immunology / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use; D006801:Humans; D016867:Immunocompromised Host; D007167:Immunotherapy; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000627:therapeutic use; D007668:Kidney / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D018417:Th1 Cells / Q000276:immunology
D000911:Antibodies, Monoclonal; D000935:Antifungal Agents; D016207:Cytokines; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D000666:Amphotericin B; D015725:Fluconazole