Introduction. Systemic infection with Candida albicans results in different patterns of disease depending on host genetic and yeast strain factors, with a correlation between disease outcome and the predominant T helper (Th) cell response. In particular, healing infection is associated with strong delayed type hypersensitivity (DTH), high levels of interleukin-2 (IL-2) acid interferon gamma (IFN-gamma) and low levels of IL-4 and IL-10, thus indicating the predominant involvement of the Th1 subset. In non healing infection, a reverse pattern is observed in which susceptibility to C. albicans is accompanied by the detection of CD4(+) Th2 cells producing IL-4, IL-5 and IL-10 and mediating humoral and allergic responses. The various experimental C. albicans infection models, described in the literature, are discussed and new personal experimental data are presented. Methods. To gain insight into the ability of cytokines to influence the development of protective or exacerbative CD4(+)Th cells in systemic candidiasis, we administered anti-cytokine monoclonal antibodies (mAb) or cytokine antagonists or cytokines such as, IL-12, IL-4, IL-10 and IFN-gamma in vivo in experimental models of healing and non healing infections. These models were obtained by inoculating low virulence C. albicans (PCA-2) into CD2F1 mice (healing infection) or susceptible DBA/2 mice (non healing infection) or highly virulent C. albicans (CA-6) into CD2F1 mice (non healing infection). Results. A conversion from a non healing to a healing phenotype was obtained by administering IL-4 neutralizing mAb or soluble IL-4 receptor to CD2 F1 mice challenged with CA-6, or by administering anti-IL-10 mAb to PCA-2 infected DBA/2 mice. Conversely, the administration of anti-IFN-gamma and anti-IL-12 to healer mice, while not affecting the outcome of primary infection, impaired the development of acquired resistance to a subsequent lethal challenge which was accompanied by the detection of Th2-mediated responses. Conclusion. The current understanding of cytokine-dependent, cross-regulatory Th1/Th2 responses in murine candidiasis may pave the way for possible therapeutic strategies aimed at restoring protective cell-mediated immunity in human infection. In fact, some cytokines (IL-12 and IL-4), more than others (IFN-gamma and IL-10), exert potent and opposing regulatory effects on the induction of a protective cell-mediated anticandidal response. Therefore, cytokine replacement therapy or, conversely, cytokine neutralization could modify resistance to infection. However, because of the complexity of their actions, the use of recombinant cytokines may lead to pleiotropic, redundant, or undesirable side effects. Perhaps more fruitful will be an approach based on the use of specific cytokine antagonists.

RATIONALE FOR CYTOKINE AND ANTI-CYTOKINE THERAPY OF CANDIDA-ALBICANS INFECTION

MENCACCI, Antonella;CENCI, Elio;SPACCAPELO, Roberta;ROMANI, Luigina
1995

Abstract

Introduction. Systemic infection with Candida albicans results in different patterns of disease depending on host genetic and yeast strain factors, with a correlation between disease outcome and the predominant T helper (Th) cell response. In particular, healing infection is associated with strong delayed type hypersensitivity (DTH), high levels of interleukin-2 (IL-2) acid interferon gamma (IFN-gamma) and low levels of IL-4 and IL-10, thus indicating the predominant involvement of the Th1 subset. In non healing infection, a reverse pattern is observed in which susceptibility to C. albicans is accompanied by the detection of CD4(+) Th2 cells producing IL-4, IL-5 and IL-10 and mediating humoral and allergic responses. The various experimental C. albicans infection models, described in the literature, are discussed and new personal experimental data are presented. Methods. To gain insight into the ability of cytokines to influence the development of protective or exacerbative CD4(+)Th cells in systemic candidiasis, we administered anti-cytokine monoclonal antibodies (mAb) or cytokine antagonists or cytokines such as, IL-12, IL-4, IL-10 and IFN-gamma in vivo in experimental models of healing and non healing infections. These models were obtained by inoculating low virulence C. albicans (PCA-2) into CD2F1 mice (healing infection) or susceptible DBA/2 mice (non healing infection) or highly virulent C. albicans (CA-6) into CD2F1 mice (non healing infection). Results. A conversion from a non healing to a healing phenotype was obtained by administering IL-4 neutralizing mAb or soluble IL-4 receptor to CD2 F1 mice challenged with CA-6, or by administering anti-IL-10 mAb to PCA-2 infected DBA/2 mice. Conversely, the administration of anti-IFN-gamma and anti-IL-12 to healer mice, while not affecting the outcome of primary infection, impaired the development of acquired resistance to a subsequent lethal challenge which was accompanied by the detection of Th2-mediated responses. Conclusion. The current understanding of cytokine-dependent, cross-regulatory Th1/Th2 responses in murine candidiasis may pave the way for possible therapeutic strategies aimed at restoring protective cell-mediated immunity in human infection. In fact, some cytokines (IL-12 and IL-4), more than others (IFN-gamma and IL-10), exert potent and opposing regulatory effects on the induction of a protective cell-mediated anticandidal response. Therefore, cytokine replacement therapy or, conversely, cytokine neutralization could modify resistance to infection. However, because of the complexity of their actions, the use of recombinant cytokines may lead to pleiotropic, redundant, or undesirable side effects. Perhaps more fruitful will be an approach based on the use of specific cytokine antagonists.
1995
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1038295
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