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

Introduction. Systemic infection with Candida albicans results in diff erent patterns of disease depending on host genetic and yeast strain f actors, with a correlation between disease outcome and the predominant T helper (Th) cell response. In particular, healing infection is asso ciated 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 i n which susceptibility to C. albicans is accompanied by the detection of CD4(+) Th2 cells producing IL-4, IL-5 and IL-10 and mediating humor al and allergic responses. The various experimental C. albicans infect ion models, described in the literature, are discussed and new persona l experimental data are presented. Methods. To gain insight into the a bility of cytokines to influence the development of protective or exac erbative CD4(+)Th cells in systemic candidiasis, we administered anti- cytokine monoclonal antibodies (mAb) or cytokine antagonists or cytoki nes 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 obtain ed by inoculating low virulence C. albicans (PCA-2) into CD2F1 mice (h ealing infection) or susceptible DBA/2 mice (non healing infection) or highly virulent C. albicans (CA-6) into CD2F1 mice (non healing infec tion). Results. A conversion from a non healing to a healing phenotype was obtained by administering IL-4 neutralizing mAb or soluble IL-4 r eceptor 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 under standing of cytokine-dependent, cross-regulatory Th1/Th2 responses in murine candidiasis may pave the way for possible therapeutic strategie s aimed at restoring protective cell-mediated immunity in human infect ion. In fact, some cytokines (IL-12 and IL-4), more than others (IFN-g amma and IL-10), exert potent and opposing regulatory effects on the i nduction of a protective cell-mediated anticandidal response. Therefor e, cytokine replacement therapy or, conversely, cytokine neutralizatio n could modify resistance to infection. However, because of the comple xity of their actions, the use of recombinant cytokines may lead to pl eiotropic, redundant, or undesirable side effects. Perhaps more fruitf ul will be an approach based on the use of specific cytokine antagonis ts.