Physiopathological role of cytokines induced by Candida. Rational basis for immunotherapy

We have recently reported that selective activation of either one of the CD4(+) Th subsets occurs in infections with the fungus Candida albicans, whose dissemination from the gastrointestinal tract often results in fatal, progressive disease in humans. Studies in mice have shown that a strong correlation exists between disease outcome and nature of the predominant T helper (Th) response, with healer mice developing a Th1 response and nonhealer mice a predominant Th2 response. Ln genetically resistant mice, a protective Th1 response to virulent C. albicans is observed after mouse vaccination with a live vaccine strain of the yeast, PCA-2 but the same attenuated vaccine results in nonprotective Th2 responses in genetically susceptible DBA/2 mice. Because Th1 and Th2 cells are known to secrete distinct patterns of cytokines, that mediate most of their action in vivo, we studied the pathogenetic role of cytokines in murine candidiasis by administering cytokines and/or anticytokines in different yeast/host combinations. The results can be summarized as follows: a) treatment with neutralizing Mabs or soluble interleukin-4 (IL-4) receptor changed the nonhealer phenotype to a healer one, in that mice survived both primary and secondary infections, developed strong delayed type hypersensitivity (DTH) reactions and stopped producing IL-4 and IL-10; b) healing phenotype was also obtained by neutralization of early IL-10 production; c) conversely, treatment with recombinant IL-4 or recombinant IL-10 exacerbated the course of both disseminated and gastrointestinal infections; d) neutralization of endogenous interferon-gamma (IFN-gamma) or IL-12, while not affecting the outcome of a primary sublethal infection, rendered the mice susceptible to a secondary challenge with virulent C. albicans cells. These data indicate that cytokines can contribute to the appearance of protective and nonprotective T helper responses in C. albicans infection and that the ability to control emerging Th cell phenotype offers the potential to induce an appropriate immune response in fungal infections.