Initiation of T-helper cell immunity to Candida albicans by IL-12: the role of neutrophils.

The Th1/Th2 paradigm of acquired immunity is proving essential for a better understanding of immunoregulation in candidiasis and perhaps other fungal infections, conditions that may be life-threatening in humans and difficult to control by chemotherapy alone, especially in neutropenic and severely immunocompromised patients. In its basic conception applied to Candida infection in mice, this paradigm calls for: (i) an association between Th1 responses and the onset/maintenance of phagocyte-dependent immunity, critical for opposing infectivity of the commensal, focusing an infection, and clearing the yeast from infected tissue; (ii) the ability of the yeast to activate Th2 response as an evasive strategy; (iii) the reciprocal regulation of Th1 and Th2 responses, resulting in a dynamic balance between these two types of reactivity. This balance, in concert with a variety of environmental factors, may regulate the status of the yeast as a commensal or pathogen in the mucosal tissue of colonized humans, but may also determine the outcome of deep-seated systemic infections once hematogenous dissemination of the yeast has occurred. An important corollary of this hypothesis may be the possible combined effects on Th immunity of Candida carriage/infection and various disease states. While immune deficiency or dysregulation, resulting in an altered cytokine balance as may occur in AIDS, can reasonably be expected to increase local infectivity of the yeast, it is even more intriguing that antifungal chemotherapy will resolve some of the unusual skin (atopic dermatitis-like) disorders frequently observed in this clinical setting, patients with AIDS. Besides, an immunopathologic role for Candida has been suggested for atopic dermatitis, atopy, and other conditions, overtly associated or not with Candida. Thus, the Th cell dichotomy to Candida may have important implications not only for regulation of the balance between commensalism and infection, but may also contribute to the onset or dominance of Th2 responses in other disease states. A similar example, although with different effects, may be provided by the temporary improvement seen in atopic dermatitis patients in concomitance with acute severe infections, an effect that has been proposed to result from transient down-regulation of the predominant Th2 cell reactivity. With a view to either controlling Candida infections or opposing Candida-related immunopathology, the promotion of yeast-specific Th1 responses appears to be a promising immunotherapeutic approach. This, in principle, could be achieved by subtraction of Th2 cytokines or by administration of Th1-promoting cytokines. However, our initial studies with exogenous IL-12 were unsuccessful, suggesting that the recombinant cytokine: (i) is unable to oppose Th2 differentiation driven in vivo by IL-4/IL-10; (ii) may induce endogenous IL-10 production as a regulatory response, and (iii) may potentate local inflammatory responses in gastrointestinal infection or even trigger IFN-gamma-dependent mechanisms of fungal septic shock.. More recent studies seem to provide encouraging results, at least under specific conditions of testing. In acute candidemia, neutrophils appear to be a major source of the directive cytokines, IL-12 and IL-10, thus contributing to the selection of Th1 and Th2 cell responses to LVS or virulent infection, respectively. Neutrophils may also be an important source of IL-10 released in response to challenge with exogenous IL-12. As a result, the Th1-promoting role of IL-12 may be largely unopposed (by IL-10 induction) in neutropenic mice, which would otherwise succumb to LVS challenge. These animals are, in fact, cured by replacement therapy with IL-12 and acquire durable, Th1-associated anticandidal protection. These findings may be very important for immunotherapy of fungal infections in humans. Neutropenic patients are those at the highest risk for developing systemic candidal infections.