Anti-Cytokine Therapy of Murine Candidiasis

Abstract

One major feature of antimicrobial resistance in human and experimental settings is the dichotomy of the response against intracellular and extracellular pathogens. The major mechanism in resistance to intracellular pathogens is cytotoxicity occurring through the activity of cytotoxic or phagocytic cells, or mediated by antibody. In contrast, resistance to extracellular pathogens mostly relies on antibodies with neutralizing or opsonizing activity. These two types of response are primarily characterized by the induction of delayed type hypersensitivity (DTH) and help for antibody synthesis, respectively, thus providing a possible explanation for the separate and often reciprocal regulation of humoral and cell-mediated responses to microbial pathogens. Indeed, in most microbial infection models, cellular and humoral responses seem to be reciprocally regulated both in time and intensity (1). As a matter of fact, either type of response is governed by one of the two major T cell subsets known as Th1 and Th2 (2, 3). Strong DTH and low antibody responses are associated with the activation of Thl cells, whereas high antibody levels, including IgE, and poor or absent footpad responses, mainly result from Th2 cell activation. Such an orchestrated picture derives largely from studies of murine cutaneous Leishmania major infection, where susceptibility or resistance are genetically determined. As a result, resistant mice are characterized by strong DTH responses and production of cytokines of the Thl secretion profile, whereas susceptible mice have high antibody levels and produce a preponderance of Th2 cytokines (4). Although less clearly defined, a similar situation may apply to other infectious disease models, including those with bacteria, protozoa and viruses (5). In contrast, no data are available on Th responses to fungi.