Abstract
The outcome of the Th1/Th2 balance is a critical determinant of the outcome in invasive aspergillosis. The innate immune system encounters the pathogen first. Dendritic cells (DC) appear to be the critical fulcrum at the intersection of the innate immune system, and which receptors are engaged, particularly which Toll-like receptors are triggered by the pathogen, likely determines which co-stimulatory molecules are expressed during the DC maturation process, and thus which cytokine pathway will eventually dominate. Some proinflammatory cytokines initially produced by naïve phagocytes may also direct dendritic cell direction. Thus DC are the main connections of the innate and adaptive immune systems. The cytokine pathway may be affected by the antigen load, whether and what type of immunosuppressive drug or immunosuppressive co-morbidity is present, the pathogen's success in converting from conidia to hyphae, the pathogen's production of toxins, and later whether appropriate antimicrobial chemotherapy is given. Chemokines triggered by cellular interaction with the pathogen call different host cell populations to the site of infection, collectins affect the phagocyte-fungus interaction, and the cytokines produced by the adaptive immune system then regulate the antifungal power of mononuclear phagocytes and polymorphonuclear neutrophils. In these ways the innate and adaptive immune systems work together in host defense. The key cytokines associated with a successful outcome of Aspergillus infection are upregulation of Th1 and proinflammatory cytokines IFNγ, TNFα, IL-12, GM-CSF, IL-1, IL-6 and IL-18, and down-regulation of IL-4 and IL-10. The converse is associated with progressive disease. The most data about favorable cytokine effects on phagocytes vs. Aspergillus concerns IFNγ, GM-CSF and G-CSF, and for unfavorable effects, IL-10 and IL-4. GM-CSF and IFNγ have also been shown to possess the ability to reverse the down-regulating effects of immunosuppressants on anti-Aspergillus phagocyte function. Neutralization of several Th1 cytokines in vivo has been shown directly to result in a bad outcome of infection, whereas administering Th1 or proinflammatory cytokines or neutralizing Th2 cytokines has been shown to produce a favorable outcome. Antifungal chemotherapy is associated with a switch to a Th1 profile, and antifungal chemotherapy combined with Th1 cytokine immunotherapy acts synergistically. Thus improved definition of the Th1/Th2 balance is essential for future prospects for immunotherapy, antimicrobial chemotherapy, and vaccination.