| Despite available vaccines and therapies, pulmonary disease causes significant mortality and morbidity. Immunomodulation is an antigen-free strategy characterized by nonspecific immune activation, enhancing host defense to disease. To investigate the prophylactic possibilities of immunomodulation in the respiratory tract, we evaluated the effects of vaccine adjuvants on the pulmonary immune response before and after pathogen challenge. The adjuvants used are well characterized and promote strong immune responses with distinct immunological biases: Th2-biasing cholera toxin (CT), mixed Th1/Th2-biasing R192G heat-labile E. coli toxin (mLT), and Th1-biasing CpG ODNs.;Groups of mice (CBA/J and Balb/c) were per nasally treated twice, one week apart, with adjuvant (CT, mLT, CpG), saline or left untreated. Mice were sacrificed at various timepoints afterward for immunologic analysis or challenged 24hrs after the last treatment with C. neoformans (CBA/J mice) or influenza virus (Balb/c mice). Challenged mice were monitored for survival or sacrificed for immunologic and microbial analysis. In the absence of infection, CT, mLT or CpG treatments induce transient inflammation, characterized by inflammatory cytokines, chemokines, and immune cell infiltration. The magnitude, duration, and Th1/Th2 bias of these changes were dependent on both mouse strain and adjuvant treatment.;Adjuvant pre-treated mice challenged with C. neoformans exhibited reduced airway neutrophils, eosinophils, chemokines, and lung fungal burden, but increased CD4 T-cells and dendritic cells after one week. However, survival was enhanced only with CpG treatment, and aggravated with CT treatment. In contrast, survival of influenza virus was enhanced with all adjuvant treatments, but day 4 lung viral burden was reduced only with CT and mLT treatments. During influenza infection, all adjuvant treatments increased airway CD4 T-cells, B-cells, dendritic cells, iBALT-like lung tissue structures and CD80 expression, while reducing airway chemokine levels.;These results suggest that adjuvant treatments induce unique immunomodulatory mechanisms, which differentially influence pulmonary host defense in a pathogen-specific manner. Successful modulation of cryptococcal infection requires a strong Th1-bias strategy (apparent only late in infection), while Th1-, Th1/Th2, or Th2-biased strategies protect against influenza. These studies begin to unravel the dynamics of immunomodulation, host immune response, and pathogen challenge in the pulmonary mucosa. |
