IL-12 induces protective innate and adaptive immunity against Streptococcus pneumoniae infection

IL-12 has proven to be an effective mucosal adjuvant to induce both systemic and respiratory antibody production after intranasal immunization. Based on this information, IL-12 was given i.n. together with conjugate vaccine to elicit serotype-specific anti-capsular polysaccharide (PS) antibody in my first part of the study. I examined the biological activity of respiratory antibody in protecting mice against nasal colonization with S. pneumoniae . The results indicated that parenteral vaccination to induce serum antibodies is not sufficient to protect against nasal carriage and that mucosal-derived IgA antibody is necessary to clear a noninflammatory condition in which there is likely to be no leakage of serum antibody into the upper respiratory tract.; I then investigated the potential role of IL-12 during innate defense against pneumococcal infection. The results demonstrated that exogenous IL-12 given i.n. to mice can induce protection against respiratory pneumococcal infection. It was concluded that i.n. inoculation of IL-12 can induce a cascade of events beginning with NK cell activation and IFN-gamma production, followed by induction of TNF-alpha secretion by macrophages. This TNF-alpha then mediates neutrophil recruitment through enhanced Keratinocyte-derived chemokine (KC) expression. Increased neutrophil levels in the lung is likely responsible for the observed IL-12-mediated protection.; Since I found that IL-12 and the Gram-positive extracellular bacterium, S. pneumoniae, act synergistically to induce in vivo IFN-gamma production from naive animals, I conducted extensive in vitro studies to clarify the mechanism of the observed synergy between IL-12 and S. pneumoniae in IFN-gamma induction. I found that IL-12 and heat-killed pneumococci synergistically induced IFN-gamma production from murine spleen and lung NK cells which was dependent on signaling by TNF-alpha. Additional results showed that IFN-gamma induction required expression of TNFR p75. NK cells were identified as the main source of IFN-gamma but not TNF-alpha after stimulation with IL-12 and heat-killed pneumococci.; Overall, the present study shows that exogenous IL-12 induces protective innate and adaptive immunity against S. pneumoniae lung infection.