Manipulation of antigen presenting cells to enhance host immune responses to bacterial infection

Vaccine development for intracellular pathogens, where a protective and long lasting T cell response is desirable, has proved to be a significant challenge. Dendritic cell (DC) vaccination has been used to both elucidate mechanisms important in providing protection against a range of pathogens and more recently as a vaccine strategy in its own right. Additionally, targeting of vaccine antigens via monoclonal antibodies specific to DCs has developed as a more clinically appropriate alternative. This thesis investigates whether DC manipulation can enhance survival and reduce bacterial load in murine models of anthrax and melioidosis. Prophylactic DC vaccination for B. anthracis required CpG ODN 1826 for the maturation of antigen-stimulated DCs in vitro. Following their adoptive transfer, DCs failed to induce an antigen-specific response. However, when combined with the rPA and alum anthrax vaccine, DC vaccination enhanced antigen-specific T cell responses. This approach increased murine survival and significantly reduced bacterial load. DC vaccination as a therapeutic strategy for B. pseudomallei again required CpG ODN 1826 for DC maturation and activation. Antigen stimulated DCs migrated to lymph nodes within 48 hours of adoptive transfer where they induced an antigen-specific T cell response with a mixed Th1/Th17 profile. DC vaccination failed to affect survival with increased splenic weight and bacterial load in two out of three murine efficacy studies. Targeting of the protective B. pseudomallei antigen LolC, conjugated to a monoclonal antibody specific for DEC205, an endocytic DC receptor, failed to induce either a specific immune response or impact survival or bacterial load. Overall, DC vaccination reduced B. anthracis bacterial load when used prophylactically in combination with rPA and alum. As a therapeutic strategy the results are suggestive of DC vaccination enhancing B. pseudomallei infection. Future studies should examine the potential for antigen specific immune responses generated by DC vaccination to be used as an adjunct to antibiotic therapy, when B. pseudomallei replication is controlled.Open Acces