Manipulation of antigen presenting cells to enhance host immune responses to bacterial infection
File(s)
Author(s)
Thompson, Iain James
Type
Thesis
Abstract
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.
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.
Version
Open Access
Date Issued
2015-06
Date Awarded
2016-04
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Knight, Stella
Williamson, Diane
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)