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Dissertation
A characterization of merozoite surface protein-1 subunit antigen acquisition by dendritic cells and the immunogenicity of dendritic cell vaccination in a murine model of lethal malarial infection
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2005
DOI:
https://doi.org/10.17918/00008506
Abstract
Vaccination with the C-terminal portion of the major merozoite surface protein, MSP-1, is capable of protecting mice from challenge infection with an otherwise lethal murine malarial parasite when administered in Freund's adjuvant. Our laboratory has demonstrated that vaccination with the protective fragment in less potent adjuvants fails to confer protection from challenge infection with the lethal parasite Plasmodium yoelii 17XL. The inability to achieve clinical efficacy with selected MSP-1 vaccine candidates in an adjuvant suitable for use in humans is the chief impediment to translating these promising findings in a rodent malarial model to a human vaccine trial. Adjuvant-mediated recruitment of antigen-presenting cells (APCs) and the subsequent acquisition of immunogen at the site of inoculation are the seminal events in the initiation of vaccine-mediated immunity. In the experimental series described herein, we have characterized the acquisition of MSP-1 subunit antigens by murine dendritic cells (DCs) in vitro, and subsequently investigated the immunogenicity of malarial vaccine-candidate-loaded DCs in vivo. DCs exhibit differential uptake of the 42 kDa MSP-1 C-terminal fragment (MSP1-42), and a 19 kDa progeny polypeptide (MSP1-19) arising through proteolysis of MSP1-42. Internalization of MSP1-42 proceeds at a markedly greater rate compared with that of MSP1-19, and the kinetics of acquisition implicate a receptor-mediated mechanism in the acquisition of MSP1-42 by DCs in vitro. We have shown that DC-mediated uptake of MSP-1 subunit antigens may be enhanced through post-translational modification of antigen, or via the linkage of polypeptide epitopes that likely bind DC surface-expressed antigen receptors. DCs incubated with MSP1-42 in vitro elicited robust antigen-specific cellular and humoral responses subsequent to DC-based immunization of naive recipients. Indeed, DCs loaded with P. yoelii MSP1-42 derived from recombinant bacteria conferred protection from challenge infection with an otherwise lethal murine parasite that was comparable to protection conferred by antigen-in-FA. Practical methods of targeting antigen to DCs in situ are presently under development. We have provided proof-of-principle that targeting the 42 kDa fragment of MSP-1 to DCs establishes protective immunity from an otherwise lethal malarial challenge infection, and that mature, antigen-loaded DCs confer protection that is comparable to immunization with the gold-standard antigen-in-adjuvant formulation.
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Details
- Title
- A characterization of merozoite surface protein-1 subunit antigen acquisition by dendritic cells and the immunogenicity of dendritic cell vaccination in a murine model of lethal malarial infection
- Creators
- Yannek Isaac Leiderman
- Contributors
- Carole A. Long (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 245 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021888958004721