Meltzer, Ulrike Anne; (2004) Dendritic cell maturation and antigen presentation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Modulation of dendritic cell (DC) function and control of DC maturation are critical control points in the generation of antigen specific immune responses. In this thesis DC function was studied in three different settings: age-related development of functional competence during early life, interaction of DCs and polysaccharide and glycoconjugate vaccine antigens and the pre-clinical evaluation of novel protein vaccine antigens in a DC-based culture system. Human DCs were generated from peripheral blood monocytes. Comparison of infant and adult DCs revealed that infant DCs underwent the phenotypic and morphological changes observed in adult DCs upon maturation. In contrast, DCs from infants at least up to two years of age were severely impaired in their capacity to produce IL- 12p70. This defect is likely to limit the Thl-driving capacity of the infant DCs and may contribute to the increased susceptibility of infants to infection. Infants are particularly susceptible to infection with encapsulated bacteria. Given the impaired functional capacities of early life DCs, it was important to investigate the interaction of DCs and polysaccharide and glycoconjugate vaccine antigens. Incubating DCs with such antigens in vitro resulted in uptake and processing of the antigens. This is the first report to show the direct interaction between human DCs and polysaccharide (pneumococcal) vaccine antigens. In the absence of inflammatory mediators, these antigens did not induce DC maturation. However, they were capable of modulating the response of the DCs to a second signal (LPS) by altering the cytokine balance. IL-10 was significantly increased and IL-12 reduced compared to LPS alone. DC-pneumococcal interaction may affect subsequent immune responses via an altered cytokine balance which may have a profound effect on DC-driven T cell priming. Considering the limitations of conjugate vaccines, the search for novel vaccine antigens has focussed on bacterial outer membrane proteins and secreted virulence factors. Evaluating the potential of such vaccine candidates to induce efficient cellular immune responses and DC maturation in the absence and presence of adjuvant as well as evaluating DC antigen presentation to T cells, is potentially an important component of the Phase I evaluation of putative vaccine antigens. A DC-based model system for the evaluation of cellular immune responses to potential vaccine antigens during in vitro presentation was developed. A variety of microbial proteins, which are all currently being considered as potential vaccine candidates for otitis media in infants, were evaluated. Results showed that the capacity of an antigen to induce DC maturation in vitro correlated well with the presence of T cell memory. Such antigens are likely to be useful for future analysis as vaccine antigens.

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