Abstract
Vaccination has important clinical potential in the immunotherapy of both infectious disease and cancer. The central aim of the studies reported in this thesis has been the development of vaccination strategies that will be effective for therapeutic applications in cancer. Using ovalbumin antigen in a mouse model, we have examined a combination of recently developed adjuvants referred to as CASAC (combined adjuvants for synergistic stimulation of cellular immunity) to optimise the efficacy of vaccination induced T cell mediated immunity. These studies have examined the effect of repeated rounds of vaccination with one, or alternating cycles of two different helper peptides. The hypothesis was that repeated stimulation of the same clonal population of CD4+ T helper cells with a single MHC class II peptide could induce anergy, exhaustion, clonal deletion and/or stimulation of regulatory T-cells, resulting in reduced and shorter lived immunity. These studies have also examined the effect of inclusion of other immune regulatory components, and in particular a cocktail of cytokines generated by phytohemagglutinin stimulation of human peripheral blood mononuclear cells (referred to as IRX-2). Another important issue for vaccination mediated immune therapy that was addressed is the age-associated loss of immunological competence (immunesenescence). A comparative analysis is reported of the magnitude and duration of responses to vaccination with a single MHC class-I presented peptide in combination with the same or alternating MHC class-II presented peptides. In addition, we have quantified the number of antigen specific CDS T cells, their effector and memory subsets and in vivo antigen specific cytolytic activity to examine the effect of CASAC vaccination alone or in combination with IRX-2. The induction of immunological responses in young and aged immune backgrounds was also examined.Vaccinations with ovalbumin peptides in the CASAC adjuvant have shown higher percentages and numbers of antigen specific CDS T cells with improved cytolytic activity when helper functions are stimulated by two different class-II peptides used in alternating cycles of vaccination, rather than repeated stimulation by the same class-II peptide. This conclusion can be confirmed with a repeated experiment. Analysis of T cells with a regulatory (Treg) phenotype (CD4+CD25+Foxp3+) showed that their expansion was reduced with the alternating T-helper peptide vaccination regimen. The addition of IRX-2 to the CASAC vaccination regimen was found to enhance the in vivo antigen specific cytolytic activity. This was particularly significant in the aged mice which were found to have increased levels of Tregs.
| Date of Award | 2012 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Farzin Farzaneh (Supervisor) & Linda Barber (Supervisor) |