Investigating the contributions of inflammation and antigen depot to adjuvant function in vivo.

While we think that we understand how vaccines work, it is clear that we don't really know how the magnitude and type of immune response a vaccine induces is controlled. This is important, as a number of vaccines are only feasible if we can modulate the size and type of immune response generated. In vaccination, this function is performed by 'adjuvants' and we don't really understand how they work either. Experiments in culture suggest an important role for cells, known as dendritic cells, in controlling vaccine-induced responses. However, cells of the immune system do not work in isolation and it has been difficult to analyse the interactions of dendritic cells and other immune cells in real physiological environments. We have therefore developed a number of state of the art techniques that allow us to characterise the function of dendritic cells, their interactions with other immune cells and the effects of these processes on vaccine-induced responses, in a physiological environment in real time. Only by analysing these interactions in a physiological environment in real time, can we understand how vaccines and adjuvants control the magnitude and type of immune response. This fundamental information will help produce agents to enhance the immune response to vaccines against infections or cancers, as well as to turn off inappropriate immune responses associated with diseases such as allergy, asthma and autoimmunity.

The reasons why certain vaccine adjuvants and/or delivery systems are more or less effective at inducing immune responses or promoting the preferential induction of particular types of response are unknown. Specifically, it is unclear what impact inflammatory and depot-forming adjuvants have on APC factors known to regulate these responses, in particular phenotype, activation state, magnitude and duration of antigen presentation and the consequences these factors have on T cell activation, differentiation and function. Furthermore, very few of these parameters have been defined for these agents in vivo. This is a significant omission as it is clear that the component parts of the immune system do not work in isolation and their interactions are dynamic and occur in distinct and specialised micro- and macroanatomical locations that can only be fully determined in real time, in the physiological context, in vivo. Therefore, in this application we will analyse the impact that inflammatory and depot-forming adjuvants have on the phenotype, activation state, processing and presenting capacity of APC and the subsequent consequences of this for T cell activation, differentiation and function. Only by performing such detailed and fundamental studies in vivo can we fully understand the cellular and molecular interactions that control the immune response. This information is a prerequisite if we are truly to design, build and target vaccines and therapeutic strategies effectively.