Driving protective immune responses by targeting Mycobacterium bovis and Foot-and-Mouth Disease virus antigens to bovine dendritic cell subsets

These studies will help design new vaccines for two important diseases of cattle, bovine tuberculosis and Foot-and-Mouth disease virus. Mycobacterium bovis is the causative agent of bovine tuberculosis (TB), a disease increasing in incidence in UK cattle herds causing major economic losses and potential human health risks. At present control of bovine TB relies solely on the use of diagnostic tests which do not have 100% sensitivity or specificity. Foot and mouth disease virus (FMDV) has a wide host range including all cloven-hoofed animals and causes an acute vesicular disease in domestic ruminants and pigs, which results in debilitation, pain and loss of productivity. Vaccines have been shown to be highly valuable in controlling a variety of infectious diseases, including bacteria and viruses. However, effective vaccines require portions of the infectious agent to be delivered to specialised cells, called dendritic cells. Dendritic cells are the only cells in the body capable of starting an immune response to an agent the body hasn't seen before. Targeting portions of the infectious agents to dendritic cells has been shown to stimulate a strong immune response. Unfortunately, the situation is more complicated than it first appears, there is more than one type of dendritic cell and each cell type can stimulate a different type of immune response. Specific immune responses may be required to control different infections. Acute viral infections, for example Foot-and-Mouth disease, may require an antibody response to control infection. In contrast, slow growing bacterial infections, for example tuberculosis may require immune T cells to control them. In this programme of work we plan to target components of Foot-and-Mouth disease virus or cattle tuberculosis bacteria to particular dendritic cell subsets to determine whther a protective immune response can be stimulated

Dendritic cells (DC) are unique in their capacity to stimulate responses of naive T lymphocytes and are central to the induction of immune responses. DC are therefore a pivotal control point determining the outcome of infectious challenge or vaccination. The potential to manipulate or target DC in vaccination strategies is of significant importance. Studies of DC have identified the presence of subsets with differences in phenotype and function and suggest that the type of DC can influence the bias of the ensuing T cell response, or may even induce tolerance. However, many of these studies rely on the isolation and culture of DC in vitro which may not necessarily reflect their in vivo biological properties. The model in which afferent lymph draining the skin of cattle is collected by cannulation after removal of the prescapular lymph nodes allows the isolation of large numbers of afferent lymph DC (ALDC) without the need for lengthy isolation procedures or culture. These cells most closely represent in vivo DC providing significant advantages compared to DC derived in vitro by culture of monocytes or bone marrow progenitors. Exploiting the afferent lymphatic cannulation model in cattle provides a powerful and unique opportunity to study DC directly ex vivo in a way that is not possible in mice or in humans. A number of in vivo studies have been performed in mice to demonstrate that antigen loaded DCs can induce antigen specific T-cell responses and humoral responses. Targeting of antigens to DCs has immense potential for improving vaccine efficacy. Optimal targeting strategies will require knowledge about functional specialisation among DC subpopulations and identification of molecules for targeting appropriate DCs. The proposed programme of work will determine whether targeting DC subsets with specific antigen can stimulate enhanced protective immune responses and so influence rationale vaccine design.