The route to identification of the

Defining correlates of protection and understanding how they can be elicited are integral components of strategic vaccine design. The route to defining these immunological correlates is dependent on the appropriate reagents to study immune responses that then allow the investigation of cell-cell interactions. In this project we aim to characterise myeloid and T cell subsets in cattle and sheep to generate an understanding of immune of cell-surface molecules, intracellular transcription factors and cytokines that have been ascribed to phenotypically-distinct macrophage, dendritic cell (DC) and T cell subsets in other species. The cloned and expressed molecules will be used to screen existing commercially-available monoclonal antibodies (Mab) for species cross-reactivity. Such studies will confirm the specificity of any such Mab that are identified and hence they can be used with confidence for studies in cattle and sheep. Where we fail to find Mab we will produce Mab to the targets of interest. In this project we aim to develop new techniques to enable the investigation of the activation and regulation of the immune systems of cattle and sheep. These techniques will be applied herein to studies on cells activated under different conditions. This work will facilitate the identification of immunological correlates of protection to many different diseases of cattle and sheep and will also inform on the best ways to deliver new vaccines to maximise their effects. Ultimately this will lead to more strategic approaches to the management and control of infectious diseases of farmed ruminants. This will benefit the agricultural sector and the general public through improved animal welfare, animal production and food security. Furthermore, the work will be done in conjunction with an Industrial Partner, ensuring that the techniques developed in the project will be made widely available to the research community.

Effective vaccines are the most efficient way of preventing the transmission and spread of infectious diseases. This applies to diseases of both humans and animals. However there are still many diseases for which no effective vaccines exist. This may be because no vaccines have yet been tested, because vaccines that have been tested do not protect, or because vaccines that have been tested present a hazard in themselves (benefit versus risk). In the past, vaccines were developed empirically. In contrast, strategic approaches to the development of safe and effective vaccines relies on an understanding of how the immune system is activated and regulated so that optimum protection is achieved (benefit) with minimum adverse effects (risk). Investigation of the immune system reveals the correlates of protection that should be mimicked by a good vaccine. Since the correlates of protection are not the same for every infection, vaccines against different diseases need to stimulate different components of the immune system. The capability to identify immunological correlates of protection in farmed ruminants such as cattle and sheep is relatively poor compared to small laboratory animals such as mice that are commonly used as models of human disease. This is largely due to a relative paucity of immunological techniques in ruminants. The most effective way of understanding immune responses to infection is to study the natural host. Cattle and sheep offer an excellent opportunity to do this, and are hosts for economically important diseases, but the lack of knowledge of their immune systems is a major block to strategic vaccine development. Furthermore, these animals may represent better models for developing solutions to human diseases than mice. In this project we aim to develop new techniques to investigate the activation and regulation of the immune systems of cattle and sheep. These techniques will be applied to studies on cells activated under different conditions. This work will facilitate the identification of immunological correlates of protection to many different diseases of cattle and sheep and will also inform on the best ways to deliver new vaccines to maximise their effects. Ultimately this will lead to more strategic approaches to the management and control of infectious diseases of farmed ruminants. This will benefit the agricultural sector and the general public through improved animal welfare, animal production and food security. Furthermore, the work will be done in conjunction with an Industrial Partner, ensuring that the techniques and reagents developed in the project will be made widely available to the research community.

A novel population of CD16++ myeloid cells have been identified in bovine and ovine peripheral blood which are highly pro-inflammatory