Understanding the function of dendritic cells in the chicken - a species lacking lymph nodes.

The UK poultry industry faces increasing challenges in the 21st century. Many of the drugs used to control diseases in poultry are being withdrawn from use. At the same time, improving welfare standards mean that the industry is becoming more free-range. But the downside is that free-range chickens face higher rates of disease challenge, for example through contact with wild birds. One answer to this problem is to develop novel vaccines. To do this, we need to understand the bird's immunity to disease, so that we can identify ways to control that response. We already know that in birds and mammals the immune response can be divided into two arms - the innate response and the adaptive response. The latter is a very specific response, which hopefully leads to immune 'memory', in other words the ability to respond rapidly to subsequent infections with the same pathogen. This is how vaccination works. The innate immune response is a generalised response that recognises components of a wide range of pathogens, for example, specific types of molecules in a bacterial coat. It serves two roles - it limits infection until the adaptive immune response can kick in, and also provides signals that control the adaptive immune response. The main link between the two responses is a specialised cell type, the dendritic cell or DC. These cells are 'professional antigen presenting cells'. They present 'antigen' (little bits of the pathogen) from pathogens to cells of the adaptive immune response, so they can be recognised as foreign, and provide signals to the same cells to help them respond in the correct way. To date, the function of DC have only been understood for a small number of mammalian species. We are the first people to have been able to grow chicken DC in the lab, and now wish to begin to understand their function. If we can understand how chicken DC work, then we can begin to figure out how we can manipulate them to give better responses to vaccines. We propose to determine how chicken DC respond to different pathogens, how they move around the body from the site of infection to the site of antigen presentation (in other words, to where they talk directly to the cells of the adaptive response), and how they control the cells of the adaptive immune response. From this should come clues as to which molecules are able to influence the function of chicken DC, and therefore which have the potential to act as vaccine adjuvants, in other words to give a stronger response to existing and novel vaccines, to give better protection to the pathogen the vaccine is designed against.

The UK poultry industry faces many challenges to remain sustainable, including moves to more extensive rearing systems; withdrawal of antibiotics and other drugs such as anti-coccidials; resistance and residue problems with anti-helminthics. These will all impact on poultry health, but also the potential to impact on human health. Increased incidence of zoonotic pathogens in chickens, such as avian influenza, could lead to an increase in these diseases in man. One approach to these challenges is to develop novel and more effective vaccines. For this to be a realistic and sustainable approach, we need a better understanding of host-pathogen interactions in chickens. This proposal seeks to build on our unique capability to grow dendritic cells (DC) in a non-mammalian species. DC in mammals are professional antigen presenting cells, providing a link between innate and adaptive immune responses, driving the adaptive response to that necessary to clear infection with a particular pathogen. In mammals, antigen presentation takes place primarily in lymph nodes (LN). The chicken, like most non-mammalian vertebrates, lacks LN but antigen presentation still occurs. This proposal forms part of our efforts to understand antigen presentation in a species lacking LN. This proposal aims to understand DC biology in the chicken in more depth. Firstly, we wish to define the phenotype of DC, both immature DC and those matured in vitro under different conditions, in more depth. In mammals and presumably in the chicken, DC travel to the site of infection, and thence to the site of antigen presentation, under the influence of chemokines. We intend to determine which chemokines have functional effects on chicken DC. Preliminary data suggests that DC can be matured to either a Th1 or TH2 phenotype. We will determine if DC can bias T cells to a Th1 or Th2 phenotype in vitro. We then want to characterise ex vivo-isolated DC, and finally begin to analyse chicken DC migration in vivo.