- Dr. Alexandra F. Sharland, Principal Investigator
- Dr. Dale Christiansen, Co-Investigator
- Dr. Mark Gorrell, Co-Investigator
- Dr. Peter MacDonald, Research Associate
- Dr. Peter Tran, Research Associate
- University of Sydney, Sydney, Australia
- Pig Molecules which Activate Human Lymphocytes
Transplantation is a life-saving treatment for patients with organ failure. However, access to this treatment is steadily declining. Availability of donor organs is expected to worsen as the incidence of organ failure due to conditions such as diabetes and hepatitis C increases sharply over the next two decades. Pig to human xenotransplantation holds great promise as a means of alleviating this critical shortage, but its successful implementation poses many challenges. Hyperacute rejection results from binding of naturally occurring antibodies to carbohydrate molecules on the surface of pig cells. Initial results suggest that organs transplanted from genetically modified pigs lacking these carbohydrates are not subject to hyperacute rejection, and survive longer than any previous pig to human grafts. Whilst these reports are very encouraging, the genetic modification does not prevent the vigorous human anti-pig cellular immune response, and the gains in graft survival were achieved in the context of very significant immunosuppression, which remains a barrier to clinical applicability. Increasing our understanding of the function of NK cells and other components of the cellular response is now essential if progress towards ultimate clinical xenotransplantation is to continue.
NKG2D is an activating receptor, found on NK cells, T cells and macrophages (cells responsible for graft rejection). Activation through this receptor leads to target cell killing, and secretion of substances which can directly damage the graft. Some types of pig cells have surface molecules (ligands) which can bind to the human NKG2D receptor, and expression of these ligands can be induced in pig kidneys during transplantation. Interactions between pig ligands and the human NKG2D receptor are potentially of central importance in initiating and maintaining the human anti-pig cellular immune response, and are thus targets for therapeutic intervention. Understanding more about the ligands and their binding to human NKG2D is now imperative, and will allow us to determine the most appropriate strategy for preventing/blocking these interactions. In this project, we will examine expression of the ligands in normal and transplanted pig tissues, measure ligand-receptor binding and evaluate the ability of these ligands to activate human NK cells in vitro.