- Dr. Julian Pratt, Principal Investigator
- Prof. Steven Sacks, Head of Department
- King's College, University of London, London, UK
- T Cell Costimulation through Complement Receptors in Kidney Transplantation
We propose that complement activated and deposited at the site of tissue injury promotes T cell activation,which can destroy transplanted organs. In this way damaged tissues in the graft could directly present sufficient signals to host T cells even in the absence of other molecules thought to be required to activate T cells. The activation of complement specifically at the site of tissue injury either through the classical or alternative pathway could therefore label the donor organ as damaged. T cells could then respond if they directly engage their specific antigen expressed by the “foreign” tissue of the graft. We hope to identify complement receptors expressed by T cells that can promote T cell activation and T cell responses independently of other pathways, such as CD28. Based on our preliminary data we expect to show that complement can mediate costimulation to T cells in the absence of and equivalent to costimulation through the usual pathways such as CD28. We will test our hypothesis by transplanting kidneys from allogeneic donors into C3-receptor-deficient hosts and hope to show prolongation of graft survival. These experiments will test the involvement of complement receptors in triggering an immune response in graft rejection.
This work could contribute to understand how innate immunity directs T cell responses. We hope to define a mechanism of injury that could assist self/non-self discrimination by adaptive immunity, now thought to be required in order to initiate an immune response. Transplantation activates complement either through ischemia-reperfusion injury or the involvement of immunoglobulins, and we have already shown that it is complement produced by the transplanted kidney itself that is most active in this process. We hope our study will define a new mechanism by which host T cells become activated so that therapeutic options can be investigated in the future.