Title:
Targeting complement at the time of transplantation.

Abstract:
Complement activation occurs in at least two phases when an organ is transplanted into a naive recipient: during reperfusion with recipient blood particularly when the donor organ has undergone a significant period of ischaemia and then during acute rejection once the recipient immune system has recognised the donor tissue as non-self. Both of these reactions are most obvious in the extravascular compartment of the transplanted organ and involve local synthesis of some of the key complement components as well as loss of controls that limit the activation of the pivotal component C3. In contrast, sensitised individuals with pre-existing circulating antibodies have an immediate reaction against the transplant organ that is also complement dependent but is enacted in the intravascular space. All three types of injury (ischaemia-reperfusion, acute rejection, hyperacute rejection) have a critical effect on transplant outcome. Here we discuss therapeutic strategies that are designed to overcome the impact of these factors at the start of transplantation with the aim of improving long-term transplant outcomes. These include the concept of treating the donor organ with modified therapeutic regulators that are engineered to be retained by the donor organ after transplantation and prevent inflammatory injury during the critical early period. By targeting the donor organ with anchored therapeutic proteins, the systemic functions of complement including host defence remain intact. The control of complement activation during the first stages of transplantation, including the possibility that this will reduce the capacity of the graft for stimulating the adaptive immune system, offers an important prospect for increasing the longevity of the transplant and offsetting demand on the limited supply of donor organs. It also provides a model in which the benefits and indications for localised therapy to maximise therapeutic efficiency and minimise the systemic disturbance may be instructive in other complement-related disorders.