The complement system plays a crucial role in both the innate and adaptive immune system. In the setting of transplantation, complement system activation and subsequent generation of complement split-products have been implicated in various clinical processes such as ischemia/reperfusion injury, delayed graft function, acute antibody-mediated rejection, and chronic antibody-mediated rejection. Therapeutically, complement inhibitors prevent antibody-mediated injury—including the direct effect of donor-specific antibodies—and exert broad inhibitory effects on a number of immune cell types. Furthermore, there has been a growing interest in targeting the complement system in the field of xenotransplantation, whether by direct inhibition, or by up-regulation of complement regulatory pathways. Therefore, complement inhibition has an important role in protecting transplanted organs and prolonging graft survival, both in xeno- and allotransplantation.
Several complement inhibitors have been tested in kidney transplant recipients with mixed outcomes, depending on indication and disease severity. With the increased specificity of new agents targeting each step of complement cascade, there is a need to robustly examine the impact of these drugs in the context of transplantation.
We will review current and novel anti-complement strategies in the transplant setting, including deceased donor-directed therapies, prevention of delayed graft function and ischemia/reperfusion injury, and prevention of T-cell and antibody-mediated rejection, particularly in highly sensitized patients. We will also explore the effects of systemic and local complement synthesis and inhibition, long-term effects of complement inhibition on alloimmune compartments, and other therapeutic applications such as improvement of normothermic perfusion and reduction of innate activation in deceased donors.
The complement system plays a crucial role in both the innate and adaptive immune system. In the setting of transplantation, complement system activation and subsequent generation of complement split-products have been implicated in various clinical processes such as ischemia/reperfusion injury, delayed graft function, acute antibody-mediated rejection, and chronic antibody-mediated rejection. Therapeutically, complement inhibitors prevent antibody-mediated injury—including the direct effect of donor-specific antibodies—and exert broad inhibitory effects on a number of immune cell types. Furthermore, there has been a growing interest in targeting the complement system in the field of xenotransplantation, whether by direct inhibition, or by up-regulation of complement regulatory pathways. Therefore, complement inhibition has an important role in protecting transplanted organs and prolonging graft survival, both in xeno- and allotransplantation.
Several complement inhibitors have been tested in kidney transplant recipients with mixed outcomes, depending on indication and disease severity. With the increased specificity of new agents targeting each step of complement cascade, there is a need to robustly examine the impact of these drugs in the context of transplantation.
We will review current and novel anti-complement strategies in the transplant setting, including deceased donor-directed therapies, prevention of delayed graft function and ischemia/reperfusion injury, and prevention of T-cell and antibody-mediated rejection, particularly in highly sensitized patients. We will also explore the effects of systemic and local complement synthesis and inhibition, long-term effects of complement inhibition on alloimmune compartments, and other therapeutic applications such as improvement of normothermic perfusion and reduction of innate activation in deceased donors.
