To summarize the current knowledge regarding mechanisms linking the complement system to transplant injury, highlighting findings reported since 2013.
Building upon the documentation that complement activation is a pathogenic mediator of posttransplant ischemia-reperfusion injury, emerging evidence from animal models indicates that blocking either the classical or lectin pathways attenuates ischemia-reperfusion injury. Immune cell-derived and locally activated complement, including intracellular C3, positively modulates alloreactive T-cell activation and expansion, whereby simultaneously inhibiting regulatory T-cell induction and function, and together promoting transplant rejection. Although alloantibody-initiated complement activation directly injures target cells, complement-dependent signals activate endothelial cells to facilitate T-cell-dependent inflammation. Complement activation within allografts contributes to progressive chronic injury and fibrosis.
The complement cascade, traditionally considered to be relevant to transplantation only as an effector mechanism of antibody-initiated allograft injury, is now understood to damage the allograft through multiple mechanisms. Complement activation promotes posttransplant ischemia-reperfusion injury, formation and function of alloantibody, differentiation and function of alloreactive T cells, and contributes to chronic progressive allograft failure. The recognition that complement affects transplant injury at many levels provides a foundation for targeting complement as a therapy to prolong transplant survival and improve patient health.
Department of Medicine, Translational Transplant Research Center, Recanati Miller Transplant Institute and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Correspondence to Peter S. Heeger, MD, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1243, NY, NY 10029, USA. Tel: +1 212 241 6324; fax: +1 212 987 0389; e-mail: firstname.lastname@example.org