Integration of complement and leukocytes in response to allotransplantation

Beginning with ischemia-reperfusion injury and extending through acute and chronic rejection, complement can be activated by acute phase proteins, mannose binding lectin, and alloantibodies. Vascular endothelial and smooth muscle cells, macrophages, T cells, and B cells are stimulated through specific receptors for split products of the early complement components to produce proinflammatory cytokines and chemokines. Deposition of sublytic amounts of the terminal components of complement C5b-C9 has extensive effects on arterial tissues. These include the release of large molecular weight von Willebrand factor from endothelial cells and platelets in the high-shear environment of large vessels. Smooth muscle cell proliferation and remodeling of the extracellular matrix are also stimulated by deposition of C5b-C9. Arterial injury can be expanded by macrophages and vascular smooth muscle cells producing complement and cytokines in autocrine and paracrine feedback loops. As a result of these stimulatory mechanisms on leukocytes and parenchymal cells, complement activation can initiate and perpetuate transplant injury.