Figure 1.

Immune response activation during reperfusion and transplantation. Reperfusion can lead endothelial cells to death initiating the immune response. Endogenous ligands are released and recognized by Toll-like receptors (TLRs) on antigen presenting cells (APCs) or endothelial cells. This activation generates inflammatory cytokines enhancing the inflammatory response and activating other cells from the immune system. During reperfusion, complement proteins can also be activated by the decreased expression of complement inhibitors by endothelial cells. This activation can generate the membrane attack complex leading to endothelial cell lysis. Complement activation can also produce chemokines and anaphylatoxins, and together with an increase in adhesion molecules expression, neutrophils migrate to the graft and produce more inflammatory cytokines and reactive oxygen species (ROS), which can contribute to cell death. Natural killer T (NKT) cells contribute to neutrophils activation and to cytokines production. During reperfusion, T cells in the lymph node are somehow activated, amplifying cytokines production and leading to B cells maturation, providing immunoglobulins (Igs) release. Igs can activate complement and act as opsonins, contributing to the whole process of immune response. This activation persists after transplantation, and donor antigens enhance the immune response when they are processed by APCs (donor or recipient) in the graft that migrate to the lymph node and present them to T cells. T cells can proliferate and amplify the response with an increase in cytokines. The activation of all these components contributes to graft rejection by establishing the local inflammation, leading to endothelial cell death, cell proliferation and cell migration. Donor antigen presentation reinforces the whole process and the persistence of the immune response activation in the graft can change the cytokine profile and favors the fibrosis development.