Hyperacute rejection is characterized by thrombotic occlusion of the graft vasculature that begins within minutes to hours after host blood vessels are anastomosed to graft vessels and is mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens (Fig. 16-8A). Binding of antibody to endothelium activates complement, and antibody and complement products together induce a number of changes in the graft endothelium that promote intravascular thrombosis. Complement activation leads to endothelial cell injury and exposure of subendothelial basement membrane proteins that activate platelets. The endothelial cells are stimulated to secrete high-molecular-weight forms of von Willebrand factor that cause platelet adhesion and aggregation. Both endothelial cells and platelets undergo membrane vesiculation, leading to shedding of lipid particles that promote coagulation. Endothelial cells lose the cell surface heparan sulfate proteoglycans that normally interact with antithrombin III to inhibit coagulation. These processes contribute to thrombosis and vascular occlusion (Fig. 16-9A), and the grafted organ suffers irreversible ischemic damage.
In the early days of transplantation, hyperacute rejection was often mediated by preexisting IgM alloantibod-ies, which are present at high titer before transplantation. Such "natural antibodies" are believed to arise in response to carbohydrate antigens expressed by bacteria that normally colonize the intestine. The best known examples of such alloantibodies are those directed against the ABO blood group antigens expressed on red blood cells, discussed later. ABO antigens are also expressed on vascular endothelial cells. Today, hyperacute rejection by anti-ABO antibodies is extremely rare because all donor and recipient pairs are selected so that they have the same ABO type. As we shall discuss later in this chapter, hyper-acute rejection caused by natural antibodies is the major barrier to xenotransplantation and limits the use of animal organs for human transplantation.
Currently, hyperacute rejection of allografts, when it occurs, is usually mediated by IgG antibodies directed against protein alloantigens, such as donor MHC molecules, or against less well defined alloantigens expressed on vascular endothelial cells. Such antibodies generally arise as a result of previous exposure to alloantigens through blood transfusion, previous transplantation, or multiple pregnancies. If the titer of these alloreactive antibodies is low, hyperacute rejection may develop slowly, during several days. In this case, it is sometimes referred to as accelerated allograft rejection because the onset is still earlier than that typical for acute rejection. As we will discuss later in this chapter, patients in need of allografts are routinely screened before grafting for the presence of antibodies that bind to cells of a potential organ donor to avoid hyperacute rejection.
In rare cases in which grafts have to be done in ABO-incompatible recipients, survival may be improved by rigorous depletion of antibodies and B cells. Sometimes, if the graft is not rapidly rejected, it survives even in the presence of anti-graft antibody. One possible mechanism of this resistance to hyperacute rejection is increased expression of complement regulatory proteins on graft endothelial cells, a beneficial adaptation of the tissue that has been called accommodation.
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