The frequency of T cells that can recognize the foreign antigens in a graft is much higher than the frequency of T cells specific for any microbe. For this reason, immune responses to allografts are stronger than responses to pathogens. Predictably, these strong reactions can destroy grafts rapidly, and their control requires powerful immunosuppressive agents.
Mechanisms of Graft Rejection
Graft rejection is classified into hyperacute, acute, and chronic, on the basis of clinical and pathologic features. This classification was devised by nephrologists and pathologists based on rejection of kidney allografts, and has stood the test of time remarkably well. Each type of rejection is mediated by a particular kind of immune response. In the following discussion, the description of the morphology of rejection is limited to kidney allografts, but similar changes are seen in other organ transplants.
• Hyperacute rejection is mediated by preformed antibodies specific for antigens on graft endothelial cells. The preformed antibodies may be natural IgM antibodies specific for blood group antigens, or may be antibodies specific for allogeneic MHC molecules that were induced by prior exposure through blood transfusions, pregnancy, or organ transplantation. Immediately after the graft is implanted and blood flow is restored, the antibodies bind to antigens on the graft http://ebooksmedicine.net
Blood vessel Endothelial cell Circulating alloantigen-specific antibody Complement activation, endothelial damage, inflammation and thrombosis Alloantigen (e.g., blood group antigen)
Fig. 5.31 Hyperacuterejection.(A)Depositionofantibodyonendotheliumandactivationofcomplementcausesthrombosis.(B)Hyperacuterejectionofakidneyallograftshowingplateletfibrinthrombiandsevereischemicinjuryinaglomerulus.
endothelium and activate the complement and clotting systems, leading to endothelial injury, thrombus for mation, and ischemic necrosis of the graft (Fig. 5.31A ). Hyperacute rejection is not a common problem, because every donor and recipient are matched for blood type and potential recipients are tested for antibodies against the cells of the prospective donor, a test called a cross-match.
MORPHOLOGYInhyperacuterejection,theaffectedkidneyrapidlybecomescyanotic,mottled,andanuric.Virtuallyallarteriolesandarteriesexhibitacutefibrinoidnecrosisoftheirwallsandnarrowingorcompleteocclusionoftheirlumensbythrombi(
Fig.5.31B ).Neutrophilsrapidlyaccumulatewithinarterioles,glomeruli,andperitubularcapillaries.Asthesechangesintensifyandbecomediffuse,theglomerularcapillariesalsoundergothromboticocclusion,andeventuallythekidneycortexundergoesoutrightnecrosis(infarction).Affectedkidneysarenonfunctionalandhavetoberemoved.
• Acute rejection is mediated by T cells and antibodies that are activated by alloantigens in the graft. It occurs within days or weeks after transplantation, and is the principal cause of early graft failure. It also may appear suddenly months or even years later, after immunosuppression is tapered or terminated. Based on the role of T cells or antibodies, acute rejection is divided into two types, although in most rejecting grafts, both patterns are present.
In acute cellular rejection, CD8+ CTLs may directly destroy graft cells, or CD4+ cells secrete cytokines and induce inflammation, which damages the graft (
Fig.
5.32A ). T cells also may react against graft vessels, leading to vascular damage. Current immunosuppressive therapy is designed mainly to prevent and reduce acute rejection by blocking the activation of alloreactive T cells.