Graft rejection is classified into hyperacute, acute, and chronic, on the basis of clinical and pathologic features (Fig. 1). This historical classification was devised by clinicians based on rejection of kidney allografts, and it has stood the test of time remarkably well. It also has become apparent that each type of rejection is mediated by a particular type of immune response.

Fig1. Mechanisms and histopathology of graft rejection. A representative histologic appearance of each type of rejection is shown on the right. A, In hyperacute rejection, preformed antibodies react with alloantigens on the vascular endothelium of the graft, activate complement, and trigger rapid intravascular thrombosis and necrosis of the vessel wall. B, In acute rejection, CD8+ T lymphocytes reactive with alloantigens on graft endothelial cells and parenchymal cells or antibodies reactive with endothelial cells cause damage to these cell types. Inflammation of the endothelium is called endothelialitis. The histology shows acute cellular rejection in i and humoral (antibody-mediated) rejection in ii. C, In chronic rejection with graft arteriosclerosis, T cells reactive with graft alloantigens may produce cytokines that induce inflammation and proliferation of intimal smooth muscle cells, leading to luminal occlusion. APC, Antigen-presenting cells.

• Hyperacute rejection occurs within minutes of transplantation and is characterized by thrombosis of graft vessels and ischemic necrosis of the graft. Hyperacute rejection is mediated by circulating antibodies that are specific for antigens on graft endothelial cells and that are present before transplantation. These preformed antibodies may be natural IgM antibodies specific for blood group antigens , or they may be antibodies specific for allogeneic MHC molecules that were induced by previous exposure to allogeneic cells due to blood transfusions, pregnancy, or prior organ transplantation. Almost immediately after trans plantation, the antibodies bind to antigens on the graft vascular endothelium and activate the complement and clotting systems, leading to injury to the endothelium and thrombus formation. Hyperacute rejection is not a common problem in clinical transplantation, because every donor and recipient are matched for blood type and potential recipients are tested for antibodies against the cells of the prospective donor. (The test for antibodies is called a cross-match.) However, hyperacute rejection is a major barrier to xenotransplantation, as discussed later.

 • Acute rejection occurs within days or weeks after transplantation and is the principal cause of early graft failure. Acute rejection is mediated by T cells and antibodies specific for alloantigens in the graft. The T cells may be CD8+ CTLs that directly destroy graft cells or CD4+ cells that secrete cytokines and induce inflammation, which destroys the graft. T cells may also react against cells in graft vessels, leading to vascular damage. Antibodies contribute especially to the vascular com ponent of acute rejection. Antibody-mediated injury to graft vessels is caused mainly by complement activation by the classical pathway. Current immunosuppressive therapy is designed to prevent and reduce acute rejection by blocking the activation of alloreactive T cells.

• Chronic rejection is an indolent form of graft dam age that occurs over months or years, leading to progressive loss of graft function. Chronic rejection may be manifested as fibrosis of the graft and by gradual narrowing of graft blood vessels, called graft arteriosclerosis. In both lesions, the culprits are believed to be T cells that react against graft alloantigens and secrete cytokines, which stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells in the graft. Alloantibodies may also contribute to chronic rejection. Although treatments to prevent or curtail acute rejection have steadily improved, leading to better 1-year survival of transplants, chronic rejection is refractory to most of these therapies and is becoming the principal cause of graft failure.

مواضيع ذات صلة

Induction of Immune Responses Against Transplants

Transplantation Antigens

Glycans and Immunity

Immune Responses Against Transplants

Cancer Immunotherapy : Stimulation of Host Antitumor Immune Responses by Vaccination With Tumor Antigens

Cancer Immunotherapy: Immune Checkpoint Blockade

Cancer Immunotherapy: Adoptive T Cell Therapy

Cancer Immunotherapy: Passive Immunotherapy With Monoclonal Antibodies

Evasion of Immune Responses by Tumors

PROCESS OF PHAGOCYTOSIS

GRANULOCYTIC CELLS

B Cell Epitope Binding Predictions