The role of apoptosis in hepatic graft rejection

In 1965, Kerr described a type of death, apoptosis, with different characteristics from necrosis. Apoptosis has an important role in the development and cell homeostasis. Excessive or insufficient apoptosis contributes to the pathogenesis of pathology like ischemia, neurodegeneration, autoimmunity, viral infection, and tumor growth or regression. Apoptosis is subdivided into four sequential phases: order of death; death of cell; phagocytosis of apoptotic bodies and degradation of apoptotic bodies. Death programs converge on sequential activation of a proteases family, caspases. Some aspects of graft rejection can be interpreted as failure of apoptosis in host immunity cells; sometimes rejection involves induction of apoptosis. Apoptotic-type lesions were found in early vascular occlusions, one of the cause of graft failure. Then, an augmented apoptosis in hepatic graft biopsy can be used like a signal of early vascular occlusion. In hepatic transplantation, apoptosis is followed by a proteolytic cascade, which causes sequential activation of caspases. Synthetic inhibitor of caspases can be used, then, in the prevention and/or treatment of pathologies with implication of apoptosis due to ischemia-reperfusion. These inhibitors are not enough for prevention of hepatic lesions, even if caspases inhibitor can be a strategy for treatment of hepatic graft rejection.     

Local events in graft rejection

It appears that allograft rejections can be considered as a series of cellular and molecular cascades of inflammation triggered by the immune response. In acute rejection, inflammatory changes with a prominent blast cell component dominate. The main result is toxic damage of several parenchymal components, particularly the microvascular endothelium, resulting in necrosis of the parenchyma and loss of the allograft within days after transplantation. In the chronic type of rejection, inflammation also exists, but the major manifestations are different. Adventitial inflammation and perivascular cuffing of leukocytes result in concentric intimal proliferation and atherosclerosis. Very little experimental data exist, at present, on the mechanisms of transplant atherosclerosis and chronic rejection.     

Renal allograft rejection. Possible involvement of antibody-dependent cell-mediated cytotoxicity

We have demonstrated that serum from appropriately sensitized patients can contain IgG antibodies that bind to cultured renal epithelial cells. The presence of such antibodies on the surface of renal cells enables otherwise nonlytic PBMC to lyse these renal cells by an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. Experiments involving cell-sorting and specific complement-mediated lysis showed that the ADCC effector cells were of the CD3 -ve, C16 +ve phenotype characteristic of NK cells. In this report it is argued that an ADCC mechanism may be of importance in mediating chronic renal cell damage in the absence of acute allograft rejection.     

Renal graft irradiation in acute rejection

To evaluate the effect of graft irradiation in the treatment of acute rejection of renal transplants, a randomized study was conducted from 1978 to 1981. Patients with acute rejection were given standard medical management in the form of intravenous methylprednisolone, and were chosen randomly to receive either graft irradiation (175 rads every other day, to a total of 525 rads) or simulated (sham) irradiation. Eighty-three rejections occurring in 64 grafts were randomized to the protocol. Rejection reversal was recorded in 84.5% of control grafts and 75% of the irradiated grafts. Recurrent rejections were more frequent and graft survival was significantly lower in the irradiated group (22%) than in the control group (54%). Graft irradiation does not appear to be beneficial in the treatment of acute rejection of renal transplants when used in conjunction with high-dose steroids.     

Molecular phenotypes of kidney graft rejection

In the last decade, gene expression studies of kidney transplants provided an opportunity to better understand the development and regulation of kidney graft rejection. This review outlines the progress in the definition of biomarkers of rejection and, above all, concentrates on studies of the molecular phenotype of rejection. This phenotype, rather than morphological characterization, may be critical for assessing the ongoing processes in the graft and for the outcome prediction.