TUMOR NECROSIS FACTOR-β IS ASSOCIATED WITH THYMIC APOPTOSIS DURING ACUTE REJECTION

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Abstract

Background.

Intrathymic events undergoing allograft rejection remain undefined. The present study investigated the role of tumor necrosis factor-β on acute thymic involution in rat hepatic allograft recipients during rejection.

Methods.

Apoptosis and cellular phenotypic changes in the thymus were studied after hepatic transplantation.

Results.

Thymocytes in both the medulla and cortext were sparse during acute rejection. Phenotypically, CD4+CD8+ T cells decreased significantly, whereas there were relative increases in CD4-CD8-, CD4+CD8-, and CD4-CD8+ T cells in untreated allograft recipients. Additionally, thymic apoptosis was found by in situ DNA end labeling and electron microscopy. Apoptotic cells were predominantly distributed in the cortex. Biologic lymphotoxin (tumor necrosis factor-β)/tumor necrosis factor-α cytotoxic activity in the serum was significantly increased in untreated hepatic allograft recipients. Tumor necrosis factor-β mRNA was detected in untreated allograft livers, and intraperitoneal administration of recombinant human tumor necrosis factor-β induced extensive apoptosis of thymocytes in vivo. In contrast, no significant thymic involution was observed in donor-specific blood transfusion-treated allograft and isograft recipients Intraperitoneal administration of rabbit anti-human tumor necrosis factor-β polyclonal antibody or recombinant human interleukin-10 inhibited thymic apoptosis in untreated hepatic allograft recipients.

Conclusions.

Allograft rejection, but not donor-specific transfusion-induced immunologic unresponsiveness, is associated with thymic involution, a process that may be mediated by tumor necrosis factor-β.

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