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Sustained apoptosis in human cardiac allografts despite histologic resolution of rejection1

Masri, Sofia C.2; Yamani, Mohamad H.3; Russell, Mary A.2; Ratliff, Norman B.4; Yang, Jiacheng2; Almasan, Alex5; Apperson-Hansen, Carolyn6; Li, Jianbo6; Starling, Randall C.3; McCarthy, Patrick7 8; Young, James B.3 8; Bond, Meredith2 9

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Background. We investigated the occurrence of apoptosis during and after resolution of cardiac allograft rejection. Apoptosis could play different roles in graft survival depending on the target cells; thus, we also determined the cell types involved.

Methods. Endomyocardial biopsy specimens were evaluated during the first 6 months after transplantation as follows: group I, no current or prior rejection; group II, during an episode of moderate rejection; and group III, histologic resolution after an episode of moderate rejection.

Results. Groups II and III showed significantly increased apoptotic activity, indicated by increased caspase-8 and caspase-3 activity; however, activated caspase-3 was undetectable in group I. Activated caspase-3 was detected only in groups II and III. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling was detected in groups II and III but not group I and predominantly in inflammatory cells.

Conclusions. Increased caspase activity and apoptosis of infiltrating cells not only occurs during acute cardiac allograft rejection but persists after histologic resolution. Thus, programmed cell death occurs beyond the period of histologic resolution and may play a role in regulation of the rejection process.

Apoptosis occurs during acute cardiac allograft rejection; however, the question of whether apoptosis is resolved during resolution of the rejection episode is unknown. Furthermore, the major cell type undergoing apoptosis is controversial. Depending on the target cells, apoptosis could play different roles in graft survival (1,2). Some studies show a direct correlation between increased cardiomyocyte apoptosis and grade of rejection (3,4), suggesting that apoptosis of the cardiac myocytes contributes to allograft damage and dysfunction, whereas other studies did not show evidence of apoptosis in cardiomyocytes, even in regions of cardiomyocyte damage but instead report most terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells among leukocyte infiltrates (5,6). Apoptosis of T lymphocytes could thus be a mechanism to decrease an ongoing immune response. In fact, some immunosuppressive drugs currently used in clinical transplantation such as steroids act, in part, through induction of apoptosis in infiltrating lymphocytes (7,8), suggesting another mechanism of increased programmed cell death in cardiac allografts.

The changes associated with apoptosis are attributable to actions of caspases that play a key role in the regulation and execution of apoptotic cell death (9,10). One of the apoptotic signals is mediated by interaction of Fas ligand with Fas receptor-expressing cells, leading to activation of caspase-8, which then activates downstream effectors such as caspase-3, and leads to the morphologic and biochemical features of apoptosis (10–12). In cardiac transplant rejection, activation of T cells induces expression of Fas ligand (13,14) and is paralleled by increased expression of inducible nitric oxide synthase (2,4).

We performed a comprehensive evaluation of apoptotic activity in human cardiac biopsy specimens. We studied biopsy specimens from allografts with no history of rejection, during an episode of moderate rejection, and after resolution of cellular infiltrates. Our results indicate that the major cells undergoing apoptosis are inflammatory cells and that apoptosis persists despite histologic resolution of the rejection episode. The prolonged elevation of caspase activity and TUNEL-positive staining after the rejection episode is resolved suggests that rejection may be controlled by apoptosis of inflammatory infiltrates.

© 2003 Lippincott Williams & Wilkins, Inc.