Apoptosis in Murine Cardiac Grafts1,2,3

Abstract

Apoptosis, or the induction of programmed cell death, is a mechanism commonly used by cytotoxic T cells to cause target cell lysis. We evaluated the frequency and distribution of apoptotic cells in DBA/2-->DBA/2 heterotopic cardiac isografts, acutely rejecting DBA/2-->C57BL/6 cardiac allografts, and accepted, 60 day DBA/2-->C57BL/6 allografts from mice treated with anti-CD4 Mab (GK1.5) or gallium nitrate (GN). Apoptosis was identified in histologic sections via TUNEL analysis of nuclear DNA fragmentation. We observed the following. (1) Cardiac isografts display no detectable TUNEL+ cells. (2) Rejecting cardiac allografts display rare (<1% of nucleated cells/field), diffuse TUNEL+ cells, peaking on day 3 and declining to 50% of peak by the day of rejection (approximately day 10), and TUNEL+ cells were localized to regions of cellular infiltrate rather than myocyte regions. (3) Accepted cardiac allografts display relatively high numbers of TUNEL+ cells localized in and around the large cardiac arteries (about 20% of nucleated cells/periarterial field). These arteries often showed evidence of transplant vascular sclerosis characteristic of chronic allograft rejection. While a few TUNEL+ cells were found in the arterial tissue, most were observed in the periarterial cellular infiltrate. Similar frequencies and distributions of TUNEL+ cells were observed in grafts that were accepted due to treatment with the anti-CD4 mAb GK 1.5 or gallium nitrate. In general, apoptosis did not correlate with graft failure or parenchymal cell damage, suggesting that cytotoxic T cell-mediated destruction of graft tissues is rare in cardiac allografts. While apoptosis does not appear to be indicative of acute rejection, the characteristic periarterial clustering of apoptosis in accepted grafts may be indicative of immunoregulatory processes that maintain graft acceptance or repair processes that promote chronic vascular remodeling.

Immune activation is required for the induction of liver allograft tolerance: Implications for immunosuppressive therapy

“…In murine heart allografts, there was prominent apoptosis of cells in the perivascular infiltrates of recipients that had been treated to prevent acute rejection with anti-CD4 antibody. 68 Similarly, in a model of mouse cardiac allograft tolerance induced with antibody to CD40 ligand plus donor immature dendritic cells, there was increased apoptosis of infiltrating leukocytes and T cells in the recipient lymphoid tissues. 66 Induction of tolerance to murine skin grafts with a combination of antibody to CD40 ligand, CTLA4Ig, and rapamycin was associated with marked increase of apoptosis of alloreactive T cells.…”

Mitochondrial Permeability Transition in Cardiomyocyte Apoptosis during Acute Graft Rejection

“…Apoptosis has also been shown to occur after kidney, liver and heart transplantation (5)(6)(7). Despite important recent findings, the mechanism of cardiomyocyte apoptosis associated with acute cardiac graft rejection remains unclear (8)(9)(10). The involvement of mitochondria in apoptosis has gained increasing interest due to the demonstration that mitochondria can exert a pro-apoptotic effect in in vitro models, and because of the localization of proteins of the Bcl-2 family on the outer membrane of this organelle (11,12).…”

Increased Expression of p53 Protein Correlates With the Extent of Myocyte Damage in Cardiac Allograft Rejection

“…Cells undergoing apoptosis can be distinguished from those undergoing necrosis by several characteristic features, including blebbing of the cell membrane, a reduction in cell volume, and condensation of nuclear chromatin. In animal studies, there is compelling evidence of myocardial apoptosis 1–3 . Some studies have reported myocardial apoptosis in cardiomyopathies or in acute myocardial infarctions in humans 4 .…”