APOPTOSIS IN MURINE CARDIAC GRAFTS

Apoptosis, or the induction of programmed cell death, is a mechanism c ommonly used by cytotoxic T cells to cause target cell lysis. We evalu ated the frequency and distribution of apoptotic cells in DBA/2-->DBA/ 2 heterotopic cardiac isografts, acutely rejecting DBA/2-->C57BL/6 car diac allografts, and accepted, 60 day DBA/2-->C57BL/6 allografts from mice treated with anti-CD4 Mab (GK1.5) or gallium nitrate (GN). Apopto sis was identified in histologic sections via TUNEL analysis of nuclea r DNA fragmentation. We observed the following. (1) Cardiac isografts display no detectable TUNEL+ cells. (2) Rejecting cardiac allografts d isplay rare (< 1% of nucleated cells/field), diffuse TUNEL+ cells, pea king on day 3 and declining to 50% of peak by the day of rejection (ap proximately day 10), and TUNEL+ cells were localized to regions of cel lular infiltrate Father than myocyte regions. (3) Accepted cardiac all ografts display relatively high numbers of TUNEL+ cells localized in a nd around the large cardiac arteries (about 20% of nucleated cells/per iarterial field). These arteries often showed evidence of transplant v ascular sclerosis characteristic of chronic allograft rejection. While a few TUNEL+ cells were found in the arterial tissue, most were obser ved in the periarterial cellular infiltrate. Similar frequencies and d istributions of TUNEL+ cells were observed in grafts that were accepte d due to treatment with the anti-CD4 mAb GK 1.5 or gallium nitrate. In general, apoptosis did not correlate with graft failure or parenchyma l cell damage, suggesting that cytotoxic T cell-mediated destruction o f graft tissues is rare in cardiac allografts, While apoptosis does no t appear to be indicative of acute rejection, the characteristic peria rterial clustering of apoptosis in accepted grafts may be indicative o f immunoregulatory processes that maintain graft acceptance or repair processes that promote chronic vascular remodeling.