Prolonged survival of heart allografts from p53-deficient mice

Background. Acute rejection of the heart allograft is the major cause of he art failure in the first month after transplantation. Most studies on the p revention of acute rejection have concentrated on immune suppression of the recipients, whereas little is known about the effects of genetically manip ulated donor organs on heart allograft survival. Herein, we describe a mous e model of heart allografts donated by p53-/- mice that can prolong the sur vival time of the grafts. Methods. Hearts of p53-/- or p53+/+ C57BL/6J mice were grafted to the neck carotid artery and jugular vein of BALB/c mice using a cuff technique. The graft survival was observed daily. The hearts were analyzed using several t echniques, including histology, immunofluorescence, terminal deoxynucleotid yl transferase-mediated dUTP-biotin nick end labeling (TUNEL), and Western blot analysis. Results. p53+/+ allografts ceased beating at 7.6+/-0.5 days, whereas p53-/- hearts were beating at 10.5+/-1.1 days after transplantation (P<0.01). Mea n histological rejection scores were significantly lower in allografts dona ted by p53-deficient mice. Furthermore, apoptotic cells, determined by TUNE L and a reagent kit for detection of cardiac apoptosis, were of high number s in the allograft sections from wild-type hearts but rare in p53-/- allogr afts (4.2+/-1.3 vs. 0.7+/-0.5/250x field). Immunofluorescence staining and Western blot analysis revealed that high levels of p53 and proapoptotic pro tein Bax were expressed in wild-type grafts but not p53-/- allografts, Inte restingly, Bcl-2, an antiapoptotic protein, was abundant in cardiac allogra fts from p53-/- mice and almost undetectable in grafts from wild-type mice. Conclusions. Thus, p53 is involved in cardiac apoptosis induced by alloimmu ne reaction, and prolonged survival of heart allografts can be achieved whe n p53 is lacking.