Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy

Graft loss from chronic rejection has become the major obstacle to the long -term success of whole organ transplantation. In cardiac allografts, chroni c rejection is manifested as a diffuse and accelerated form of arterioscler osis, termed cardiac allograft vasculopathy. It has been suggested that T-c ell recognition of processed alloantigens (allopeptides) presented by recip ient antigen-presenting cells through the indirect pathway of allorecogniti on plays a critical role in the development and progression of chronic reje ction. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunize d MHC inbred miniature swine with synthetic polymorphic peptides spanning t he alpha (1) domain of an allogeneic donor-derived swine leukocyte antigen class I gene, Pigs immunized with swine leukocyte antigen class I allopepti des showed in vitro proliferative responses and in vivo delayed-type hypers ensitivity responses to the allogeneic peptides. Donor MHC class I disparat e hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean s urvival time = 5.5 +/- 1.7 vs. 54.7 +/- 3,8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earl ier than unimmunized controls (<9 vs. >30 days), These results definitively link indirect allorecognition and cardiac allograft vasculopathy.