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, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. 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 immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the alpha(1) domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time = 5.5 +/-1.7 vs. 54.7 +/-3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.
The Transplantation Biology Research Center and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
R S
RS
Lee
K
K
Yamada
S L
SL
Houser
K L
KL
Womer
M E
ME
Maloney
H S
HS
Rose
M H
MH
Sayegh
J C
JC
Madsen
D000818:Animals; D003324:Coronary Artery Disease / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007518:Isoantibodies / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D013556:Swine, Miniature; D014184:Transplantation, Homologous / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies; D007519:Isoantigens; D010455:Peptides; D016753:Interleukin-10; D007371:Interferon-gamma