Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy

Abstract

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 ␣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.

Predominant expression of the Th2 response in chronic cardiac allograft rejection

“…These immunosuppressive agents, however, are inadequate for averting late graft loss caused by chronic rejection. There is increasing evidence that indirect allo-recognition plays a critical role in chronic rejection [6,23,421. However, the types of alloreactive responses generated by this pathway that precipitate chronic rejection are not well characterized.…”

“…Similar data were reported by Vella et al [42] in kidney allograft recipients experiencing chronic rejection. Direct experimental data for the role of indirect recognition in chronic allograft rejection were recently provided by Lee et al [23], who demonstrated that pre-immunization of pigs with donor class-I allopeptides promoted the development of chronic cardiac allograft rejection.…”

MHC Alloantigens Elicit Secondary, But Not Primary, Indirect In Vitro Proliferative Responses

“…The contribution of the indirect pathway to allorecognition and to both acute (6) and chronic (7,8) forms of allograft rejection has also been validated by numerous studies. One pertinent example is that of Auchincloss et al (9), who reported the rapid rejection of skin allografts derived from MHC class II-knockout mice, thereby demonstrating that indirect recognition alone can be an effective pathway of alloreactivity in this small animal model.…”

Antigen Location Contributes to the Pathological Features of a Transplanted Heart Graft

“…19,20,31,[35][36][37] The complexity of such transplant-reactive immune repertoires has limited our ability to independently test whether antigen location in the target organ affects the downstream pathological consequences. In an effort to circumvent this limitation, we performed a series of experiments using a CD4 T cell receptor (TCR) transgenic mouse as transplant recipients such that we could control the specificity of the induced effector T cells.…”