De novo autoimmunity to cardiac myosin after heart transplantation and itscontribution to the rejection process

Allograft rejection is initiated by an immune response to donor MHC protein s. We recently reported that this response can result in breakdown of immun e tolerance to a recipient self Ag, However, the contribution of this autoi mmune response to graft rejection has yet to be determined. Here, we found that after mouse allogeneic heart transplantation, de novo CD4(+) T cell an d B cell autoimmune response to cardiac myosin (CM), a major contractile pr otein of cardiac muscle, is elicited in recipients. Importantly, CM is the autoantigen that causes autoimmune myocarditis, a heart autoimmune disease whose histopathological features resemble those observed in rejected cardia c transplants. Furthermore, T cell responses directed to CM peptide myhc(al pha) 334-352, a known myocarditogenic determinant, were detected in heart-t ransplanted mice. No responses to CM were observed in mice that had receive d an allogeneic skin graft or a syngeneic heart transplant, demonstrating t hat this response is tissue specific and that allogeneic response is necess ary to break tolerance to CM, Next, we showed that sensitization of recipie nt mice with CM markedly accelerates the rejection of allogeneic heart. The refore, posttransplant autoimmune response to CM is relevant to the rejecti on process. We conclude that transplantation-induced autoimmune response to CM represents a new mechanism that may play a significant role in cardiac transplant rejection.