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K. survival. == Conclusions == This large-animal study supports the relevance of autoimmunity to CM in the rejection of minor antigen disparate cardiac allotransplants. Keywords:Heart transplantation, Swine, Autoimmunity, Cardiac myosin The transplantation of allogeneic organs triggers a massive inflammatory immune response mediated by recipient T lymphocytes recognizing donor major histocompatibility complex (MHC) molecules. Allorecognition takes place primarily in the recipients secondary lymphoid organs where T cells interact with intact allo-MHC molecules present on donor dendritic cells (direct allorecognition) and with donor MHC peptides processed and presented by recipient antigen presenting cells (indirect allorecognition) (1). In addition, minor histocompatibility antigens, defined as peptides derived from non-MHC donor polymorphic proteins, are presented directly or indirectly, and can induce an alloimmune response (2). The activation of alloreactive CD4+and CD8+T cells triggers a Osthole cascade of events including cytotoxic T-cell differentiation, delayed type hypersensitivity (DTH) reactions, and anti-donor antibody production that lead to the rejection of allografts. On the other hand, the involvement of tissue-specific antigens in anti-graft immunity has long been postulated (3). Although some of these antigens have been identified, little is known regarding their contribution to the rejection of allografts. Recent studies in our laboratory and others have demonstrated that rodents receiving allogeneic heart or lung transplants mount an autoimmune response to graft tissue-specific antigens (46). In a mouse heart transplant model, we have reported that this T-cell response to donor MHC class I molecules is followed by an autoimmune response to cardiac myosin (CM), a contractile protein expressed by cardiomyocytes (4). CM also represents the target autoantigen in experimental autoimmune myocarditis (EAM), a mouse model of autoimmune heart disease (7). These findings suggest that anti-CM immunity may cause damage to the transplanted heart, thereby contributing to its rejection by the host. There Osthole is a report supporting this view that induction of an autoimmune response to CM in mouse Rabbit Polyclonal to TUT1 recipients before transplantation accelerates the rejection of allogeneic heart transplants (4). In this case, the anti-CM autoimmune response was mediated by activated MHC class II-restricted CM-specific CD4+TH1 cells (4). In addition, high titers of IgG1 anti-CM autoantibodies were detected in the serum of transplanted mice (4). Most importantly, tolerance induction to CM and collagen type V has been shown to significantly prolong the survival of heart and lung transplants, respectively (8,9). Finally, several studies have provided evidence suggesting the relevance of CM autoimmunity in clinical cardiac transplantation (1013). Collectively, these studies suggest that secondary immunity to tissue-specific antigens may represent an essential component of allograft rejection. However, the actual relevance of this phenomenon to the rejection of minor antigen-mismatched allografts in a large-animal model remains to be established. In this study, we investigated the influence of CM autoimmunity around the rejection of minor antigen-mismatched cardiac allografts performed in a swine Osthole model. We observed that this induction of an anti-CM response led to the rejection of minor antigen-mismatched cardiac allografts. The implications of these findings for the design of novel diagnostic tools and therapies in transplantation are discussed. == RESULTS == In this study, Osthole we investigated the effect of CM sensitization around the rejection of minor antigen-mismatched cardiac allografts in miniature swine. To address this question, we compared DTH, T-cell proliferation and antibody responses with CM and transplant rejection in swine immunized with CM emulsified in Freunds adjuvant and control nontreated or adjuvant-immunized recipients. None of the five control (nonimmunized or immunized with adjuvant alone) swine (C1C5) acutely rejected its graft, an expected result given the poor immunogenicity of minor antigens (Figs. 1and2). Although histological examination of these grafts at posttransplant day 60, 120, and 180 revealed some inflammatory cell infiltrates, no signs of cardiac allograft vasculopathy were observed (Fig. 1). No DTH response (induration<1 mm) to CM was detected in the control animals (Table 1). In contrast, experimental swine P1, P2, and P3 mounted potent DTH responses to CM (> 10 mm) (Table 1) and rejected their allografts in an acute fashion (grade 3R,Figs. 1and2) (P=0.02). The fourth swine (P4) mounted a poor DTH response after immunization with CM (8 mm) and was diagnosed with a low grade (1R at day 62) acute rejection characterized by focal perivascular or interstitial infiltrate.