Transplant-associated autoimmunity to cardiac myosin after cardiac transplantation in non-human primates (145.29)

Abstract

Abstract Background: Immune responses to autoantigens have recently been described in rodent and human allograft recipients. Here we report that immunity to cardiac myosin (CM), a heart-specific autoantigen, develops after transplantation in primates. Methods: Cynomolgus monkeys received a heart allograft and either: 1) transient CD28 blockade (aCD28), where delayed acute rejection (AR) occurs ≤35 days; 2) cyclosporine A (CsA), where chronic rejection (CAV) occurs ≤90 days; or 3) CsA plus B-cell depletion (CsA+ Rituximab). Antibodies against CM were assayed by ELISA at the time of graft rejection, or graft removal at day 90. Results: AR was consistently associated with increased CM IgM and/or IgG levels (6/6). CsA was associated with moderate to severe CAV and CM Abs were detected in 83% (5/6). When AR and CAV were prevented with B-cell depletion, CM Abs were not detected. Immunity to CM correlated with anti-donor antibody and intra-graft C4d. Conclusion: Detection of humoral immunity to cardiac myosin is closely associated with acute and chronic rejection of cardiac allografts, but not when CAV is prevented. We conclude that antibody against CM may serve as a biological marker for cardiac allograft injury. Whether loss of immunoregulation (tolerance) to the autologous CM protein is an epiphenomenon or pathogenic remains to be determined. If immunity against CM contributes significantly to allograft injury, inducing robust tolerance to CM may help attenuate heart allograft injury.