Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy

BACKGROUND: Herein we study the role of donor-specific antibodies (DSA) to mismatched human leukocyte antigen (HLA) and antibodies (Abs) to the cardiac self-antigens myosin (MYO) and vimentin (VIM) in the pathogenesis of acute antibody-mediated rejection (AMR) in the early post-transplant period (EP, <12 months) and cardiac allograft vasculopathy (CAV) in the late post-transplant period (LP, >12 months) after heart transplantation (HTx). METHODS: One hundred forty-eight HTx recipients (65 in EP, 83 in LP) were enrolled in the study: Development of DSA was determined by Luminex. Circulating Abs against MYO and VIM in sera were measured using enzyme-linked immunoassay (ELISA). Frequency of CD4(+) T-helper cells (CD4(+) Th) secreting interferon (IFN)-gamma, interleukin (IL,)-17, IL-10 or IL-5 specific to either MYO or VIM were analyzed in vitro using ELISpot assays. RESULTS: AMR patients were more likely DSA positive (AMR(-): 15%; AMR(+): 70%; p = 0.03) and demonstrated increased Abs to MYO (AMR(-): 144 +/- 115 mu g/ml; AMR(+): 285 +/- 70 mu g/ml; p = 0.033) and VIM (AMR(-): 37 +/- 19 mu g/ml; AMR(+): 103 +/- 43 mu g/ml; p = 0.014). AMR patients demonstrated increased IL-5 CD4(+) Th cells specific to MYO (5.2 +/- 0.9 fold, p = 0.003) and VIM (7.3 +/- 2.9-fold, p = 0.004) and decreased IL-10 CD4(+) Th cells specific to MYO (2.2 +/- 0.4-fold, p = 0.009) and VIM (1.7 +/- 0.2-fold, p = 0.03). CAV patients were more likely DSA positive (CAV(-): 25%; CAV(+): 79%; p = 0.03) and demonstrated increased Abs to MYO (CAV(-): 191 +/- 120 mu g/ml; CAV(+): 550 +/- 98 mu g/ml; p = 0.025) and VIM (CAV(-): 55 +/- 25 mu g/ml; CAV(+): 255 +/- 49 mu g/ml; p = 0.001). CAV patients demonstrated increased IL-17 CD4(+) Th cells specific to MYO (10.5 +/- 7.3-fold, p = 0.002) and VIM (7.0 +/- 3.9-fold, p = 0.003). CONCLUSIONS: The presence of DSA in AMR and CAV is significantly associated with development of Abs to MYO and VIM in post-HTx patients. Induction of high CD4(+) Th cells specific to cardiac self-antigens that secrete predominantly IL-5 and IL-17 plays a significant role in the development of Abs to self-antigens leading to AMR and CAV, respectively. J Heart Lung Transplant 2010;29:1277-85 (C) 2010 International Society for Heart and Lung Transplantation. All rights reserved.