*Purpose: Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) directed against mismatched donor HLA is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non-HLA antibodies has become more prominent as AMR can occur in the absence of circulating DSA.

*Methods: We assessed a single-center cohort of 64 heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients at the time of ≥pAMR1 (n=43) and non-AMR controls (n=21) were tested for reactivity to a panel of 44 non-HLA autoantigens (Immucor. Inc) to identify relevant antigenic targets.

*Results: The AMR group had a significantly greater percentage of patients with positivity (defined as mean fluorescence intensity above threshold) to autoantigens compared to non-AMR (p=0.002) and healthy controls (n=94, p<0.0001). DSA-positive AMR patients exhibited greater reactivity to autoantigens compared to DSA-negative (p<0.0001) and AMR patients with DSA and PRA>10% were identified as the subgroup with significantly elevated responses. Non-HLA autoantibodies did not appear to contribute to DSA-negative AMR. Serum reactivity to four antigens, vimentin (p=0.03), tubulin alpha 1B (p=0.03), lamin A/C (p=0.03) and apolipoprotein L2 (p=0.004), were significantly increased between AMR and non-AMR. Moreover, increased reactivity to these antigens was associated with graft dysfunction due to rejection.

*Conclusions: These results suggest that antibodies to non-HLA are associated with DSA-positive AMR although their specific role in mediating allograft injury is not yet understood.

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