A Role for Antibodies to Human Leukocyte Antigens, Collagen-V, and K-α1-Tubulin in Antibody-Mediated Rejection and Cardiac Allograft Vasculopathy

BACKGROUND: We determined the role of donor-specific antibodies (DSA) and antibodies (Abs) to self-antigens, collagen-V (Col-V), and K-α1-Tubulin (KAT) in pathogenesis of acute antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) after human heart transplantation (HTx). METHODS: One hundred thirty-seven HTx recipients, with 60 early period (≤ 12 months) and 77 late period (>12 months), were enrolled in this study. Circulating DSA was determined using LUMINEX. Abs against Col-I, II, IV, V, and KAT were measured using ELISA. Frequency of CD4+T helper cells (CD4+Th) secreting interferon (IFN)-γ, interleukin (IL)-5, -10, or -17 specific to self-antigens were determined using Enzyme Linked Immunosorbent Spot assay. RESULTS: A significant association between AMR and DSA was demonstrated. Development of DSA in AMR patients correlated well with the development of auto-Abs to Col-V (AMR[+]: 383 ± 72 μg/mL, AMR[-]: 172 ± 49 μg/mL, P=0.033) and KAT (AMR[+]: 252 ± 49 μg/mL, AMR[-]: 61 ± 21 μg/mL, P=0.014). Patients who developed AMR demonstrated increased frequencies of CD4+Th secreting IFN-γ and IL-5 with reduction in IL-10 specific for Col-V/KAT. Patients diagnosed with CAV also developed DSA and auto-Abs to Col-V (CAV[+]: 835 ± 142 μg/mL, CAV[-]: 242 ± 68 μg/mL, P=0.025) and KAT (CAV[+]: 768 ± 206 μg/mL, CAV[-]: 196 ± 72 μg/mL, P=0.001) with increased frequencies of CD4+Th secreting IL-17 with reduction in IL-10 specific for Col-V/KAT. CONCLUSIONS.: Development of Abs to human leukocyte antigens and self-antigens are associated with increases in CD4+Th secreting IFN-γ and IL-5 in AMR and IL-17 in CAV, with reduction in CD4+Th secreting IL-10 in both AMR and CAV.