Non-HLA Antibodies Impact on C4d staining, Stellate Cell Activation and Fibrosis in Liver Allografts.

Background: Recent data has shown an increased risk for rejection, fibrosis progression, and death in liver transplant (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. Methods: We analyzed 1269 primary LT recipients from 1/2000-4/2009 with known HLA DSA status for Angiotensin II Type-1 Receptor and Endothelin-1 Type A receptor autoantibodies(anti-AT1R-Abs and anti-ETAR-Abs respectively) pre-LT and year-1 post-LT. Results: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death [Hazard Ratio (HR)=1.66; p=0.02] especially if the HLA DSA was of the IgG3 subclass (HR=2.28; p=0.01). A single de novo non-HLA autoantibody was associated with an increased risk for TCMR or AMR rejection(68% vs. 41%, p=0.01) and fibrosis progression (HR=1.84; p=0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared to HLA DSA(71% vs. 3%; p

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