Functional and phenotypic profiles of HLA-specific antibodies in relation to antibody-mediated kidney transplant rejection

Donor Specific Antibodies (DSAs) are associated with a higher risk of Antibody Mediated Rejection (AMR). However, not all DSAs are pathogenic, and patients that raise DSAs have a wide spectrum of outcomes ranging from the complete absence of graft injury to severe AMR. Hence, characterization of both the qualitative features and titer of DSAs has the potential to predict AMR risk and treatment outcome for sensitized patients. Here, using HLA-A2+ cell-based assays, we investigate the qualitative features of immunoglobulin G (IgG) alloantibodies including Fc receptor binding properties and Fc-mediated effector function over time. Compared to seronegative controls, reactive antibodies in seropositive participants were predominantly IgG1, and exhibited elevated levels of binding to the receptors involved in Antibody Dependent Cellular Phagocytosis (ADCP) and Antibody Dependent Cellular Cytotoxicity (ADCC) activity. Further analysis of seropositive individuals revealed that these activities were predictive of AMR status. Collectively, these results suggest a role for phagocytic and cytotoxic antibody effector functions of DSA in contributing to graft injury.