Pre-existing graft-reactive antibodies in patient sera have long been associated with rejection and graft loss. While most studies have focused on characterizing HLA-specific abs, the contribution of non-HLA-reactive abs has been largely overlooked (with the exception of ABO blood group reactivity). Recently, we characterized polyreactive monoclonal abs derived from kidney graft recipients amidst rejection. These abs react to a broad range of common self-antigens as well as HLA for some of them. Their one constant, however, was a capacity to bind to apoptotic cells (AC). Here we assessed the presence of such abs reactive to AC in pre-transplant patient sera and examined their contribution to graft outcomes. Pre-transplant sera from 301 patients along with sera from 20 healthy subjects were used in this study. IgG reactivity to HLA was assessed by Luminex. IgG and IgM reactivity to generic AC was measured by flow cytometry. Overall, serum IgG reactivity to AC was significantly higher in pre-transplant patients compared to healthy subjects (p=0.0269). In contrast, IgM reactivity to AC showed no significant different between populations. IgG reactivity to AC also correlated with reactivity to HLA class I or class II >1000 (p=0.0003, p<0.0001), whereas, there was no correlation between IgM reactivity to AC and serum IgG reactivity to HLA. IgG purified from patient serum with high reactivity to AC had the capacity to activate the classical complement pathway, resulting in C4d deposition on target AC. Further analyses revealed that the IgG1 and IgG3 comprised most of the IgG reactivity to AC. Lastly, pre-transplant IgG reactivity to AC was significantly increased in patients who experienced graft loss(p=0.0267) In conclusion, we show here a strong correlation between pre-transplant serum IgG reactivity to AC and reactivity to HLA class I and class II. Based on our previous studies, we propose that this reactivity results in part from polyreactive antibodies that cross-react to HLA and AC. Additionally, the correlation between high serum reactivity to AC pre-transplant and graft loss suggest that these antibodies may be pathogenic. Overall, our findings support the view that antibodies cross-reactive to AC contribute to “pre-sensitization” in patients on the kidney transplant waiting list.

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