*Purpose: Chronic antibody-mediated rejection (cABMR) caused by de novo donor specific HLA antibodies (DSA) is one of major obstacles to long term graft outcome. ABO incompatible kidney transplantation (ABO-I) has shown favorable graft survival, probably caused by accommodation. In vitro study demonstrated that anti-A/B antibody binding to endothelial cells could upregulate complement regulatory proteins (CD55, CD59) and downregulate HLA-DR expression through inactivation of ERK and mTOR pathway, respectively, exhibiting a protective effect against antibody-mediated injury. We have recently reported a lower production of de novo DR-associated DSA in ABO-I, possibly resulting in a reduced incidence of cABMR. The purpose of this study was to clarify the significance of HLA epitope mismatch analysis and investigate the beneficial effect of ABO incompatibility on de novo DSA production.

*Methods: This retrospective observational cohort study included 691 living donor kidney transplantations (454 ABO-Id/C and 237 ABO-I) with a mean observation period of 67 months. Patients in ABO-I were additionally pretreated with rituximab (RIT, n=168), splenectomy (SPX, n=10) and neither (none, n=59) due to low anti-A/B antibody titers. De novo DSA production was annually examined by LABScreen SAB and the prevalence was analyzed by HLA-DRB1/3/4/5 and DQB epitope mismatch (MM) levels.

*Results: De novo DSA were detected in 101 recipients (14.6%) including class I (n=12), class I+DQ/DR (n=3), DR (n=17), DQ (n=60) and DR+DQ (n=9). Logistic regression analysis revealed that significant factors for de novo DSA were ABO-I (OR=0.589 (0.362-0.957), p=0.326) and epitope MM (DRB and DQB) (OR=1.034 (1.018-1.051), p<0.0001). Epitope MM levels of DRB and DQB were significantly correlated with production of DR and DQ DSA, respectively. 5-year cumulative incidence of de novo DSA in low (0-5), moderate (6-15) and high (16-44) DRB epitope MM levels were 0%, 5.3% and 8.5% in ABO-Id/C, whereas those were 0%, 0% and 4.8% in ABO-I (Table 1). Similarly, ABO-I showed a beneficial effect in moderate (1-5) DQB epitope MM level. ABO-I without rituximab pretreatment or splenectomy also exhibited the favorable results for de novo DSA production. 5-year cumulative incidences of de novo DSA were 6.1% in none, 8.9% in RIT and 10.0% in SPX.

*Conclusions: DRB and DQB epitope MM levels could predict the risk of de novo DSA production. ABO-incompatibility which exhibits a protective effect against de novo DSA production, could increase a safety margin of epitope MM levels to 0-15 (DRB) and 0-5 (DQB), respectively. Potential suppression of de novo DSA-induced cABMR in ABO-I may contribute to favorable graft survival.

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