*Purpose: Many kidney allografts fail due to rejections caused by the donor and recipient HLA incompatibility. Recent studies have shown that HLA-DR and DQ mismatches are particularly harmful by inducing donor-specific HLA antibodies and causing antibody-mediated rejection. However, due to the absence of HLA-specific biomarkers, it remains unknown which HLA mismatches contribute the most to the development of T-cell mediated rejection (TCMR). In this study, we aimed to investigate the associations of the different donor-HLA-derived T-cell epitope targets, PIRCHE-II scores, and the occurrence of TCMR after kidney transplantation.

*Methods: Patients who underwent kidney transplantation between 2004-2013 were included in this study (N=926 with 3515 biopsies, both indication and protocol biopsies). These patients and donors were genotyped at the 2^nd field high-resolution HLA level. We used the PIRCHE-II algorithm to calculate the different donor-HLA-derived T-cell epitope scores for all HLA loci.

*Results: The median PIRCHE-II score of our cohort was 311.5 (IQR 205-453), and highest in HLA-DQA₁B₁ molecule (76.5; IQR 7-162). 277 patients (29.9%) developed TCMR and 134 (14.5%) developed only borderline changes on at least one allograft biopsy. In a multivariable analysis adjusted for confounders (Figure 1), the total PIRCHE-II score was independently associated with an increased risk for developing TCMR (per 10, HR=1.007; 95%CI 1.001-1.013; p=0.03), mainly explained by the PIRCHE-II scores for HLA-DRB₁ (HR=1.071; 95%CI 1.028-1.116; p=0.001) and HLA-DQA₁B₁ molecules (HR=1.013; 95%CI 1.002-1.025; p=0.02). The same associations with PIRCHE-II scores for HLA-DRB₁ and DQA₁B₁ were found when borderline changes are counted as TCMR. In a sensitivity analysis restricted to HLA-DSA negative patients, again, only the T-cell epitope targets originating from the donor’s HLA-DRB₁ and HLA-DQA₁B₁ molecules were associated with TCMR. Finally, the same PIRCHE-II scores for HLA-DRB₁ (HR=1.042; 95%CI 1.005-1.081; p=0.02) and HLA-DQA₁B₁ molecules (HR=1.015; 95%CI 1.005-1.026; p=0.0035) were risk factors for all-cause graft failure, independent of HLA-DSA antibodies.

*Conclusions: PIRCHE-II scores for HLA-DRB₁ and HLA-DQA₁B₁ are independent predictors for TCMR development and independent risk factors for all-cause graft failure after kidney transplantation, and could be used for improved risk stratification.

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