Association of Predicted HLA T-Cell Epitope Targets and T-Cell–Mediated Rejection After Kidney Transplantation

ABSTRACT

Rationale and objective

The relationship between HLA molecular mismatches and T-cell mediated rejection (TCMR) is unknown. We investigated the associations between the different donor-HLA-derived T-cell targets and the occurrence of TCMR and borderline histologic changes suggestive of TCMR after kidney transplantation.

Study design

Retrospective cohort study.

Setting and participants

All kidney transplant recipients (N=893) between 2004-2013 with available biopsy data and a DNA sample for high-resolution HLA donor/recipient typing.

Exposure

PIRCHE-II scores and HLA-eplet mismatches.

Outcomes

TCMR, borderline changes suggestive of TCMR, and allograft failure.

Analytical approach

Multivariable cause-specific hazards models were fit to characterize the association between HLA epitopes targets and study outcomes.

Results

277 patients developed TCMR and 134 developed only borderline changes suggestive of TCMR on at least one biopsy. In multivariable analyses, only the PIRCHE-II scores for HLA-DRB1 and HLA-DQB1 were independently associated with the occurrence of TCMR and with allograft failure; this was not the case for HLA class I molecules. If restricted to rejection episodes within the first 3 months after transplantation, only the T-cell epitope targets originating from the donor's HLA-DRB₁ and HLA-DQB₁, but not class I molecules, were associated with the early acute TCMR. Also, the median number of PIRCHE-II scores for HLA class II was statistically different between the patients with TCMR compared to the patients without TCMR (129, IQR=60-240; vs. 201, IQR=96-298; p<0.0001, respectively). These differences were not observed for class I PIRCHE-II scores.

Limitations

Observational clinical data and residual confounding.

Conclusions

In the absence of HLA-DSA, HLA class II but not class I mismatches were associated with early episodes of acute TCMR and allograft failure. This suggests that current immunosuppressive therapies are largely able to abort the most deleterious HLA class I-directed alloimmune processes, however alloresponses against HLA-DRB₁ and HLA-DQB₁ molecular mismatches remain insufficiently suppressed.