PMID- 35690154 OWN - NLM STAT- MEDLINE DCOM- 20221123 LR - 20230131 IS - 1523-6838 (Electronic) IS - 0272-6386 (Linking) VI - 80 IP - 6 DP - 2022 Dec TI - Association of Predicted HLA T-Cell Epitope Targets and T-Cell-Mediated Rejection After Kidney Transplantation. PG - 718-729.e1 LID - S0272-6386(22)00708-9 [pii] LID - 10.1053/j.ajkd.2022.04.009 [doi] AB - RATIONALE & OBJECTIVE: The relationship between human leukocyte antigen (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 & PARTICIPANTS: All kidney transplant recipients at a single center between 2004 and 2013 with available biopsy data and a DNA sample for high-resolution HLA donor/recipient typing (N = 893). EXPOSURE: Scores calculated by the HLA matching algorithm PIRCHE-II and HLA eplet mismatches. OUTCOME: 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: We found 277 patients developed TCMR, and 134 developed only borderline changes suggestive of TCMR on at least 1 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 PIRCHE-II score 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], respectively; P < 0.0001). 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 are 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. PLAIN-LANGUAGE SUMMARY: Genetic differences in the human leukocyte antigen (HLA) complex between kidney transplant donors and recipients play a central role in T-cell-mediated rejection (TCMR), which can lead to failure of the transplanted kidney. Evaluating this genetic disparity (mismatch) in the HLA complex at the molecular (epitope) level could contribute to better prediction of the immune response to the donor organ posttransplantation. We investigated the associations of the different donor HLA-derived T-cell epitope targets and scores obtained from virtual crossmatch algorithms with the occurrence of TCMR, borderline TCMR, and graft failure after kidney transplantation after taking into account the influence of donor-specific anti-HLA antibodies. This study illustrates the greater importance of the molecular mismatches in class II molecules compared to class I HLA molecules. CI - Copyright (c) 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. FAU - Senev, Aleksandar AU - Senev A AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium. FAU - Van Loon, Elisabet AU - Van Loon E AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium. FAU - Lerut, Evelyne AU - Lerut E AD - Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium. FAU - Coemans, Maarten AU - Coemans M AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium. FAU - Callemeyn, Jasper AU - Callemeyn J AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium. FAU - Daniels, Liesbeth AU - Daniels L AD - Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium. FAU - Kerkhofs, Johan AU - Kerkhofs J AD - Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium. FAU - Koshy, Priyanka AU - Koshy P AD - Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium. FAU - Kuypers, Dirk AU - Kuypers D AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. FAU - Lamarthee, Baptiste AU - Lamarthee B AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium. FAU - Sprangers, Ben AU - Sprangers B AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. FAU - Tinel, Claire AU - Tinel C AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium. FAU - Van Craenenbroeck, Amaryllis H AU - Van Craenenbroeck AH AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. FAU - Van Sandt, Vicky AU - Van Sandt V AD - Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium. FAU - Emonds, Marie-Paule AU - Emonds MP AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium. FAU - Naesens, Maarten AU - Naesens M AD - KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. Electronic address: maarten.naesens@kuleuven.be. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220609 PL - United States TA - Am J Kidney Dis JT - American journal of kidney diseases : the official journal of the National Kidney Foundation JID - 8110075 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-DRB1 Chains) RN - 0 (HLA Antigens) SB - IM CIN - Am J Kidney Dis. 2022 Dec;80(6):704-706. PMID: 36057468 MH - Humans MH - *Kidney Transplantation/adverse effects MH - Epitopes, T-Lymphocyte MH - Graft Rejection/epidemiology MH - Graft Survival MH - Retrospective Studies MH - HLA-DRB1 Chains MH - T-Lymphocytes MH - HLA Antigens/genetics MH - Histocompatibility Testing OTO - NOTNLM OT - Allograft failure OT - HLA eplet mismatch OT - HLA mismatch OT - T-cell-mediated rejection (TCMR) OT - alloimmune response OT - donor-specific anti-HLA antibodies (HLA-DSA) OT - end-stage renal disease (ESRD) OT - graft dysfunction OT - graft rejection OT - indirect allorecognition OT - kidney biopsy OT - kidney transplantation EDAT- 2022/06/12 06:00 MHDA- 2022/11/24 06:00 CRDT- 2022/06/11 19:24 PHST- 2021/07/16 00:00 [received] PHST- 2022/04/09 00:00 [accepted] PHST- 2022/06/12 06:00 [pubmed] PHST- 2022/11/24 06:00 [medline] PHST- 2022/06/11 19:24 [entrez] AID - S0272-6386(22)00708-9 [pii] AID - 10.1053/j.ajkd.2022.04.009 [doi] PST - ppublish SO - Am J Kidney Dis. 2022 Dec;80(6):718-729.e1. doi: 10.1053/j.ajkd.2022.04.009. Epub 2022 Jun 9.