PMID- 33776988 OWN - NLM STAT- MEDLINE DCOM- 20210623 LR - 20210623 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - Donor/Recipient HLA Molecular Mismatch Scores Predict Primary Humoral and Cellular Alloimmunity in Kidney Transplantation. PG - 623276 LID - 10.3389/fimmu.2020.623276 [doi] LID - 623276 AB - Donor/recipient molecular human leukocyte antigen (HLA) mismatch predicts primary B-cell alloimmune activation, yet the impact on de novo donor-specific T-cell alloimmunity (dnDST) remains undetermined. The hypothesis of our study is that donor/recipient HLA mismatches assessed at the molecular level may also influence a higher susceptibility to the development of posttransplant primary T-cell alloimmunity. In this prospective observational study, 169 consecutive kidney transplant recipients without preformed donor-specific antibodies (DSA) and with high resolution donor/recipient HLA typing were evaluated for HLA molecular mismatch scores using different informatic algorithms [amino acid mismatch, eplet MM, and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II)]. Primary donor-specific alloimmune activation over the first 2 years posttransplantation was assessed by means of both dnDSA and dnDST using single antigen bead (SAB) and IFN-gamma ELISPOT assays, respectively. Also, the predominant alloantigen presenting pathway priming DST alloimmunity and the contribution of main alloreactive T-cell subsets were further characterized in vitro. Pretransplantation, 78/169 (46%) were DST+ whereas 91/169 (54%) DST-. At 2 years, 54/169 (32%) patients showed detectable DST responses: 23/54 (42%) dnDST and 31/54 (57%) persistently positive (persistDST+). 24/169 (14%) patients developed dnDSA. A strong correlation was observed between the three distinct molecular mismatch scores and they all accurately predicted dnDSA formation, in particular at the DQ locus. Likewise, HLA molecular incompatibility predicted the advent of dnDST, especially when assessed by PIRCHE-II score (OR 1.014 95% CI 1.001-1.03, p=0.04). While pretransplant DST predicted the development of posttransplant BPAR (OR 5.18, 95% CI=1.64-16.34, p=0.005) and particularly T cell mediated rejection (OR 5.33, 95% CI=1.45-19.66, p=0.012), patients developing dnDST were at significantly higher risk of subsequent dnDSA formation (HR 2.64, 95% CI=1.08-6.45, p=0.03). In vitro experiments showed that unlike preformed DST that is predominantly primed by CD8+ direct pathway T cells, posttransplant DST may also be activated by the indirect pathway of alloantigen presentation, and predominantly driven by CD4+ alloreactive T cells in an important proportion of patients. De novo donor-specific cellular alloreactivity seems to precede subsequent humoral alloimmune activation and is influenced by a poor donor/recipient HLA molecular matching. CI - Copyright (c) 2021 Meneghini, Crespo, Niemann, Torija, Lloberas, Pernin, Fontova, Melilli, Fava, Montero, Manonelles, Cruzado, Palou, Martorell, Grinyo and Bestard. FAU - Meneghini, Maria AU - Meneghini M AD - Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. FAU - Crespo, Elena AU - Crespo E AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. FAU - Niemann, Matthias AU - Niemann M AD - Director of Technology, PIRCHE-II AG, Berlin, Germany. FAU - Torija, Alba AU - Torija A AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. FAU - Lloberas, Nuria AU - Lloberas N AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. FAU - Pernin, Vincent AU - Pernin V AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. AD - Department of Nephrology, Dialysis and Transplantation, Montpellier University Hospital, Montpellier, France. AD - Institute for Regenerative Medicine & Biotherapy (IRMB), University of Montpellier, INSERM, Montpellier, France. FAU - Fontova, Pere AU - Fontova P AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. FAU - Melilli, Edoardo AU - Melilli E AD - Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. FAU - Fava, Alexandre AU - Fava A AD - Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. FAU - Montero, Nuria AU - Montero N AD - Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. FAU - Manonelles, Anna AU - Manonelles A AD - Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. FAU - Cruzado, Josep Maria AU - Cruzado JM AD - Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. FAU - Palou, Eduard AU - Palou E AD - Laboratory of Immunology and Histocompatibility, Hospital Clinic, Barcelona, Spain. FAU - Martorell, Jaume AU - Martorell J AD - Laboratory of Immunology and Histocompatibility, Hospital Clinic, Barcelona, Spain. FAU - Grinyo, Josep Maria AU - Grinyo JM AD - Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. FAU - Bestard, Oriol AU - Bestard O AD - Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. AD - Translational Transplantation and Nephrology Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain. LA - eng PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20210310 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (HLA-DQ Antigens) SB - IM MH - Adult MH - Aged MH - B-Lymphocytes/*immunology/pathology MH - CD4-Positive T-Lymphocytes/*immunology/pathology MH - CD8-Positive T-Lymphocytes/*metabolism/pathology MH - Female MH - Follow-Up Studies MH - Graft Rejection/*immunology/pathology MH - Graft Survival/*immunology MH - HLA-DQ Antigens/*immunology MH - *Histocompatibility Testing MH - Humans MH - *Immunity, Cellular MH - *Immunity, Humoral MH - *Kidney Transplantation MH - Male MH - Middle Aged PMC - PMC7988214 OTO - NOTNLM OT - HLA mismatch OT - T cell OT - alloreactive OT - donor-specific antibodies OT - kidney transplantation COIS- MN is an employee of PIRCHE AG that runs the PIRCHE web-portal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/03/30 06:00 MHDA- 2021/06/24 06:00 PMCR- 2020/01/01 CRDT- 2021/03/29 06:24 PHST- 2020/10/29 00:00 [received] PHST- 2020/12/31 00:00 [accepted] PHST- 2021/03/29 06:24 [entrez] PHST- 2021/03/30 06:00 [pubmed] PHST- 2021/06/24 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.623276 [doi] PST - epublish SO - Front Immunol. 2021 Mar 10;11:623276. doi: 10.3389/fimmu.2020.623276. eCollection 2020.