Importance and What to Watch Out for De Novo Donor Specific Anti-HLA Antibodies after Kidney Transplantation

BackgroundIn kidney transplantation, evaluating mismatches of HLA eplets—small patches of surface-exposed amino acids of the HLA molecule—instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes.MethodsTo evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches.ResultsDe novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell– or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch.ConclusionsEplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA1 and DQB1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.

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Clinical Significance of Shared T Cell Epitope Analysis in Early De Novo Donor-Specific Anti-HLA Antibody Production After Kidney Transplantation and Comparison With Shared B cell Epitope Analysis

Frontiers in Immunology ◽

10.3389/fimmu.2021.621138 ◽

2021 ◽

Vol 12 ◽

Author(s):

Toshihide Tomosugi ◽

Kenta Iwasaki ◽

Shintaro Sakamoto ◽

Matthias Niemann ◽

Eric Spierings ◽

...

Keyword(s):

T Cells ◽

Kidney Transplantation ◽

T Cell ◽

De Novo ◽

Memory T Cells ◽

Cell Epitope ◽

T Cell Epitopes ◽

Hla Antibodies ◽

Epitope Analysis ◽

Hla Antibody

In pre-sensitizing events, immunological memory is mainly createdviaindirect allorecognition where CD4+T cells recognize foreign peptides in the context of self-HLA class II (pHLA) presented on antigen-presenting cells. This recognition makes it possible for naive CD4+T-helper cells to differentiate into memory cells, resulting in the creation of further antibody memory. These responses contribute to effective secretion of donor-specific anti-HLA antibodies (DSA) after second encounters with the same peptide. Preformed donor-reactive CD4+memory T cells may induce early immune responses after transplantation; however, the tools to evaluate them are limited. This study evaluated shared T cell epitopes (TEs) between the pre-sensitizing and donor HLA using anin silicoassay, an alternative to estimate donor-reactive CD4+memory T cells before transplantation. In 578 living donor kidney transplants without preformed DSA, 69 patients had anti-HLA antibodies before transplantation. Of them, 40 had shared TEs and were estimated to have donor-reactive CD4+memory T cells.De novoDSA formation in the early phase was significantly higher in the shared TE-positive group than in the anti-HLA antibody- and shared TE-negative groups (p=0.001 and p=0.02, respectively). In conclusion, evaluation of shared TEs for estimating preformed donor-reactive CD4+memory T cells may help predict the risk of earlyde novoDSA formation after kidney transplantation.

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