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

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Association of Predicted HLA T-Cell Epitope Targets and T-Cell–Mediated Rejection After Kidney Transplantation
American Journal of Kidney Diseases ( IF 9.4 ) Pub Date : 2022-06-09 , DOI: 10.1053/j.ajkd.2022.04.009
Aleksandar Senev ₁ , Elisabet Van Loon ₂ , Evelyne Lerut ₃ , Maarten Coemans ₂ , Jasper Callemeyn ₂ , Liesbeth Daniëls ₄ , Johan Kerkhofs ₄ , Priyanka Koshy ₃ , Dirk Kuypers ₅ , Baptiste Lamarthée ₂ , Ben Sprangers ₅ , Claire Tinel ₂ , Amaryllis H Van Craenenbroeck ₅ , Vicky Van Sandt ₄ , Marie-Paule Emonds ₁ , Maarten Naesens ₅

Affiliation

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.

中文翻译：

预测的 HLA T 细胞表位靶标与肾移植后 T 细胞介导的排斥反应的关联

理由和目标

人类白细胞抗原 (HLA) 分子错配与 T 细胞介导的排斥反应 (TCMR) 之间的关系尚不清楚。我们研究了不同供体 HLA 来源的 T 细胞靶标与 TCMR 的发生以及肾移植后提示 TCMR 的临界组织学变化之间的关联。

学习规划

回顾性队列研究。

设置和参与者

2004 年至 2013 年间在一个中心的所有肾移植受者，具有可用的活检数据和用于高分辨率 HLA 供体/受体分型的 DNA 样本（N = 893）。

接触

通过 HLA 匹配算法 PIRCHE-II 和 HLA eplet 不匹配计算的分数。

结果

TCMR、提示 TCMR 的临界变化和同种异体移植物失败。

分析方法

多变量特定原因危害模型适合描述 HLA 表位目标与研究结果之间的关联。

结果

我们发现 277 名患者出现了 TCMR，而 134 名患者至少在 1 次活检中仅出现提示 TCMR 的临界变化。在多变量分析中，只有 HLA-DRB1 和 HLA-DQB1 的 PIRCHE-II 评分与 TCMR 的发生和同种异体移植失败独立相关；HLA I 类分子的情况并非如此。如果仅限于移植后前 3 个月内的排斥反应，只有来自供体 HLA-DRB1 和 HLA-DQB1 的 T 细胞表位靶标与早期急性 TCMR 相关，而 I 类分子则没有。此外，与没有 TCMR 的患者相比，具有 TCMR 的患者的 HLA II 类 PIRCHE-II 评分中位数有统计学差异（分别为 129 [IQR，60-240] 和 201 [IQR，96-298]；P < 0.0001）。I 类 PIRCHE-II 分数没有观察到这些差异。