The Comprehensive Transplant Center (CTC) at Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Department of Surgery, Addenbrooke's Hospital, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
Front Immunol. 2024 Mar 27;15:1377535. doi: 10.3389/fimmu.2024.1377535. eCollection 2024.
We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT).
All patients with available DNA samples (N=32) who participated in a phase 2 clinical trial (NCT00498160) where they received an HLA mismatched co-transplantation of living donor kidney and facilitating cell-enriched HSCT were included in this study. High-resolution HLA genotyping data were used to calculate HLA amino acid mismatches (AAMM), Eplet MM, three-dimensional electrostatic mismatch scores (EMS-3D), PIRCHE scores, HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence MM, and KIR ligands MM between the donor and recipient in both directions. HLA MM were analyzed to test for correlation with the development of chimerism, graft vs. host disease (GvHD), DSA, and graft rejection.
Follow-up time of this cohort was 6-13.5 years. Of the 32 patients, 26 developed high-level donor or mixed stable chimerism, followed by complete withdrawal of immunosuppression (IS) in 25 patients. The remaining six of the 32 patients had transient chimerism or no engraftment and were maintained on IS (On-IS). In host versus graft direction, a trend toward higher median number of HLA-DRB1 MM scores was seen in patients On-IS compared to patients with high-level donor/mixed chimerism, using any of the HLA MM modalities; however, initial statistical significance was observed only for the EMS-3D score (0.45 [IQR, 0.30-0.61] vs. 0.24 [IQR, 0.18-0.36], respectively; p=0.036), which was lost when applying the Bonferroni correction. No statistically significant differences between the two groups were observed for AAMM, EMS-3D, Eplet MM, and PIRCHE-II scores calculated in graft versus host direction. No associations were found between development of chimerism and GvHD and non-permissive HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence, and KIR ligands MM.
Our results suggest an association between HLA-DRB1 molecular mismatches and achieving stable chimerism, particularly when electrostatic quality of the mismatch is considered. The non-permissive HLA-DPB1 T-cell epitope group, HLA-B leader sequence, and KIR ligands MM do not predict chimerism and GvHD in this combined kidney/HSCT transplant patient cohort. Further work is needed to validate our findings.
https://clinicaltrials.gov/study/NCT00498160, identifier NCT00498160.
我们研究了 HLA 分子错配（MM）在实现稳定嵌合体中的潜在作用，使接受异体肾和造血干细胞移植（HSCT）的患者能够获得供者特异性耐受。
所有参与 2 期临床试验（NCT00498160）并接受 HLA 错配共移植的患者均纳入本研究，这些患者的 DNA 样本可用于分析（N=32）。高分辨率 HLA 基因分型数据用于计算 HLA 氨基酸错配（AAMM）、Eplet MM、三维静电失配评分（EMS-3D）、PIRCHE 评分、供受者间 HLA-DPB1 T 细胞表位组 MM、HLA-B 前导序列 MM 和 KIR 配体 MM。分析 HLA MM 与嵌合体的发展、移植物抗宿主病（GvHD）、DSA 和移植物排斥之间的相关性。
该队列的随访时间为 6-13.5 年。32 例患者中，26 例患者出现高水平供者或混合稳定嵌合体，随后 25 例患者完全停止免疫抑制（IS）。32 例患者中有 6 例出现短暂嵌合体或无植入，仍接受 IS（On-IS）。在宿主与移植物方向，与高水平供者/混合嵌合体患者相比，On-IS 患者的 HLA-DRB1 MM 评分中位数更高，使用任何一种 HLA MM 方式；然而，仅当应用 Bonferroni 校正时，EMS-3D 评分才具有统计学意义（0.45[IQR，0.30-0.61] vs. 0.24[IQR，0.18-0.36]；p=0.036）。在宿主与移植物方向计算的 AAMM、EMS-3D、Eplet MM 和 PIRCHE-II 评分中，两组间未见统计学差异。未发现嵌合体的发展与 GvHD 之间存在关联，也未发现非许可性 HLA-DPB1 T 细胞表位组 MM、HLA-B 前导序列和 KIR 配体 MM 之间存在关联。
我们的结果表明 HLA-DRB1 分子错配与稳定嵌合体的形成有关，特别是当考虑错配的静电质量时。在本联合肾/HSCT 移植患者队列中，非许可性 HLA-DPB1 T 细胞表位组、HLA-B 前导序列和 KIR 配体 MM 并不能预测嵌合体和 GvHD。需要进一步的工作来验证我们的发现。
https://clinicaltrials.gov/study/NCT00498160，标识符 NCT00498160。
