抑制性炎症信号和髓系来源的抑制性细胞积累会降低循环单核细胞 HLA-DR 密度，并且可能与长期肾移植受者的恶性肿瘤风险相关。

Dampened Inflammatory Signalling and Myeloid-Derived Suppressor-Like Cell Accumulation Reduces Circulating Monocytic HLA-DR Density and May Associate With Malignancy Risk in Long-Term Renal Transplant Recipients.

机构信息

Oxford Kidney Unit, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.

出版信息

Front Immunol. 2022 Jul 1;13:901273. doi: 10.3389/fimmu.2022.901273. eCollection 2022.

DOI:10.3389/fimmu.2022.901273

PMID:35844527

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9283730/

Abstract

BACKGROUND

Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients.

METHODS

A cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks.

RESULTS

Monocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density.

CONCLUSIONS

Dampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.

摘要

背景

恶性肿瘤是移植受者发病和死亡的主要原因。识别高危人群有助于进行预防性干预，如减少免疫抑制。在普通人群中，循环单核细胞 HLA-DR 密度降低是免疫抑制的标志物，与危重病患者的预后较差相关。最近，它已被用于肾移植中的过继细胞治疗试验的安全标志物。尽管它作为免疫反应减弱的标志物具有潜在作用，但尚未在移植受者中评估影响单核细胞 HLA-DR 密度的因素及其长期临床后果。

方法

对稳定的长期肾移植受者进行了队列研究。通过流式细胞术定量检测循环单核细胞 HLA-DR 密度和其他白细胞群。使用 Nanostring nCounter 平台进行单核细胞基因表达，使用 13 元细胞因子珠阵列定量血清浓度。主要结局是在一年的随访期间发生恶性肿瘤。使用单变量和多变量比例风险模型计算恶性肿瘤风险，包括和不包括竞争风险的调整。

结果

长期肾移植受者（n=135）的单核细胞 HLA-DR 密度稳定，与非免疫抑制对照（n=29）相似，但接受泼尼松龙治疗的受者则受到抑制。mHLA-DRd 降低与 CD14+CD11b+CD33+HLA-DRlo 单核细胞髓系来源抑制性样细胞的积累有关。通路分析显示，低 HLA-DR 密度的单核细胞中细胞因子和趋化因子信号通路下调；然而，这些组之间的主要细胞因子血清浓度没有差异。在随访期间，HLA-DR 密度降低与恶性肿瘤风险独立增加相关。