Clinical & Translational Immunology最新文献_第6页

SARS-CoV-2-infected human airway epithelial cell cultures uniquely lack interferon and immediate early gene responses caused by other coronaviruses 感染了 SARS-CoV-2 的人类气道上皮细胞培养物独特地缺乏由其他冠状病毒引起的干扰素和即刻早期基因反应

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-04-15 DOI: 10.1002/cti2.1503

Ying Wang, Melissa Thaler, Clarisse Salgado-Benvindo, Nathan Ly, Anouk A Leijs, Dennis K Ninaber, Philip M Hansbro, Fia Boedijono, Martijn J van Hemert, Pieter S Hiemstra, Anne M van der Does, Alen Faiz

Objectives

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of a class of highly pathogenic coronaviruses. The large family of coronaviruses, however, also includes members that cause only mild symptoms, like human coronavirus-229E (HCoV-229E) or OC43 (HCoV-OC43). Unravelling how molecular (and cellular) pathophysiology differs between highly and low pathogenic coronaviruses is important for the development of therapeutic strategies.

Methods

Here, we analysed the transcriptome of primary human bronchial epithelial cells (PBEC), differentiated at the air–liquid interface (ALI) after infection with SARS-CoV-2, SARS-CoV, Middle East Respiratory Syndrome (MERS)-CoV and HCoV-229E using bulk RNA sequencing.

Results

ALI-PBEC were efficiently infected by all viruses, and SARS-CoV, MERS-CoV and HCoV-229E infection resulted in a largely similar transcriptional response. The response to SARS-CoV-2 infection differed markedly as it uniquely lacked the increase in expression of immediate early genes, including FOS, FOSB and NR4A1 that was observed with all other coronaviruses. This finding was further confirmed in publicly available experimental and clinical datasets. Interfering with NR4A1 signalling in Calu-3 lung epithelial cells resulted in a 100-fold reduction in extracellular RNA copies of SARS-CoV-2 and MERS-CoV, suggesting an involvement in virus replication. Furthermore, a lack in induction of interferon-related gene expression characterised the main difference between the highly pathogenic coronaviruses and low pathogenic viruses HCoV-229E and HCoV-OC43.

Conclusion

Our results demonstrate a previously unknown suppression of a host response gene set by SARS-CoV-2 and confirm a difference in interferon-related gene expression between highly pathogenic and low pathogenic coronaviruses.

目标严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）是一类高致病性冠状病毒。然而，冠状病毒大家族中也有一些只引起轻微症状的成员，如人类冠状病毒-229E（HCoV-229E）或 OC43（HCoV-OC43）。了解高致病性冠状病毒和低致病性冠状病毒的分子（和细胞）病理生理学有何不同对于制定治疗策略非常重要。方法在此，我们使用大容量 RNA 测序分析了原代人支气管上皮细胞（PBEC）的转录组，这些细胞在感染 SARS-CoV-2、SARS-CoV、中东呼吸综合征（MERS）-CoV 和 HCoV-229E 后在气液界面（ALI）分化。结果 ALI-PBEC 能有效感染所有病毒，SARS-CoV、MERS-CoV 和 HCoV-229E 感染导致的转录反应基本相似。感染 SARS-CoV-2 后的反应则明显不同，因为它独特地缺乏在所有其他冠状病毒中观察到的即时早期基因（包括 FOS、FOSB 和 NR4A1）表达的增加。这一发现在公开的实验和临床数据集中得到了进一步证实。干扰 Calu-3 肺上皮细胞中的 NR4A1 信号可使 SARS-CoV-2 和 MERS-CoV 的胞外 RNA 拷贝减少 100 倍，这表明 NR4A1 参与了病毒复制。此外，高致病性冠状病毒与低致病性病毒 HCoV-229E 和 HCoV-OC43 之间的主要区别在于缺乏对干扰素相关基因表达的诱导。结论我们的研究结果表明，SARS-CoV-2 对宿主反应基因集的抑制作用以前不为人知，并证实了高致病性冠状病毒和低致病性冠状病毒之间在干扰素相关基因表达方面的差异。

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引用次数: 0

Chimeric antigen receptor T cells in the fast lane among autoimmune disease therapies 嵌合抗原受体 T 细胞驶入自身免疫性疾病疗法的快车道

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-04-12 DOI: 10.1002/cti2.1502

Zhoujie Ding, David Tarlinton

In this commentary, we highlight recent studies demonstrating the feasibility and promise of chimeric antigen receptor (CAR) T-cell therapy in treating a number of autoimmune disorders including systemic lupus erythematosus and compare CAR T cells to other therapies aimed at depleting B-lineage cells in treating such diseases.

在这篇评论中，我们重点介绍了最近的一些研究，这些研究证明了嵌合抗原受体（CAR）T细胞疗法在治疗包括系统性红斑狼疮在内的多种自身免疫性疾病方面的可行性和前景，并将CAR T细胞与其他旨在消耗B系细胞以治疗此类疾病的疗法进行了比较。

引用次数: 0

CD177 drives the transendothelial migration of Treg cells enriched in human colorectal cancer CD177 驱动人类结直肠癌中富集的 Treg 细胞跨内皮迁移

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-04-09 DOI: 10.1002/cti2.1506

Shouyu Ke, Yi Lei, Yixian Guo, Feng Xie, Yimeng Yu, Haigang Geng, Yiqing Zhong, Danhua Xu, Xu Liu, Fengrong Yu, Xiang Xia, Zizhen Zhang, Chunchao Zhu, Wei Ling, Bin Li, Wenyi Zhao

Objectives

Regulatory T (Treg) cells regulate immunity in autoimmune diseases and cancers. However, immunotherapies that target tumor-infiltrating Treg cells often induce unwanted immune responses and tissue inflammation. Our research focussed on exploring the expression pattern of CD177 in tumor-infiltrating Treg cells with the aim of identifying a potential target that can enhance immunotherapy effectiveness.

Methods

Single-cell RNA sequencing (scRNA-seq) data and survival data were obtained from public databases. Twenty-one colorectal cancer patient samples, including fresh tumor tissues, peritumoral tissues and peripheral blood mononuclear cells (PBMCs), were analysed using flow cytometry. The transendothelial activity of CD177⁺ Treg cells was substantiated using in vitro experiments.

Results

ScRNA-seq and flow cytometry results indicated that CD177 was exclusively expressed in intratumoral Treg cells. CD177⁺ Treg cells exhibited greater activation status and expressed elevated Treg cell canonical markers and immune checkpoint molecules than CD177⁻ Treg cells. We further discovered that both intratumoral CD177⁺ Treg cells and CD177-overexpressing induced Treg (iTreg) cells had lower levels of PD-1 than their CD177⁻ counterparts. Moreover, CD177 overexpression significantly enhanced the transendothelial migration of Treg cells in vitro.

Conclusions

These results demonstrated that Treg cells with higher CD177 levels exhibited an enhanced activation status and transendothelial migration capacity. Our findings suggest that CD177 may serve as an immunotherapeutic target and that overexpression of CD177 may improve the efficacy of chimeric antigen receptor T (CAR-T) cell therapy.

目的调节性 T（Treg）细胞在自身免疫性疾病和癌症中调节免疫。然而，针对肿瘤浸润 Treg 细胞的免疫疗法往往会诱发不必要的免疫反应和组织炎症。我们的研究重点是探索 CD177 在肿瘤浸润 Treg 细胞中的表达模式，目的是确定一个能提高免疫疗法效果的潜在靶点。方法从公共数据库中获取单细胞 RNA 测序（scRNA-seq）数据和生存数据。利用流式细胞术分析了 21 例结直肠癌患者样本，包括新鲜肿瘤组织、瘤周组织和外周血单核细胞（PBMCs）。体外实验证实了 CD177+ Treg 细胞的跨内皮细胞活性。结果 ScRNA-seq 和流式细胞术结果表明，CD177 只在瘤内 Treg 细胞中表达。与 CD177- Treg 细胞相比，CD177+ Treg 细胞表现出更高的活化状态，并表达出更高的 Treg 细胞典型标志物和免疫检查点分子。我们进一步发现，瘤内 CD177+ Treg 细胞和 CD177 高表达诱导 Treg（iTreg）细胞的 PD-1 水平都低于 CD177- Treg 细胞。此外，CD177 过表达能显著增强 Treg 细胞在体外的跨内皮迁移。结论这些结果表明，CD177 水平较高的 Treg 细胞表现出更强的活化状态和跨内皮迁移能力。我们的研究结果表明，CD177 可作为免疫治疗靶点，过表达 CD177 可提高嵌合抗原受体 T（CAR-T）细胞疗法的疗效。

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引用次数: 0

Identification of distinct immune signatures in inclusion body myositis by peripheral blood immunophenotyping using machine learning models 利用机器学习模型通过外周血免疫分型鉴定包涵体肌炎的独特免疫特征

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-04-03 DOI: 10.1002/cti2.1504

Emily McLeish, Anuradha Sooda, Nataliya Slater, Kelly Beer, Ian Cooper, Frank L Mastaglia, Merrilee Needham, Jerome D Coudert

Objective

Inclusion body myositis (IBM) is a progressive late-onset muscle disease characterised by preferential weakness of quadriceps femoris and finger flexors, with elusive causes involving immune, degenerative, genetic and age-related factors. Overlapping with normal muscle ageing makes diagnosis and prognosis problematic.

Methods

We characterised peripheral blood leucocytes in 81 IBM patients and 45 healthy controls using flow cytometry. Using a random forest classifier, we identified immune changes in IBM compared to HC. K-means clustering and the random forest one-versus-rest model classified patients into three immunophenotypic clusters. Functional outcome measures including mTUG, 2MWT, IBM-FRS, EAT-10, knee extension and grip strength were assessed across clusters.

Results

The random forest model achieved a 94% AUC ROC with 82.76% specificity and 100% sensitivity. Significant differences were found in IBM patients, including increased CD8⁺ T-bet⁺ cells, CD4⁺ T cells skewed towards a Th1 phenotype and altered γδ T cell repertoire with a reduced proportion of Vγ9⁺Vδ2⁺ cells. IBM patients formed three clusters: (i) activated and inflammatory CD8⁺ and CD4⁺ T-cell profile and the highest proportion of anti-cN1A-positive patients in cluster 1; (ii) limited inflammation in cluster 2; (iii) highly differentiated, pro-inflammatory T-cell profile in cluster 3. Additionally, no significant differences in patients' age and gender were detected between immunophenotype clusters; however, worsening trends were detected with several functional outcomes.

Conclusion

These findings unveil distinct immune profiles in IBM, shedding light on underlying pathological mechanisms for potential immunoregulatory therapeutic development.

目的包涵体肌炎（IBM）是一种渐进性晚发肌肉疾病，以股四头肌和手指屈肌无力为特征，病因难以捉摸，涉及免疫、退行性、遗传和年龄相关因素。该病与正常肌肉老化重叠，因此诊断和预后存在问题。方法我们使用流式细胞术鉴定了 81 名 IBM 患者和 45 名健康对照者的外周血白细胞。使用随机森林分类器，我们确定了 IBM 与 HC 相比的免疫变化。K-means 聚类和随机森林单对单模型将患者分为三个免疫表型群。对不同群组的功能结果进行评估，包括 mTUG、2MWT、IBM-FRS、EAT-10、膝关节伸展和握力。结果随机森林模型的 AUC ROC 为 94%，特异性为 82.76%，灵敏度为 100%。在 IBM 患者中发现了显著差异，包括 CD8+ T-bet+ 细胞增加、CD4+ T 细胞偏向 Th1 表型、γδ T 细胞群发生改变，Vγ9+Vδ2+ 细胞比例降低。IBM 患者形成了三个群：(i) 活化和炎症性 CD8+ 和 CD4+ T 细胞谱，抗 N1A 阳性患者比例最高的是第 1 群；(ii) 局限性炎症的是第 2 群；(iii) 高分化、促炎症性 T 细胞谱的是第 3 群。此外，免疫表型群组之间在患者年龄和性别方面没有发现明显差异；但在几种功能结果方面发现了恶化趋势。结论这些发现揭示了 IBM 患者不同的免疫特征，为潜在免疫调节疗法的开发揭示了潜在的病理机制。

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引用次数: 0

Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway 组蛋白去乙酰化酶抑制剂的协同整合显然能通过NKG2D途径提高细胞因子诱导的多发性骨髓瘤杀伤细胞的效率

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-03-25 DOI: 10.1002/cti2.1500

Jingjing Pu, Amit Sharma, Ting Liu, Jian Hou, Ingo GH Schmidt-Wolf

Objectives

The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine-induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study.

Methods

We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilising various in vitro methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions.

Results

The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN-γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings.

Conclusions

Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.

目的人们迅速认识到表观遗传操作在限制癌细胞能力方面的潜力，这推动了包括组蛋白去乙酰化酶抑制剂（HDACis）在内的转化项目的开展。对多发性骨髓瘤（MM）的临床试验表明，HDACis 具有显著疗效，细胞因子诱导的杀伤细胞（CIK）免疫疗法也取得了令人鼓舞的成果。耐人寻味的是，HDACis 和 CIK 细胞免疫疗法在 MM 中的协同作用尚未被探索，这促使我们开展了这项研究。方法我们研究了与临床相关的 HDACis（panobinostat/LBH589 和 romidepsin）以及来自不同 MM 细胞系（U266、RPMI8226、OPM-2 和 NCI-H929）外周血单核细胞的 CIK 细胞。利用各种体外方法，我们研究了 HDACis 如何通过 NKG2D/NKG2D 配体的相互作用增强 CIK 细胞对骨髓瘤细胞的溶解。结果我们的分析结果表明了几个重要发现。(1）与 HDACis 结合使用时，CIK 细胞对 MM 细胞的细胞毒性增强。(2）细胞凋亡显著增加，表明 HDACis 和 CIK 可共同增强特定 MM 细胞系的细胞凋亡效应。(3）由于 HDACis 的独立活性，IFN-γ 分泌增加，颗粒酶 B 分泌发生变化。(4）值得注意的是，HDACis 增加了对诱导 NKT 细胞抗肿瘤细胞毒性至关重要的 MICA/B 和 ULBP2 的表达。用纯化的小鼠抗人 NKG2D 抗体阻断 CIK 细胞中的 NKG2D 受体进一步证实了我们的发现。结论我们的分析提供了足够的证据，可将这一临床上被遗忘的实例（HDACis-CIK 细胞组合）视为 MM 治疗的优先选择。此外，我们还发现，激活 NK/NKT 细胞的 NKG2D/NKG2D 配体相互作用可能有助于增强 CIK 细胞对 HDACis 治疗的骨髓瘤细胞裂解反应。

{"title":"Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway","authors":"Jingjing Pu, Amit Sharma, Ting Liu, Jian Hou, Ingo GH Schmidt-Wolf","doi":"10.1002/cti2.1500","DOIUrl":"https://doi.org/10.1002/cti2.1500","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine-induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilising various <i>in vitro</i> methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN-γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1500","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140209573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring NK cell receptor dynamics in paediatric leukaemias: implications for immunotherapy and prognosis 探索小儿白血病中的 NK 细胞受体动态：对免疫疗法和预后的影响

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-03-23 DOI: 10.1002/cti2.1501

Cui Tu, Irina Buckle, Ingrid Leal Rojas, Gustavo Rodrigues Rossi, David P Sester, Andrew S Moore, Kristen Radford, Camille Guillerey, Fernando Souza-Fonseca-Guimaraes

Objectives

Immunotherapies targeting natural killer (NK) cell receptors have shown promise against leukaemia. Unfortunately, cancer immunosuppressive mechanisms that alter NK cell phenotype prevent such approaches from being successful. The study utilises advanced cytometry to examine how cancer immunosuppressive pathways affect NK cell phenotypic changes in clinical samples.

Methods

In this study, we conducted a high-dimensional examination of the cell surface expression of 16 NK cell receptors in paediatric patients with acute myeloid leukaemia and acute lymphoblastic leukaemia, as well as in samples of non-age matched adult peripheral blood (APB) and umbilical cord blood (UCB). An unsupervised analysis was carried out in order to identify NK cell populations present in paediatric leukaemias.

Results

We observed that leukaemia NK cells clustered together with UCB NK cells and expressed relatively higher levels of the NKG2A receptor compared to APB NK cells. In addition, CD56^dimCD16⁺CD57⁻ NK cells lacking NKG2A expression were mainly absent in paediatric leukaemia patients. However, CD56^br NK cell populations expressing high levels of NKG2A were highly represented in paediatric leukaemia patients. NKG2A expression on leukaemia NK cells was found to be positively correlated with the expression of its ligand, suggesting that the NKG2A-HLA-E interaction may play a role in modifying NK cell responses to leukaemia cells.

Conclusion

We provide an in-depth analysis of NK cell populations in paediatric leukaemia patients. These results support the development of immunotherapies targeting immunosuppressive receptors, such as NKG2A, to enhance innate immunity against paediatric leukaemia.

目标以自然杀伤细胞（NK）受体为靶点的免疫疗法有望对抗白血病。遗憾的是，改变 NK 细胞表型的癌症免疫抑制机制阻碍了此类方法的成功。本研究利用先进的细胞计量学方法研究癌症免疫抑制途径如何影响临床样本中 NK 细胞表型的变化。方法在这项研究中，我们对急性髓性白血病和急性淋巴细胞白血病儿科患者以及非年龄匹配的成人外周血（APB）和脐带血（UCB）样本中 16 种 NK 细胞受体的细胞表面表达进行了高维检测。为了确定儿童白血病中存在的 NK 细胞群，我们进行了无监督分析。结果我们观察到白血病 NK 细胞与 UCB NK 细胞聚集在一起，与 APB NK 细胞相比，白血病 NK 细胞表达的 NKG2A 受体水平相对较高。此外，缺乏 NKG2A 表达的 CD56dimCD16+CD57- NK 细胞主要不存在于儿童白血病患者中。然而，在儿童白血病患者中，表达高水平 NKG2A 的 CD56br NK 细胞群的比例很高。研究发现，白血病 NK 细胞上 NKG2A 的表达与其配体的表达呈正相关，这表明 NKG2A-HLA-E 相互作用可能在改变 NK 细胞对白血病细胞的反应中发挥作用。结论我们对儿童白血病患者的 NK 细胞群进行了深入分析。这些结果支持开发针对免疫抑制受体（如 NKG2A）的免疫疗法，以增强针对小儿白血病的先天免疫力。

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引用次数: 0

CD39 expression defines exhausted CD4+ T cells associated with poor survival and immune evasion in human gastric cancer CD39 表达确定了与人类胃癌生存率低和免疫逃避相关的 CD4+ T 细胞衰竭情况

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-03-18 DOI: 10.1002/cti2.1499

Zhen-quan Duan, Yu-xian Li, Yuan Qiu, Yang Shen, Ying Wang, Yuan-yuan Zhang, Bao-hang Zhu, Xiao-hong Yu, Xue-ling Tan, Weisan Chen, Yuan Zhuang, Ping Cheng, Wei-jun Zhang, Quan-ming Zou, Dai-yuan Ma, Liu-sheng Peng

Objectives

CD4⁺ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4⁺ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown.

Methods

A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4⁺ T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4⁺ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity.

Results

In comparison with CD4⁺ T cells from the non-tumor tissues, significantly more GC-infiltrating CD4⁺ T cells expressed CD39. Most GC-infiltrating CD39⁺CD4⁺ T cells exhibited CD45RA⁻CCR7⁻ effector–memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39⁻CD4⁺ counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39⁺CD4⁺ T cells were positively associated with disease progression and patients' poorer overall survival.

Conclusion

Our study demonstrates that CD39 expression defines GC-infiltrating CD4⁺ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.

目标 CD4+ T 细胞在人类癌症中的辅助和调节功能已得到很好的描述。然而，肿瘤浸润性 CD4+ T 细胞衰竭的定义以及它如何导致人类胃癌（GC）的免疫反应和疾病进展在很大程度上仍是未知数。方法本研究共纳入了 128 例胃癌患者。流式细胞术分析了不同样本中 CD4+ T 细胞上 CD39 和 PD-1 的表达。根据 CD39 表达对 GC 浸润 CD4+ T 细胞亚群进行了表型和功能评估。通过抑制 CD39 酶的活性，研究了 CD39 在 GC 浸润 T 细胞免疫反应中的作用。结果与来自非肿瘤组织的 CD4+ T 细胞相比，表达 CD39 的 GC 浸润 CD4+ T 细胞明显增多。大多数GC浸润的CD39+CD4+ T细胞表现出CD45RA-CCR7-效应记忆表型，表达更多衰竭相关抑制分子和转录因子，产生的TNF-α、IFN-γ和细胞溶解分子少于CD39-CD4+同类细胞。此外，体内抑制 CD39 酶活性可提高它们的功能潜力，这体现在 TNF-α 和 IFN-γ 的产生上。最后，GC 浸润 CD39+CD4+ T 细胞百分比的增加与疾病进展和患者较差的总生存率呈正相关。结论我们的研究表明，CD39 的表达决定了 GC 浸润 CD4+ T 细胞的衰竭及其免疫抑制功能。以 CD39 为靶点可能是治疗 GC 患者的一种有前途的治疗策略。

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引用次数: 0

Graft-versus-leukaemia immunity is retained following treatment with post-transplant cyclophosphamide alone or combined with tocilizumab in humanised mice 在人源化小鼠移植后单独使用环磷酰胺或与托珠单抗联合使用后，移植物抗白血病免疫力得以保留

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-03-15 DOI: 10.1002/cti2.1497

Chloe Sligar, Ellie Reilly, Peter Cuthbertson, Kara L Vine, Katrina M Bird, Amal Elhage, Stephen I Alexander, Ronald Sluyter, Debbie Watson

Objectives

Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.

Methods

NOD-scid-IL2Rγ^null mice were injected with 2 × 10⁷ human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 10⁶ THP-1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg⁻¹) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg⁻¹) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.

Results

Mice with hPBMCs from three different donors and THP-1 cells showed similar survival, clinical score and weight loss. hCD33⁺ leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor-specific GVL responses. hPBMC-injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC-treated mice with hPBMCs showed minimal hepatic hCD33⁺ leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver.

Conclusion

Collectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.

目的供体造血干细胞移植通过诱导移植物抗白血病（GVL）免疫来治疗白血病。然而，移植物抗宿主疾病（GVHD）往往会减轻这种益处，在人源化小鼠中，移植后环磷酰胺（PTCy）单独或与托珠单抗（TOC）联合使用可减轻GVHD。本研究建立了一个临床前GVL人源化小鼠模型，并探讨了PTCy单独或与TOC联合使用是否会影响GVL免疫。方法在第 0 天向 NOD-scid-IL2Rγnull 小鼠注射 2 × 107 人外周血单核细胞（hPBMCs），在第 14 天注射 1 × 106 THP-1 急性髓性白血病细胞。在随后的实验中，还在第 3 天和第 4 天向小鼠注射 PTCy（33 毫克/千克）或 Dulbecco 磷酸盐缓冲盐水（PBS），单独或与 TOC 或对照抗体（25 毫克/千克）联合注射，每周两次，共注射 28 天。临床症状监测至第 42 天。结果使用三种不同供体的 hPBMC 和 THP-1 细胞的小鼠显示出相似的存活率、临床评分和体重减轻情况。使用两种供体的 hPBMC 重组的小鼠中 hCD33+ 白血病细胞极少，但使用第三种供体的 hPBMC 重组的小鼠中却有，这表明供体特异性 GVL 反应。单用 PTCy 和 PTCy + TOC 处理的 hPBMCs 小鼠显示肝脏 hCD33+ 白血病细胞极少，表明 GVL 免疫持续存在。此外，PTCy + TOC 的组合还减少了肺部和肝脏的组织学损伤。结论总的来说，这项研究表明，PTCy 单独或与 TOC 联合使用可在不损害 GVL 免疫力的情况下减轻 GVHD。

{"title":"Graft-versus-leukaemia immunity is retained following treatment with post-transplant cyclophosphamide alone or combined with tocilizumab in humanised mice","authors":"Chloe Sligar, Ellie Reilly, Peter Cuthbertson, Kara L Vine, Katrina M Bird, Amal Elhage, Stephen I Alexander, Ronald Sluyter, Debbie Watson","doi":"10.1002/cti2.1497","DOIUrl":"https://doi.org/10.1002/cti2.1497","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>NOD-<i>scid</i>-IL2Rγ<sup>null</sup> mice were injected with 2 × 10<sup>7</sup> human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 10<sup>6</sup> THP-1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg<sup>−1</sup>) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg<sup>−1</sup>) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mice with hPBMCs from three different donors and THP-1 cells showed similar survival, clinical score and weight loss. hCD33<sup>+</sup> leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor-specific GVL responses. hPBMC-injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC-treated mice with hPBMCs showed minimal hepatic hCD33<sup>+</sup> leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Collectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1497","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140135412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of intravenous immunoglobulin retreatment in children with Kawasaki disease using models combining lymphocyte subset and cytokine profile in an East Asian cohort 利用东亚队列中的淋巴细胞亚群和细胞因子谱相结合的模型，预测川崎病患儿静脉注射免疫球蛋白再治疗的效果

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-03-13 DOI: 10.1002/cti2.1498

Chun Zhang, Sun Chen, Yan Bian, Xiaohua Qian, Yurui Liu, Liqing Zhao, Jia Shen, Jiani Song, Peng Zhang, Lun Chen, Limin Jiang

Objectives

For children with Kawasaki disease (KD) at high risk of developing coronary artery lesions and requiring retreatment with intravenous immunoglobulin (IVIG), the availability of accurate prediction models remains limited because of inconsistent variables and unsatisfactory prediction results. We aimed to construct models to predict patient's probability of IVIG retreatment combining children's individual inflammatory characteristics.

Methods

Clinical manifestations and laboratory examinations of 266 children with KD were retrospectively analysed to build a development cohort data set (DC) and a validation cohort data set (VC). In the DC, binary logistic regression analyses were performed using R language. Nomograms and receiver operating curves were plotted. The concordance index (C index), net reclassification index, integrated discrimination improvement index and confusion matrix were applied to evaluate and validate the models.

Results

Models_5V and _9V were established. Both contained variables including the percentages of CD8⁺ T cells, CD4⁺ T cells, CD3⁺ T cells, levels of interleukin (IL)-2R and CRP. Model_9V additionally included variables for IL-6, TNF-α, NT-proBNP and sex, with a C index of 0.86 (95% CI 0.79–0.92). When model_9V was compared with model_5V, the NRI and IDI were 0.15 (95% CI 0.01–0.30, P < 0.01) and 0.07 (95% CI 0.02–0.12, P < 0.01). In the VC, the sensitivity, specificity and precision of model_9V were 1, 0.875 and 0.667, while those of model_5V were 0.833, 0.875 and 0.625.

Conclusion

Model_9V combined cytokine profiles and lymphocyte subsets with clinical characteristics and was superior to model_5V achieving satisfactory predictive power and providing a novel strategy early to identify patients who needed IVIG retreatment.

目的对于有冠状动脉病变高风险并需要静脉注射免疫球蛋白（IVIG）再治疗的川崎病（KD）患儿，由于变量不一致和预测结果不理想，准确预测模型的可用性仍然有限。我们的目标是结合儿童的个体炎症特征，构建预测患者接受 IVIG 再治疗概率的模型。方法回顾性分析了266名KD患儿的临床表现和实验室检查，建立了开发队列数据集（DC）和验证队列数据集（VC）。在DC中，使用R语言进行了二元逻辑回归分析。绘制了提名图和接收者工作曲线。应用一致性指数（C 指数）、净再分类指数、综合辨别改进指数和混淆矩阵来评估和验证模型。结果建立了_5V 和_9V 模型。这两个模型都包含 CD8+ T 细胞、CD4+ T 细胞、CD3+ T 细胞百分比、白细胞介素（IL）-2R 水平和 CRP 等变量。模型 9V 还包括 IL-6、TNF-α、NT-proBNP 和性别等变量，C 指数为 0.86（95% CI 0.79-0.92）。模型 9V 与模型 5V 相比，NRI 和 IDI 分别为 0.15（95% CI 0.01-0.30，P< 0.01）和 0.07（95% CI 0.02-0.12，P< 0.01）。在 VC 中，模型_9V 的灵敏度、特异性和精确度分别为 1、0.875 和 0.667，而模型_5V 的灵敏度、特异性和精确度分别为 0.833、0.875 和 0.625。结论 9V 模型将细胞因子图谱和淋巴细胞亚群与临床特征相结合，其预测能力优于 5V 模型，为早期识别需要 IVIG 再治疗的患者提供了一种新策略。

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引用次数: 0

Unremitting pro-inflammatory T-cell phenotypes, and macrophage activity, following paediatric burn injury 小儿烧伤后持续存在的促炎 T 细胞表型和巨噬细胞活性

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-03-08 DOI: 10.1002/cti2.1496

Donna Langley, Kate Zimmermann, Emma Krenske, Giorgio Stefanutti, Roy M Kimble, Andrew JA Holland, Mark W Fear, Fiona M Wood, Tony Kenna, Leila Cuttle

Objectives

The aim of this study was to characterise the dynamic immune profile of paediatric burn patients for up to 18 months post-burn.

Methods

Flow cytometry was used to measure 25 cell markers, chemokines and cytokines which reflected both pro-inflammatory and anti-inflammatory immune profiles. Peripheral blood mononuclear cells from 6 paediatric burn patients who had returned for repeated burn and scar treatments for > 4 timepoints within 12 months post-burn were compared to four age-matched healthy controls.

Results

While overall proportions of T cells, NK cells and macrophages remained relatively constant, over time percentages of these immune cells differentiated into effector and proinflammatory cell phenotypes including Th17 and activated γδ T cells. Circulating proportions of γδ T cells increased their expression of pro-inflammatory mediators throughout the burn recovery, with a 3–6 fold increase of IL-17 at 1–3 weeks, and NFκβ 9–18 months post-burn. T-regulatory cell plasticity was also observed, and Treg phenotype proportions changed from systemically reduced skin-homing T-regs (CCR4⁺) and increased inflammatory (CCR6⁺) at 1-month post-burn, to double-positive cell types (CCR4⁺CCR6⁺) elevated in circulation for 18 months post-burn. Furthermore, Tregs were observed to proportionally express less IL-10 but increased TNF-α over 18 months.

Conclusion

Overall, these results indicate the circulating percentages of immune cells do not increase or decrease over time post-burn, instead they become highly specialised, inflammatory and skin-homing. In this patient population, these changes persisted for at least 18 months post-burn, this ‘immune distraction’ may limit the ability of immune cells to prioritise other threats post-burn, such as respiratory infections.

目的本研究旨在描述烧伤后 18 个月内儿科烧伤患者的动态免疫特征。方法采用流式细胞术测量 25 种细胞标记物、趋化因子和细胞因子，它们反映了促炎和抗炎免疫特征。将烧伤后 12 个月内 4 个时间点反复接受烧伤和疤痕治疗的 6 名儿科烧伤患者的外周血单核细胞与 4 名年龄匹配的健康对照者的外周血单核细胞进行比较。结果虽然 T 细胞、NK 细胞和巨噬细胞的总体比例保持相对稳定，但随着时间的推移，这些免疫细胞分化成效应细胞和促炎症细胞表型（包括 Th17 和活化的 γδ T 细胞）的比例却在增加。在整个烧伤恢复过程中，循环中的γδ T 细胞增加了其促炎介质的表达比例，其中 IL-17 在烧伤后 1-3 周增加了 3-6 倍，NFκβ 在烧伤后 9-18 个月增加了 3-6 倍。还观察到 Treg 调节细胞的可塑性，Treg 表型比例从烧伤后 1 个月时全身皮肤归巢 Tregs（CCR4+）减少和炎性 Tregs（CCR6+）增加，转变为烧伤后 18 个月时血液循环中的双阳性细胞类型（CCR4+CCR6+）增加。此外，在 18 个月的时间里，还观察到 Tregs 按比例减少了 IL-10 的表达，但增加了 TNF-α。结论总体而言，这些结果表明，随着时间的推移，烧伤后循环中的免疫细胞比例不会增加或减少，相反，它们会变得高度特化、具有炎症性和皮肤归属性。在该患者群体中，这些变化在烧伤后至少持续了 18 个月，这种 "免疫分心 "可能会限制免疫细胞在烧伤后优先处理其他威胁（如呼吸道感染）的能力。

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引用次数: 0