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Infiltrating characteristics and prognostic value of tertiary lymphoid structures in resected gastric neuroendocrine neoplasm patients 切除胃神经内分泌肿瘤患者三级淋巴结构的浸润特征和预后价值
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2024-02-05 DOI: 10.1002/cti2.1489
Daming Cai, Xingzhou Wang, Heng Yu, Chunhua Bai, Yonghuan Mao, Mengjie Liang, Xuefeng Xia, Song Liu, Meng Wang, Xiaofeng Lu, Junfeng Du, Xiaofei Shen, Wenxian Guan

Objectives

Tertiary lymphoid structures (TLSs) are lymphocyte aggregates that play an anti-tumor role in most solid tumors. However, the functions of TLS in gastric neuroendocrine neoplasms (GNENs) remain unknown. This study aimed to determine the characteristics and prognostic values of TLS in resected GNEN patients.

Methods

Haematoxylin–eosin, immunohistochemistry (IHC) and multiple fluorescent IHC staining were used to assess TLS to investigate the correlation between TLSs and clinicopathological characteristics and its prognostic value.

Results

Tertiary lymphoid structures were identified in 84.3% of patients with GNEN. They were located in the stromal area or outside the tumor tissue and mainly composed of B and T cells. A high density of TLSs promoted an anti-tumor immune response in GNEN. CD15+ TANs and FOXP3+ Tregs in TLSs inhibited the formation of TLSs. High TLS density was significantly associated with prolonged recurrence-free survival (RFS) and overall survival (OS) of GNENs. Univariate and multivariate Cox regression analyses revealed that TLS density, tumor size, tumor–node–metastasis (TNM) stage and World Health Organisation (WHO) classification were independent prognostic factors for OS, whereas TLS density, tumor size and TNM stage were independent prognostic factors for RFS. Finally, OS and RFS nomograms were developed and validated, which were superior to the WHO classification and the TNM stage.

Conclusion

Tertiary lymphoid structures were mainly located in the stromal area or outside the tumor area, and high TLS density was significantly associated with the good prognosis of patients with GNEN. Incorporating TLS density into a nomogram may improve survival prediction in patients with resected GNEN.

目的 三级淋巴结构(TLS)是淋巴细胞聚集体,在大多数实体瘤中发挥抗肿瘤作用。然而,三级淋巴结构在胃神经内分泌肿瘤(GNENs)中的功能尚不清楚。本研究旨在确定切除的胃神经内分泌瘤患者体内 TLS 的特征和预后价值。 方法 采用血色素-伊红、免疫组织化学(IHC)和多重荧光 IHC 染色法评估 TLS,研究 TLS 与临床病理特征的相关性及其预后价值。 结果 84.3%的 GNEN 患者发现了三级淋巴结构。它们位于基质区或肿瘤组织外,主要由 B 细胞和 T 细胞组成。高密度的三级淋巴结构促进了 GNEN 的抗肿瘤免疫反应。TLSs中的CD15+ TANs和FOXP3+ Tregs抑制了TLSs的形成。高TLS密度与GNENs无复发生存期(RFS)和总生存期(OS)的延长明显相关。单变量和多变量考克斯回归分析显示,TLS密度、肿瘤大小、肿瘤-结节-转移(TNM)分期和世界卫生组织(WHO)分类是OS的独立预后因素,而TLS密度、肿瘤大小和TNM分期是RFS的独立预后因素。最后,制定并验证了OS和RFS提名图,该提名图优于WHO分类和TNM分期。 结论 三级淋巴结构主要位于基质区或肿瘤区以外,TLS密度高与GNEN患者的良好预后显著相关。将 TLS 密度纳入提名图可能会改善对切除 GNEN 患者的生存预测。
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引用次数: 0
SARS-CoV-2-associated T-cell infiltration in the central nervous system 中枢神经系统中与 SARS-CoV-2 相关的 T 细胞浸润
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2024-01-31 DOI: 10.1002/cti2.1487
Malte Mohme, Christoph Schultheiß, Andras Piffko, Antonia Fitzek, Lisa Paschold, Benjamin Thiele, Klaus Püschel, Markus Glatzel, Manfred Westphal, Katrin Lamszus, Jakob Matschke, Mascha Binder

Objectives

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Although an acute SARS-CoV-2 infection mainly presents with respiratory illness, neurologic symptoms and sequelae are increasingly recognised in the long-term treatment of COVID-19 patients. The pathophysiology and the neuropathogenesis behind neurologic complications of COVID-19 remain poorly understood, but mounting evidence points to endothelial dysfunction either directly caused by viral infection or indirectly by inflammatory cytokines, followed by a local immune response that may include virus-specific T cells. However, the type and role of central nervous system-infiltrating T cells in COVID-19 are complex and not fully understood.

Methods

We analysed distinct anatomical brain regions of patients who had deceased as a result of COVID-19-associated pneumonia or complications thereof and performed T cell receptor Vβ repertoire sequencing. Clonotypes were analysed for SARS-CoV-2 association using public TCR repertoire data.

Results

Our descriptive study demonstrates that SARS-CoV-2-associated T cells are found in almost all brain areas of patients with fatal COVID-19 courses. The olfactory bulb, medulla and cerebellum were brain regions showing the most SARS-CoV-2 specific sequence patterns. Neuropathological workup demonstrated primary CD8+ T-cell infiltration with a perivascular infiltration pattern.

Conclusion

Future research is needed to better define the relationship between T-cell infiltration and neurological symptoms and its long-term impact on patients' cognitive and mental health.

感染严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)会导致冠状病毒病 2019(COVID-19)。虽然急性 SARS-CoV-2 感染主要表现为呼吸系统疾病,但在 COVID-19 患者的长期治疗中,神经系统症状和后遗症越来越受到重视。人们对 COVID-19 神经系统并发症的病理生理学和神经发病机制仍然知之甚少,但越来越多的证据表明,病毒感染直接导致内皮功能障碍,或炎症细胞因子间接导致内皮功能障碍,随后可能出现包括病毒特异性 T 细胞在内的局部免疫反应。然而,中枢神经系统浸润 T 细胞在 COVID-19 中的类型和作用十分复杂,尚未完全明了。
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引用次数: 0
γδ T cells mediate robust anti-HIV functions during antiretroviral therapy regardless of immune checkpoint expression 无论免疫检查点表达如何,γδ T 细胞在抗逆转录病毒治疗期间都能发挥强大的抗艾滋病毒功能
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2024-01-29 DOI: 10.1002/cti2.1486
Kirsty R Field, Kathleen M Wragg, Stephen J Kent, Wen Shi Lee, Jennifer A Juno

Objectives

Although antiretroviral therapy (ART) efficiently suppresses HIV viral load, immune dysregulation and dysfunction persist in people living with HIV (PLWH). γδ T cells are functionally impaired during untreated HIV infection, but the extent to which they are reconstituted upon ART is currently unclear.

Methods

Utilising a cohort of ART-treated PLWH, we assessed the frequency and phenotype, characterised in vitro functional responses and defined the impact of immune checkpoint marker expression on effector functions of both Vδ1 and Vδ2 T cells. We additionally explore the in vitro expansion of Vδ2 T cells from PLWH on ART and the mechanisms by which such expanded cells may sense and kill HIV-infected targets.

Results

A matured NK cell-like phenotype was observed for Vδ1 T cells among 25 ART-treated individuals (PLWH/ART) studied compared to 17 HIV-uninfected controls, with heightened expression of 2B4, CD160, TIGIT and Tim-3. Despite persistent phenotypic perturbations, Vδ1 T cells from PLWH/ART exhibited strong CD16-mediated activation and degranulation, which were suppressed upon Tim-3 and TIGIT crosslinking. Vδ2 T cell degranulation responses to the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate at concentrations up to 2 ng mL−1 were significantly impaired in an immune checkpoint-independent manner among ART-treated participants. Nonetheless, expanded Vδ2 T cells from PLWH/ART retained potent anti-HIV effector functions, with the NKG2D receptor contributing substantially to the elimination of infected cells.

Conclusion

Our findings highlight that although significant perturbations remain within the γδ T cell compartment throughout ART-treated HIV, both subsets retain the capacity for robust anti-HIV effector functions.

目的 虽然抗逆转录病毒疗法(ART)能有效抑制 HIV 病毒载量,但 HIV 感染者(PLWH)的免疫调节紊乱和功能障碍依然存在。在未经治疗的 HIV 感染期间,γδ T 细胞功能受损,但目前尚不清楚抗逆转录病毒疗法后γδ T 细胞的重建程度。 方法 我们利用一组接受抗逆转录病毒疗法治疗的 PLWH,评估了 Vδ1 和 Vδ2 T 细胞的频率和表型、体外功能反应特征,并确定了免疫检查点标记表达对效应功能的影响。此外,我们还探索了抗逆转录病毒疗法治疗的 PLWH 的 Vδ2 T 细胞的体外扩增,以及这种扩增细胞感知和杀伤 HIV 感染目标的机制。 结果 在研究的 25 名接受抗逆转录病毒疗法(ART)治疗的患者(PLWH/ART)与 17 名未受 HIV 感染的对照组相比,观察到 Vδ1 T 细胞具有成熟的 NK 细胞样表型,2B4、CD160、TIGIT 和 Tim-3 表达增强。尽管存在持续的表型扰动,但来自 PLWH/ART 的 Vδ1 T 细胞表现出强烈的 CD16 介导的活化和脱颗粒,在 Tim-3 和 TIGIT 交联后,活化和脱颗粒受到抑制。在接受抗逆转录病毒疗法的参与者中,Vδ2 T细胞对浓度高达2 ng mL-1的磷酸抗原(E)-4-羟基-3-甲基丁-2-烯基焦磷酸的脱颗粒反应明显减弱,这种反应与免疫检查点无关。然而,PLWH/ART 扩增的 Vδ2 T 细胞仍具有强大的抗 HIV 效应功能,其中 NKG2D 受体在消除感染细胞方面做出了重大贡献。 结论 我们的研究结果表明,虽然在抗逆转录病毒疗法治疗的艾滋病毒感染者中,γδ T 细胞区仍存在明显的紊乱,但这两个亚群仍具有强大的抗艾滋病毒效应功能。
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引用次数: 0
Multi-omics integration reveals a nonlinear signature that precedes progression of lung fibrosis 多组学整合揭示了肺纤维化进展前的非线性特征。
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2024-01-24 DOI: 10.1002/cti2.1485
Céline Pattaroni, Christina Begka, Bailey Cardwell, Jade Jaffar, Matthew Macowan, Nicola L Harris, Glen P Westall, Benjamin J Marsland

Objectives

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive interstitial lung disease with poor outcomes. While decades of research have shed light on pathophysiological mechanisms associated with the disease, our understanding of the early molecular events driving IPF and its progression is limited. With this study, we aimed to model the leading edge of fibrosis using a data-driven approach.

Methods

Multiple omics modalities (transcriptomics, metabolomics and lipidomics) of healthy and IPF lung explants representing different stages of fibrosis were combined using an unbiased approach. Multi-Omics Factor Analysis of datasets revealed latent factors specifically linked with established fibrotic disease (Factor1) and disease progression (Factor2).

Results

Features characterising Factor1 comprised well-established hallmarks of fibrotic disease such as defects in surfactant, epithelial–mesenchymal transition, extracellular matrix deposition, mitochondrial dysfunction and purine metabolism. Comparatively, Factor2 identified a signature revealing a nonlinear trajectory towards disease progression. Molecular features characterising Factor2 included genes related to transcriptional regulation of cell differentiation, ciliogenesis and a subset of lipids from the endocannabinoid class. Machine learning models, trained upon the top transcriptomics features of each factor, accurately predicted disease status and progression when tested on two independent datasets.

Conclusion

This multi-omics integrative approach has revealed a unique signature which may represent the inflection point in disease progression, representing a promising avenue for the identification of therapeutic targets aimed at addressing the progressive nature of the disease.

目的:特发性肺纤维化(IPF)是一种破坏性进行性间质性肺病,治疗效果不佳。虽然数十年的研究已经揭示了与该疾病相关的病理生理机制,但我们对驱动 IPF 及其进展的早期分子事件的了解仍然有限。通过这项研究,我们旨在利用数据驱动方法建立纤维化前沿模型:方法:采用无偏方法将代表不同纤维化阶段的健康肺和 IPF 肺外植体的多种组学模式(转录组学、代谢组学和脂质组学)结合起来。对数据集进行的多组学因子分析揭示了与既定纤维化疾病(因子1)和疾病进展(因子2)相关的潜在因子:结果:因子1的特征包括纤维化疾病的公认标志,如表面活性物质缺陷、上皮-间质转化、细胞外基质沉积、线粒体功能障碍和嘌呤代谢。相比之下,因子2确定了一个特征,揭示了疾病进展的非线性轨迹。表征因子2的分子特征包括与细胞分化转录调控相关的基因、纤毛生成和内大麻素类脂质子集。根据每个因子的顶级转录组学特征训练的机器学习模型,在两个独立数据集上进行测试时,能准确预测疾病的状态和进展:这种多组学整合方法揭示了一个独特的特征,它可能代表了疾病进展的拐点,为确定治疗目标提供了一个很有希望的途径,以解决疾病的进展性。
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引用次数: 0
A phase II study to evaluate the safety and efficacy of anlotinib combined with toripalimab for advanced biliary tract cancer 评估安罗替尼联合托利帕单抗治疗晚期胆道癌的安全性和有效性的II期研究
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2024-01-12 DOI: 10.1002/cti2.1483
Mingzhen Zhou, Yuncheng Jin, Sihui Zhu, Chen Xu, Lin Li, Baorui Liu, Jie Shen

Objectives

To assess the safety and efficacy of anlotinib (a multi-targeted tyrosine kinase inhibitor) combined with toripalimab (a PD-1 monoclonal antibody) in the treatment of unresectable biliary tract cancer (BTC).

Methods

In this prospective, single-arm, single-centre exploratory clinical study, patients with locally progressed or metastatic BTC were included. Patients were treated with anlotinib (12 mg, PO, QD, for 2 weeks and then stopped for a week, 21 days for a cycle) and toripalimab (240 mg, IV, Q3W). The primary endpoint of the study was the objective response rate (ORR), as defined in RECIST version 1.1 criteria.

Results

In this study, 15 BTC patients who met the criteria were enrolled. The ORR was 26.7%, the median progression-free survival (mPFS) was 8.6 months (95% CI: 2.1–15.2), the median overall survival (mOS) was 14.53 months (95% CI: 0.8–28.2) and the disease control rate (DCR) was 87.6%. A patient with hilar cholangiocarcinoma was successfully converted after three cycles of treatment and underwent surgical resection. Furthermore, patient gene sequencing revealed that STK11 was mutated more frequently in patients with poor outcomes. In addition, patients with a CD8/Foxp3 ratio > 3 had a longer survival than those with a CD8/Foxp3 ratio ≤ 3 (P = 0.0397).

Conclusions

In patients with advanced BTC, the combination of anlotinib and toripalimab demonstrated remarkable anti-tumor potential, with increased objective response rates (ORR), longer overall survival (OS) and progression-free survival (PFS). Moreover, STK11 and CD8/Foxp3 may be as biomarkers that can predict the effectiveness of targeted therapy in combination with immunotherapy.

目的 评估安罗替尼(一种多靶点酪氨酸激酶抑制剂)联合托利帕利单抗(一种PD-1单克隆抗体)治疗无法切除的胆道癌(BTC)的安全性和有效性。 方法 在这项前瞻性、单臂、单中心探索性临床研究中,纳入了局部进展或转移性 BTC 患者。患者接受安罗替尼治疗(12 毫克,口服,每天一次,持续 2 周,然后停药一周,21 天为一个周期)和托利帕单抗治疗(240 毫克,静脉注射,每天三次)。研究的主要终点是客观反应率(ORR),其定义符合 RECIST 1.1 版标准。 结果 本研究共招募了 15 名符合标准的 BTC 患者。ORR为26.7%,中位无进展生存期(mPFS)为8.6个月(95% CI:2.1-15.2),中位总生存期(mOS)为14.53个月(95% CI:0.8-28.2),疾病控制率(DCR)为87.6%。一名患有肝门部胆管癌的患者在接受了三个周期的治疗后成功转为肝门部胆管癌,并接受了手术切除。此外,患者基因测序结果显示,STK11在预后较差的患者中发生突变的频率较高。此外,CD8/Foxp3比值为> 3的患者比CD8/Foxp3比值≤3的患者生存期更长(P = 0.0397)。 结论 在晚期 BTC 患者中,安罗替尼和托利帕利单抗的联合用药显示出显著的抗肿瘤潜力,客观反应率(ORR)提高,总生存期(OS)和无进展生存期(PFS)延长。此外,STK11和CD8/Foxp3可能是预测靶向疗法与免疫疗法联合治疗效果的生物标志物。
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引用次数: 0
Graft CD8 T-cell-based risk system predicts survival in antithymocyte globulin-based myeloablative haploidentical peripheral blood stem cell transplantation 基于移植物 CD8 T 细胞的风险系统可预测以抗胸腺细胞球蛋白为基础的髓溶性单倍体外周血干细胞移植的存活率
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2024-01-12 DOI: 10.1002/cti2.1484
Panpan Zhu, Luxin Yang, Yibo Wu, Jimin Shi, Xiaoyu Lai, Lizhen Liu, Yishan Ye, Jian Yu, Yanmin Zhao, Xiaolin Yuan, Huarui Fu, Zhen Cai, He Huang, Yi Luo

Objective

This study investigated the cellular composition of peripheral blood grafts for anti-thymocyte globulin (ATG)-based myeloablative haploidentical haematopoietic stem cell transplantation (haplo-HSCT).

Methods

Clinical characteristics were retrospectively evaluated in a training cohort with ATG-based myeloablative haplo-HSCT between January 2016 and February 2020 and confirmed in a validation cohort between March 2020 and June 2021.

Results

A higher dose of graft CD8+ T cells (≥ 0.85 × 108 kg−1) was significantly improved overall survival (OS; hazard ratio [HR], 1.750; P = 0.002) and disease-free survival (DFS; HR, 1.751; P < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; P = 0.038) and DFS (HR, 1.532; P = 0.027). Older patient age (> 46 years), older donor age (≥ 50 years) and a higher refined disease risk index (rDRI) were also related to OS. A graft CD8+ T-cell risk system based on graft CD8+ T-cell dose, donor age and rDRI was constructed using a nomogram model after LASSO Cox regression analysis. It showed acceptable discrimination, with a C-index of 0.62 and 0.63, respectively. Graft CD8+ T-cell dose was negatively correlated with donor age (P < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (P < 0.001).

Conclusion

A higher CD8+ T-cell dose in peripheral blood-derived grafts improves patients' survival with ATG-based myeloablative haplo-HSCT. Younger donors with higher lymphocyte percentages improved patients' survival with an intermediate rDRI risk.

目的 本研究调查了基于抗胸腺细胞球蛋白(ATG)的髓鞘消融性单倍体造血干细胞移植(haplo-HSCT)外周血移植物的细胞组成。 方法 回顾性评估2016年1月至2020年2月期间基于ATG的髓鞘消融单倍体造血干细胞移植培训队列的临床特征,并在2020年3月至2021年6月期间的验证队列中进行确认。 结果 根据多变量 Cox 回归分析,在训练队列中,较高剂量的移植物 CD8+ T 细胞(≥ 0.85 × 108 kg-1)可显著改善总生存期(OS;危险比 [HR],1.750;P = 0.002)和无病生存期(DFS;HR,1.751;P < 0.001)。单核细胞(MNC)剂量越高,OS(HR,1.517;P = 0.038)和DFS(HR,1.532;P = 0.027)越好。患者年龄较大(46 岁)、供体年龄较大(≥ 50 岁)和疾病风险指数(rDRI)较高也与 OS 有关。经过 LASSO Cox 回归分析后,使用提名图模型构建了基于移植物 CD8+ T 细胞剂量、供体年龄和 rDRI 的移植物 CD8+ T 细胞风险系统。该系统显示了可接受的区分度,C 指数分别为 0.62 和 0.63。移植物 CD8+ T 细胞剂量与供体年龄呈负相关(P < 0.001),与动员前外周血中较高的淋巴细胞百分比呈正相关(P < 0.001)。 结论 外周血移植物中 CD8+ T 细胞剂量越高,基于 ATG 的髓脱性单倍体造血干细胞移植患者的存活率越高。淋巴细胞百分比较高的年轻供者可提高患者的存活率,但 rDRI 风险居中。
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引用次数: 0
Cellular models in autoinflammatory disease research 自身炎症性疾病研究中的细胞模型
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2024-01-11 DOI: 10.1002/cti2.1481
Başak Şen, Banu Balcı-Peynircioğlu

Systemic autoinflammatory diseases are a heterogeneous group of rare genetic disorders caused by dysregulation of the innate immune system. Understanding the complex mechanisms underlying these conditions is critical for developing effective treatments. Cellular models are essential for identifying new conditions and studying their pathogenesis. Traditionally, these studies have used primary cells and cell lines of disease-relevant cell types, although newer induced pluripotent stem cell (iPSC)-based models might have unique advantages. In this review, we discuss the three cellular models used in autoinflammatory disease research, their strengths and weaknesses, and their applications to inform future research in the field.

全身性自身炎症性疾病是一类由先天性免疫系统失调引起的罕见遗传性疾病。了解这些疾病的复杂机制对于开发有效的治疗方法至关重要。细胞模型对于确定新病症和研究其发病机制至关重要。尽管基于诱导多能干细胞(iPSC)的新型模型可能具有独特的优势,但传统上,这些研究一直使用原代细胞和疾病相关细胞类型的细胞系。在这篇综述中,我们将讨论自身炎症性疾病研究中使用的三种细胞模型、它们的优缺点及其应用,为该领域未来的研究提供参考。
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引用次数: 0
CD14 down-modulation as a real-time biomarker in Kawasaki disease 作为川崎病实时生物标记物的 CD14 下调
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2023-12-30 DOI: 10.1002/cti2.1482
Yutaro Inada, Motoshi Sonoda, Yumi Mizuno, Kenichiro Yamamura, Yoshitomo Motomura, Aoba Takuma, Kenji Murata, Kenji Furuno, Junichiro Tezuka, Yasunari Sakai, Shouichi Ohga, Junji Kishimoto, Koki Hosaka, Satomi Sakata, Toshiro Hara

Objectives

The objectives of this study were to investigate the pathophysiology of Kawasaki disease (KD) from immunological and oxidative stress perspectives, and to identify real-time biomarkers linked to innate immunity and oxidative stress in KD.

Methods

We prospectively enrolled 85 patients with KD and 135 patients with diverse conditions including immune, infectious and non-infectious diseases for this investigation. Flow cytometry was used to analyse the surface expression of CD14, CD38 and CD62L on monocytes, along with a quantitative assessment of CD14 down-modulation. Additionally, oxidative stress levels were evaluated using derivatives of reactive oxygen metabolites (d-ROMs) and antioxidant capacity measured by a free radical elective evaluator system.

Results

During the acute phase of KD, we observed a prominent CD14 down-modulation on monocytes, reflecting the indirect detection of circulating innate immune molecular patterns. Moreover, patients with KD showed a significantly higher CD14 down-modulation compared with infectious and non-infectious disease controls. Notably, the surface expression of CD14 on monocytes was restored concurrently with responses to intravenous immunoglobulin and infliximab treatment in KD. Furthermore, d-ROM levels in patients with KD were significantly elevated compared with patients with infectious and non-infectious diseases. Following intravenous immunoglobulin treatment, oxidative stress levels decreased in patients with KD.

Conclusion

Monitoring CD14 down-modulation on monocytes in real-time is a valuable strategy for assessing treatment response, distinguishing KD relapse from concomitant infections and selecting second-line therapy after IVIG treatment in KD patients. The interplay between inflammation and oxidative stress likely plays a crucial role in the development of KD.

本研究旨在从免疫学和氧化应激的角度研究川崎病(KD)的病理生理学,并确定与川崎病先天免疫和氧化应激相关的实时生物标记物。
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引用次数: 0
Inflammatory cytokines as mediators of retinal endothelial barrier dysfunction in non-infectious uveitis 炎性细胞因子是非感染性葡萄膜炎视网膜内皮屏障功能障碍的介质
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2023-12-12 DOI: 10.1002/cti2.1479
Lisia Barros Ferreira, Keryn A Williams, Giles Best, Cameron D Haydinger, Justine R Smith

Characterised by intraocular inflammation, non-infectious uveitis includes a large group of autoimmune and autoinflammatory diseases that either involve the eye alone or have both ocular and systemic manifestations. When non-infectious uveitis involves the posterior segment of the eye, specifically the retina, there is substantial risk of vision loss, often linked to breakdown of the inner blood-retinal barrier. This barrier is formed by non-fenestrated retinal vascular endothelial cells, reinforced by supporting cells that include pericytes, Müller cells and astrocytes. Across the published literature, a group of inflammatory cytokines stand out as prominent mediators of intraocular inflammation, with effects on the retinal endothelium that may contribute to breakdown of the inner blood-retinal barrier, namely tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-17 and chemokine C-C motif ligand (CCL)2. This article reviews the function of each cytokine and discusses the evidence for their involvement in retinal endothelial barrier dysfunction in non-infectious uveitis, including basic laboratory investigations, studies of ocular fluids collected from patients with non-infectious uveitis, and results of clinical treatment trials. The review also outlines gaps in knowledge in this area. Understanding the disease processes at a molecular level can suggest treatment alternatives that are directed against appropriate biological targets to protect the posterior segment of eye and preserve vision in non-infectious uveitis.

非感染性葡萄膜炎以眼内炎症为特征,包括一大类自身免疫性和自身炎症性疾病,这些疾病或仅累及眼部,或同时伴有眼部和全身表现。当非感染性葡萄膜炎累及眼球后段,特别是视网膜时,视力丧失的风险很大,这通常与内层血液-视网膜屏障的破坏有关。该屏障由非栅栏状视网膜血管内皮细胞形成,并由包括周细胞、Müller 细胞和星形胶质细胞在内的支持细胞加固。在已发表的文献中,有一组炎性细胞因子是眼内炎症的主要介质,它们对视网膜内皮的影响可能会导致内部血液-视网膜屏障的破坏,它们是肿瘤坏死因子 (TNF)-α、白细胞介素 (IL)-1β、IL-6、IL-8、IL-17 和趋化因子 C-C motif ligand (CCL)2。本文回顾了每种细胞因子的功能,并讨论了它们参与非感染性葡萄膜炎视网膜内皮屏障功能障碍的证据,包括基础实验室检查、对非感染性葡萄膜炎患者眼液的研究以及临床治疗试验的结果。综述还概述了这一领域的知识空白。从分子水平上了解疾病的过程,可以提出针对适当生物靶点的替代治疗方案,以保护非感染性葡萄膜炎患者的眼球后段和视力。
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引用次数: 0
Enhanced and complementary benefits of a nalfurafine and fingolimod combination to treat immune-driven demyelination 纳呋拉芬和芬戈莫德联用治疗免疫驱动的脱髓鞘疾病可增强疗效并实现互补
IF 5.8 2区 医学 Q1 Nursing Pub Date : 2023-12-12 DOI: 10.1002/cti2.1480
Katharina Robichon, Rabia Bibi, Mackenzie Kiernan, Lisa Denny, Thomas E Prisinzano, Bronwyn M Kivell, Anne Camille La Flamme

Objectives

Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to myelin sheaths. While all current disease-modifying treatments (DMTs) are very effective at reducing relapses, they do not slow the progression of the disease, and there is little evidence that these treatments are able to repair or remyelinate damaged axons. Recent evidence suggests that activating kappa opioid receptors (KORs) has a beneficial effect on the progression of MS, and this study investigates the effects of KOR agonists treatment in combination with two current DMTs.

Methods

Using the well-established murine model for immune-driven demyelination of MS, experimental autoimmune encephalomyelitis, the effect of KOR agonists in combination with DMTs fingolimod or dimethyl fumarate on disease progression, immune cell infiltration and activation as well as myelination were analysed.

Results

Fingolimod in combination with the KOR agonist, nalfurafine, significantly increased each individual beneficial effect as measured by increased recovery of mice and reduced relapses. These beneficial effects correlated with a reduction in immune cell infiltration into the CNS as well as peripheral immune cell alterations including a reduction in autoreactive CD4+ T-cell cytokine production as well as increased myelination in the spinal cords of co-treated animals. In contrast, while the use of dimethyl fumarate in combination with nalfurafine did not adversely affect the benefits of nalfurafine, the combination did not significantly enhance those benefits.

Conclusion

This study indicates that KOR agonists can be used in combination with fingolimod and dimethyl fumarate with the nalfurafine–fingolimod combination providing enhanced benefits.

目标 多发性硬化症(MS)是一种以炎症和髓鞘损伤为特征的神经退行性疾病。虽然目前所有的改变病情疗法(DMTs)都能有效减少复发,但它们并不能延缓疾病的进展,而且几乎没有证据表明这些疗法能够修复或再髓鞘化受损的轴突。最近的证据表明,激活卡巴阿片受体(KORs)对多发性硬化症的进展有好处,本研究调查了KOR激动剂与目前两种DMTs联合治疗的效果。 方法 使用免疫驱动的多发性硬化脱髓鞘的成熟小鼠模型--实验性自身免疫性脑脊髓炎,分析 KOR 激动剂与 DMTs 芬戈莫德或富马酸二甲酯联用对疾病进展、免疫细胞浸润和活化以及髓鞘化的影响。 结果 芬戈莫德与 KOR 激动剂纳呋拉芬联用,能显著提高每种单药的疗效,具体表现为小鼠恢复能力增强,复发次数减少。这些有益效果与中枢神经系统免疫细胞浸润的减少以及外周免疫细胞的改变有关,包括自反应性 CD4+ T 细胞细胞因子产生的减少以及联合治疗动物脊髓髓鞘化的增加。相比之下,虽然富马酸二甲酯与纳呋拉芬联合使用不会对纳呋拉芬的疗效产生不利影响,但联合使用也不会显著增强这些疗效。 结论 本研究表明,KOR 激动剂可与芬戈莫德和富马酸二甲酯联用,纳呋拉芬-芬戈莫德联用可提高疗效。
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引用次数: 0
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Clinical & Translational Immunology
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