Clinical & Translational Immunology最新文献_第5页

Antigen-specific polyfunctional cytotoxic T cells differentiate intraocular from peripheral blood immune responses in posterior uveitis 抗原特异性多功能细胞毒性T细胞在后葡萄膜炎中区分眼内免疫反应和外周血免疫反应

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-05-15 DOI: 10.1002/cti2.70036

Kaiser Alam, Arun Raina, Bibhuprasad Das, Sandhya Bhanja, Sayantan Ghosh, John V Forrester, Soumyava Basu

Objectives

Peripheral blood is frequently used to study the immune response in human uveitis because of the inaccessibility of ocular tissue samples. To determine whether peripheral blood immune cells accurately reflect the intraocular immune response, we compared the T-cell profiles and antigen-specific cytokine responses between paired vitreous and peripheral blood samples from patients with sight-threatening posterior uveitis.

Methods

We collected paired vitreous and peripheral blood mononuclear cells (PBMCs) from 24 patients with posterior uveitis. Multi-parametric flow cytometry was employed to identify surface and intracellular cytokine markers after activation with candidate antigenic peptides [Mycobacterium tuberculosis (MTb) peptides and retinal autoantigens]. Data were analysed through manual gating, unsupervised clustering and dimensionality reduction (FlowSOM, FlowJo).

Results

The CD8⁺/CD4⁺ ratio in a representative set of seven paired samples was higher in the vitreous than in PBMCs. Vitreous CD4⁺ and CD8⁺ cells displayed greater polyfunctional potential (TNFα⁺IFNγ⁺IL-2⁺ and PMA/ionomycin activation) than PBMCs. Upon antigen-specific activation in vitro, vitreous CD8⁺ T cells (but not CD4⁺ T cells) showed a stronger polyfunctional response than PBMCs against both MTb (in TB-immunoreactive patients) and retinal autoantigens. Unsupervised clustering identified 15 distinct CD3⁺ T-cell metaclusters, each with unique profiles in the vitreous and PBMCs. Significant cluster enrichment was observed among the vitreous infiltrating cells in TB-immunoreactive cases compared to non-TB uveitis, but no such enrichment was found among PBMCs in either patient cohort.

Conclusion

The vitreous T-cell compartment in this group of uveitis patients was functionally dominated by antigen-responsive cytotoxic CD8⁺ T cells and was distinct from the corresponding peripheral blood compartment.

目的由于眼部组织样本难以获得，外周血常被用于研究人葡萄膜炎的免疫反应。为了确定外周血免疫细胞是否准确反映眼内免疫反应，我们比较了来自视力威胁后葡萄膜炎患者的配对玻璃体和外周血样本之间的t细胞谱和抗原特异性细胞因子反应。方法采集24例后葡萄膜炎患者的配对玻璃体和外周血单个核细胞（pbmc）。采用多参数流式细胞术鉴定候选抗原肽[结核分枝杆菌肽和视网膜自身抗原]激活后的细胞表面和细胞内细胞因子标志物。数据通过手动门控、无监督聚类和降维（FlowSOM、FlowJo）进行分析。结果玻璃体中CD8+/CD4+比值高于PBMCs。玻璃体CD4+和CD8+细胞表现出比pbmc更大的多功能潜能（TNFα+IFNγ+IL-2+和PMA/离子霉素激活）。在体外抗原特异性激活后，玻璃体CD8+ T细胞（而不是CD4+ T细胞）对MTb（在tb免疫反应性患者中）和视网膜自身抗原表现出比PBMCs更强的多功能反应。无监督聚类鉴定出15个不同的CD3+ t细胞元簇，每个元簇在玻璃体和pbmc中都有独特的特征。与非结核性葡萄膜炎患者相比，在结核免疫反应性患者的玻璃体浸润细胞中观察到显著的簇状富集，但在两组患者的pbmc中均未发现这种富集。结论本组葡萄膜炎患者玻璃体T细胞区室功能上以抗原反应性细胞毒性CD8+ T细胞为主，与相应的外周血区室不同。

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引用次数: 0

IgG promotes TNF-α induced osteoclastogenesis by upregulating the expression of TNFR1 and the NF-κB signalling pathway IgG通过上调TNFR1和NF-κB信号通路的表达，促进TNF-α诱导的破骨细胞生成

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-05-06 DOI: 10.1002/cti2.70034

Haifeng Yin, Yao Teng, Guo-Min Deng

Objectives

Tumor necrosis factor-α (TNF-α) plays a pivotal role in bone damage associated with inflammatory arthritis such as rheumatoid arthritis (RA). Both systemic lupus erythematosus (SLE) and rheumatoid arthritis exhibit clinical manifestations of inflammatory arthritis, yet the joint bone damage in RA is more severe than that in SLE. The reasons for this differential manifestation remain unclear. This study aimed to determine the role of IgG antibodies in TNF-α-induced osteoclastogenesis.

Methods

We conducted cellular experiments to ascertain whether IgG affects TNF-α-induced osteoclastogenesis and validate the role of IgG in TNF-α-induced cartilage destruction in mouse models of arthritis through animal studies.

Results

We found that IgG promoted TNF-α-induced osteoclastogenesis by upregulating the expression of tumor necrosis factor receptor 1 (TNFR1) and enhancing the downstream nuclear factor-kappaB (NF-κB) signalling pathway. In the TNF-α-induced arthritis mouse model, IgG further exacerbated the destruction of articular cartilage.

Conclusion

Our findings clarified that IgG aggravated TNF-α-mediated osteoclastogenesis, further elucidating the mechanistic basis for the divergent manifestations of joint bone damage in SLE and RA.

肿瘤坏死因子-α (TNF-α)在类风湿性关节炎（RA）等炎症性关节炎相关的骨损伤中起关键作用。系统性红斑狼疮（SLE）和类风湿关节炎均表现为炎性关节炎的临床表现，但RA的关节骨损伤比SLE更严重。这种不同表现的原因尚不清楚。本研究旨在确定IgG抗体在TNF-α-诱导的破骨细胞发生中的作用。方法通过细胞实验确定IgG是否影响TNF-α诱导的破骨细胞生成，并通过动物实验验证IgG在TNF-α诱导的关节炎小鼠模型软骨破坏中的作用。结果IgG通过上调肿瘤坏死因子受体1 （tumor necrosis factor receptor 1, TNFR1）的表达，增强下游核因子κ b （nuclear factor -κB, NF-κB）信号通路，促进TNF-α-诱导的破骨细胞生成。在TNF-α-诱导的关节炎小鼠模型中，IgG进一步加重了对关节软骨的破坏。结论我们的研究结果阐明了IgG可加重TNF-α介导的破骨细胞生成，进一步阐明了SLE与RA关节骨损伤不同表现的机制基础。

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引用次数: 0

Differential reactivity of SARS-CoV-2 S-protein T-cell epitopes in vaccinated versus naturally infected individuals 接种疫苗与自然感染者SARS-CoV-2 s蛋白t细胞表位的差异反应性

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-05-06 DOI: 10.1002/cti2.70031

Daniel J Browne, Pauline Crooks, Corey Smith, Denise L Doolan

Objectives

Vaccine-induced protective immunity against SARS-CoV-2 has proved difficult to sustain. Robust T-cell responses are thought to play an important role, but T-cell responses against the SARS-CoV-2 spike protein (S-protein), the core vaccine antigen, following vaccination or natural infection are incompletely understood.

Methods

Herein, the reactivity of 170 putative SARS-CoV-2 S-protein CD8⁺ and CD4⁺ T-cell peptide epitopes in the same individuals prior to vaccination, after COVID-19 vaccination, and again following subsequent natural infection was assayed using a high-throughput reverse transcription-quantitative PCR (HTS-RT-qPCR) assay.

Results

The profile of immunoreactive SARS-CoV-2 S-protein epitopes differed between vaccination and natural infection. Vaccine-induced immunoreactive epitopes were localised primarily into two extra-domanial regions. In contrast, epitopes recognised following natural infection were spread across the antigen. Furthermore, T-cell epitopes in naïve individuals were primarily recognised in association with HLA-A, while natural infection shifted epitope associations towards HLA-B, particularly the B7 supertype.

Conclusion

This study provides insight into T-cell responses against the SARS-CoV-2 S-protein following vaccination and subsequent natural infection.

疫苗诱导的针对SARS-CoV-2的保护性免疫已被证明难以维持。人们认为强大的t细胞反应发挥了重要作用，但在接种疫苗或自然感染后，t细胞对核心疫苗抗原SARS-CoV-2刺突蛋白（s -蛋白）的反应尚不完全清楚。方法采用高通量逆转录定量PCR （HTS-RT-qPCR）方法检测同一个体接种疫苗前、接种COVID-19疫苗后以及随后自然感染后170个推测的SARS-CoV-2 s蛋白CD8+和CD4+ t细胞肽表位的反应性。结果免疫反应性SARS-CoV-2 s蛋白表位谱在疫苗接种和自然感染之间存在差异。疫苗诱导的免疫反应性表位主要定位于两个域外区域。相比之下，自然感染后识别的表位在抗原上扩散。此外，naïve个体的t细胞表位主要与HLA-A相关，而自然感染将表位关联转移到HLA-B，特别是B7超型。结论本研究揭示了接种疫苗和随后的自然感染后t细胞对SARS-CoV-2 s蛋白的反应。

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引用次数: 0

Leveraging radiotherapy to improve immunotherapy outcomes: rationale, progress and research priorities 利用放射治疗改善免疫治疗结果：基本原理、进展和研究重点

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-04-08 DOI: 10.1002/cti2.70030

Faith Hartley, Martin Ebert, Alistair M Cook

The most successful immunotherapies for solid malignancies to date, immune checkpoint inhibitors, target the essential role of T cells in antitumor immunity. However, T-cell dysfunction presents a major hindrance to treatment efficacy, warranting research into combined treatment strategies for improving outcomes. The use of radiotherapy for this purpose has garnered much interest. Preclinical study has established that radiotherapy activates various immune mechanisms to improve T-cell activation, localisation and function within tumors, which improves response to immune checkpoint inhibitors. However, so far, these strategies have not been successfully translated into the clinic. Here, we briefly reflect on the development of immune checkpoint inhibitors and the mechanistic insights revealed by an evolving understanding of T-cell dysfunction in cancer, before providing an overview of the immunomodulatory effects of radiotherapy in the context of the T-cell-mediated antitumor immune response. We discuss the mixed results of clinical trials, comment on various factors that may preclude immuno-radiotherapy responses in the clinic, and highlight priorities for preclinical and clinical study. Finally, we discuss the role of emerging combinations of radiotherapy and immunotherapy to potentially provide additional treatment options and improve outcomes for patients.

迄今为止，治疗实体恶性肿瘤最成功的免疫疗法--免疫检查点抑制剂--针对的是 T 细胞在抗肿瘤免疫中的重要作用。然而，T 细胞功能障碍是影响疗效的主要障碍，因此有必要研究改善疗效的综合治疗策略。为此，放疗的应用引起了广泛关注。临床前研究证实，放疗可激活各种免疫机制，改善肿瘤内 T 细胞的活化、定位和功能，从而改善对免疫检查点抑制剂的反应。然而，迄今为止，这些策略尚未成功应用于临床。在此，我们简要回顾了免疫检查点抑制剂的发展历程，以及对癌症中 T 细胞功能障碍不断发展的认识所揭示的机理，然后概述了放疗在 T 细胞介导的抗肿瘤免疫反应中的免疫调节作用。我们讨论了临床试验喜忧参半的结果，评论了可能阻碍临床免疫放疗反应的各种因素，并强调了临床前和临床研究的重点。最后，我们讨论了新出现的放疗和免疫疗法组合的作用，它们有可能提供更多的治疗选择并改善患者的预后。

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引用次数: 0

Mucosal-associated invariant T cells correlate with myocardial ischaemia and remodelling in coronary artery disease 粘膜相关的不变性T细胞与冠状动脉疾病的心肌缺血和重构相关

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-03-24 DOI: 10.1002/cti2.70029

Jiafu Wang, Song Li, Xianling Zhou, Hongxing Wu, Xiaolan Ouyang, Zhuoshan Huang, Long Peng, Qian Chen, Yuman Wu, Zhitong Li, Ziyi Peng, Yi Yang, Yan Lu, Xixiang Tang, Yue Li, Suhua Li

Objectives

Myocardial ischaemia and remodelling are major contributors to the progression and mortality of coronary artery disease (CAD). Previous studies have shown immune cell alterations in CAD patients, but their characteristics and associations with myocardial ischaemia and remodelling remain unclear.

Methods

We compared immune cell changes among patients without CAD, those with CAD and those with CAD and heart failure (HF).

Results

We found a progressive reduction in circulating mucosal-associated invariant T (MAIT) cells across the three patient groups. MAIT cells exhibited increased expression of activation markers (CD69 and PD-1) and cytotoxic molecules (such as granzyme B). The features of MAIT cells were correlated positively with worsening clinical indicators of myocardial ischaemia and remodelling, including the Gensini score, cTnI, NT-proBNP, LVEF and E/e′. Additionally, the reduction, activation and cytotoxicity of MAIT cells were associated with indicators of myocardial fibrosis (sST2, Gal-3, PICP and PIIINP), a central pathological mechanism of myocardial remodelling. Finally, we preliminarily explored potential triggers for MAIT cell abnormalities in CAD patients and found that impaired intestinal barrier function and increased circulating bacterial antigens may contribute to these changes.

Conclusions

During CAD progression, we observed a decrease in circulating MAIT cells. Enhanced activation and cytotoxicity of MAIT cells are associated with myocardial ischaemia and remodelling in CAD patients with heart failure, potentially triggered by gut microbial leakage. Our findings suggest a novel strategy for monitoring and intervention in disease progression.

目的心肌缺血和重塑是导致冠状动脉疾病（CAD）恶化和死亡的主要原因。以前的研究显示，CAD 患者的免疫细胞发生了变化，但其特征及其与心肌缺血和重塑的关系仍不清楚。方法我们比较了无 CAD 患者、CAD 患者和 CAD 合并心力衰竭（HF）患者的免疫细胞变化。结果我们发现，在三个患者组中，循环中的粘膜相关不变 T 细胞（MAIT）逐渐减少。MAIT 细胞的活化标志物（CD69 和 PD-1）和细胞毒性分子（如颗粒酶 B）表达增加。MAIT 细胞的特征与心肌缺血和重塑的临床指标恶化呈正相关，包括 Gensini 评分、cTnI、NT-proBNP、LVEF 和 E/e′。此外，MAIT 细胞的减少、活化和细胞毒性与心肌纤维化指标（sST2、Gal-3、PICP 和 PIIINP）有关，这是心肌重塑的核心病理机制。最后，我们初步探讨了导致 CAD 患者 MAIT 细胞异常的潜在诱因，发现肠道屏障功能受损和循环细菌抗原增加可能是导致这些变化的原因。结论在 CAD 进展过程中，我们观察到循环 MAIT 细胞减少。MAIT 细胞的活化和细胞毒性增强与心力衰竭的 CAD 患者心肌缺血和重塑有关，这可能是由肠道微生物渗漏引发的。我们的研究结果为监测和干预疾病进展提供了一种新策略。

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引用次数: 0

γδ T cell characterisation in the long term after haematopoietic stem cell transplantation and its impact on CMV control and cGVHD severity 造血干细胞移植后长期γδ T细胞特征及其对CMV控制和cGVHD严重程度的影响

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-03-07 DOI: 10.1002/cti2.70027

Faisal Alagrafi, Arwen Stikvoort, Ahmed Gaballa, Martin Solders, Olle Ringden, Thomas Poiret, Lucas CM Arruda, Michael Uhlin

Objectives

The clinical outcome after allogeneic haematopoietic stem cell transplantation (aHCT) relies greatly on the efficient recovery of T cells. Several studies have investigated the short-term γδ T cell reconstitution and their role in clinical outcomes following haematopoietic stem cell transplantation. Nevertheless, their long-term characteristics and impact have remained largely unknown.

Methods

We analysed γδ T cells from 20 recipient/donor pairs at phenotypic, clonotypic and functional levels to assess their reconstitution ≥ 8 years (median 18 years) post-transplantation using high-parameter flow cytometry and next-generation sequencing of the TCR γ-chain.

Results

γδ T cells displayed comparable phenotypic characteristics between recipients and matching donors. The Vδ2⁺ subset showed a more activated phenotype and cytokine production, while the Vδ1⁺ and non-Vδ2 T cells maintained long-term CMV control. TCR γ-chain composition in long-term survivors was largely restored, with no significant differences in gene segment usage or diversity. A small cohort of recipients with severe chronic graft-versus-host disease (GVHD) showed overrepresented donor-derived private clonotypes. Furthermore, we also found elevated HLA-DR⁺Vδ1⁺ T cells in recipients with severe chronic GVHD.

Conclusion

Overall, γδ T cells reconstitute with a normalised repertoire, high functional capacity and sustained CMV control ability. An increased proportion of activated Vδ1⁺ T cells correlates with chronic GVHD severity, indicating a potential therapeutic target.

目的同种异体造血干细胞移植（aHCT）后的临床效果很大程度上依赖于T细胞的有效恢复。一些研究调查了短期γδ T细胞重构及其在造血干细胞移植后临床结果中的作用。然而，它们的长期特征和影响在很大程度上仍然是未知的。方法采用高参数流式细胞术和新一代TCR γ链测序技术，对移植后≥8年（中位18年）的20对受体/供体γδ T细胞进行表型、克隆型和功能水平的分析。结果γδ T细胞在受体和配对供体之间表现出相似的表型特征。Vδ2+ T细胞表现出更活跃的表型和细胞因子产生，而Vδ1+和非Vδ2 T细胞保持长期的CMV控制。长期幸存者的TCR γ链组成基本恢复，基因片段使用和多样性无显著差异。一小群患有严重慢性移植物抗宿主病（GVHD）的受体显示供体衍生的私有克隆型。此外，我们还发现严重慢性GVHD患者的HLA-DR+Vδ1+ T细胞升高。结论总体而言，重组的γδ T细胞具有正常的库，高功能和持续的CMV控制能力。激活的Vδ1+ T细胞比例增加与慢性GVHD严重程度相关，提示潜在的治疗靶点。

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引用次数: 0

Distinct MAIT cell phenotypes associated with sepsis clinical outcome in emergency department patients 不同的MAIT细胞表型与急诊科患者脓毒症的临床结果相关

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-03-04 DOI: 10.1002/cti2.70028

Johanna Emgård, Iva Filipovic, Christian Unge, Laura M Palma Medina, Åsa Parke, Helena Bergsten, Kirsten Moll, Majda Dzidic, Helena Alpkvist, Hong Fang, Volkan Özenci, Niklas K Björkström, Mattias Svensson, Johan K Sandberg, Kristoffer Strålin, Anna Norrby-Teglund

Objectives

Rapid diagnosis and intervention are critical for sepsis patient outcomes. However, diagnosis is challenging because of a heterogenic patient group as well as sometimes vague symptoms when the patient presents at the emergency department. Mucosal-associated invariant T (MAIT) cells are rapid responders to infection, but their role and characteristics in the early course of sepsis remain unknown. Here, we evaluate the early MAIT cell characteristics in the blood of patients triggering a clinical sepsis alert system at the emergency department.

Methods

Peripheral blood mononuclear cells were isolated from freshly drawn blood and immediately stained. MAIT cell phenotyping analyses were conducted using multiparameter flow cytometry. All analyses were completed prior to the stratification of patients into sepsis or non-sepsis groups. Soluble factors in plasma were measured using a multiplex assay.

Results

Unsupervised high-dimensional phenotyping identified distinct MAIT cell activation profiles in sepsis and non-sepsis groups. Among sepsis patients, hierarchical clustering of MAIT cell phenotypes separated clinical endotypes into three groups with different infection focus, severity and aetiology. A prominent characteristic of sepsis severity was high expression of CD69 on MAIT cells, which was associated with organ dysfunction, lymphopenia and poor outcome. Plasma levels of IL-12, IL-15, TNF, IFNγ and CXCL10 correlated with the magnitude of MAIT cell activation in sepsis patients.

Conclusions

These clinical endotype-specific MAIT cell phenotypes presenting already in the emergency department are of interest for early patient identification and prognostication in sepsis.

目的快速诊断和干预对脓毒症患者的预后至关重要。然而，诊断是具有挑战性的，因为异质的患者群体，以及有时模糊的症状，当病人出现在急诊科。粘膜相关的不变性T细胞（MAIT）对感染有快速反应，但它们在脓毒症早期过程中的作用和特征尚不清楚。在这里，我们评估了在急诊部门触发临床败血症警报系统的患者血液中的早期MAIT细胞特征。方法从新鲜抽血中分离外周血单个核细胞，立即染色。采用多参数流式细胞术进行MAIT细胞表型分析。所有的分析都是在将患者分为败血症组和非败血症组之前完成的。血浆中可溶性因子用多重测定法测定。结果无监督的高维表型鉴定了脓毒症组和非脓毒症组不同的MAIT细胞激活谱。在脓毒症患者中，MAIT细胞表型的分层聚类将临床内型分为三组，分别具有不同的感染病灶、严重程度和病因。脓毒症严重程度的一个突出特征是MAIT细胞上CD69的高表达，这与器官功能障碍、淋巴细胞减少和预后不良有关。脓毒症患者血浆IL-12、IL-15、TNF、IFNγ和CXCL10水平与MAIT细胞活化程度相关。这些临床内源性特异性MAIT细胞表型已经出现在急诊科，对脓毒症的早期患者识别和预后有重要意义。

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引用次数: 0

Decreased levels and function of dendritic cells in blood and airways predict COVID-19 severity 血液和气道中树突状细胞水平和功能的下降预示着COVID-19的严重程度

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-03-03 DOI: 10.1002/cti2.70026

Björn Österberg, Sara Falck-Jones, Sindhu Vangeti, Eric Åhlberg, Meng Yu, Diana Granja, Marijn E Snik, Ryan Falck-Jones, Guilherme WF Barros, Afandi Charles, Rico Lepzien, Niclas Johansson, Tyson H Holmes, Holden Maecker, Paulo Czarnewski, Max Bell, Anna Färnert, Anna Smed-Sörensen

Objectives

Monocytes and dendritic cells (DCs) are essential players in the immune response to infections, involved in shaping innate and adaptive immunity. However, a complete understanding of their specific roles in respiratory infections, including SARS-CoV-2, remains elusive.

Methods

To investigate the dynamics of monocytes and DCs in blood as well as the upper and lower airways, we sampled 147 patients with varying degree of COVID-19 severity longitudinally during the spring of 2020.

Results

Using flow cytometry, proteomics and in vitro TLR stimulation, we found differences in the distribution and function of monocytes and DCs in patients compared with controls, and importantly, reduced levels of DCs in both blood and airways. In fact, lower frequencies of cDC2s (Lin⁻ HLA-DR⁺ CD1c⁺) early after symptom onset predicted subsequent severe disease, and depletion of DC subsets lasted longer in patients with more severe disease. In contrast, severe COVID-19 was associated with increased frequencies of activated monocytes in the lower, but not the upper, airways. Proteomic analysis showed that monocyte and DC-related cytokines in plasma and airways associated with disease severity. During convalescence, cell frequencies and responses to TLR ligands normalised in blood, except for persistently low plasmacytoid DCs.

Conclusion

Our study reveals a distinct pattern of recruitment of monocytes but not DCs to the airways during severe COVID-19. Instead, decreased levels of DCs in both blood and airways were found, possibly contributing to more severe COVID-19. The connection between low blood DCs early in disease course and more severe outcomes provides insight into COVID-19 immunopathology, with possible therapeutic implications.

目的单核细胞和树突状细胞（DCs）是对感染作出免疫反应的重要角色，参与形成先天性和适应性免疫。然而，人们对它们在呼吸道感染（包括 SARS-CoV-2）中的具体作用仍缺乏全面了解。方法为了研究血液以及上下气道中单核细胞和 DCs 的动态，我们在 2020 年春季对 147 名 COVID-19 严重程度不同的患者进行了纵向采样。结果通过流式细胞术、蛋白质组学和体外 TLR 刺激，我们发现患者体内单核细胞和 DC 的分布和功能与对照组存在差异，重要的是，患者血液和气道中的 DC 水平均有所降低。事实上，症状出现后早期较低频率的 cDC2s（Lin- HLA-DR+ CD1c+）预示着随后的严重疾病，在疾病更严重的患者中，DC 亚群的耗竭持续时间更长。相比之下，严重的 COVID-19 与下呼吸道活化单核细胞频率增加有关，而与上呼吸道无关。蛋白质组分析表明，血浆和气道中的单核细胞和 DC 相关细胞因子与疾病的严重程度有关。在康复期间，血液中的细胞频率和对 TLR 配体的反应趋于正常，只有浆细胞型 DC 的数量持续偏低。结论我们的研究揭示了严重 COVID-19 期间单核细胞而非 DCs 招募到气道的独特模式。相反，我们发现血液和气道中的 DCs 水平都有所下降，这可能是导致 COVID-19 更为严重的原因。病程早期血液中DC含量低与更严重的结果之间的联系为COVID-19免疫病理学提供了深入的见解，并可能具有治疗意义。

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引用次数: 0

Organ-on-chip for advancing CAR therapy 器官芯片推进CAR - CAR治疗

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-02-26 DOI: 10.1002/cti2.70024

Lightson Ngashangva, Sunil Martin

Despite great strides of progress, at least 60% of the responding patients relapse to CAR therapy across the blood malignancies. Off-tumor toxicity apart from functional deficits, cytopenia and infection are the major unfavourable effect of CAR therapy. Models, which faithfully recapitulate the physiology and complexities of immunocompetent tumor microenvironment (TME), paused challenges in capturing potential off-tumor effects of CAR therapy. Importantly, a landmark change in the legislation allows US Food and Drug Administration and New Drugs and Clinical Trial Rules in India encourages researchers to replace animal testing with cell culture approaches relevant to human system. Organ-on-chip (OOC) based on microfluidics technology can potentially emulate multiple biochemical and biophysical intricacies of blood and lymph flow at microscale. Nonetheless, how the evolving microfluidics technology can be enabling to real-time testing of cell and gene is yet to be realised.

尽管取得了巨大的进展，但至少60%的应答患者在血液恶性肿瘤中复发。肿瘤外毒性除了功能缺陷外，细胞减少和感染是CAR治疗的主要不利影响。模型忠实地概括了免疫活性肿瘤微环境（TME）的生理学和复杂性，暂停了捕捉CAR治疗潜在的非肿瘤效应的挑战。重要的是，立法中具有里程碑意义的变化允许美国食品和药物管理局和印度的新药和临床试验规则鼓励研究人员用与人体系统相关的细胞培养方法取代动物试验。基于微流体技术的器官芯片（OOC）有可能在微尺度上模拟血液和淋巴流动的多种生化和生物物理复杂性。然而，如何发展微流体技术能够使细胞和基因的实时测试尚未实现。

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Effect of Bacille Calmette–Guérin vaccination on immune responses to SARS-CoV-2 and COVID-19 vaccination 卡介苗-谷氨酰胺疫苗接种对SARS-CoV-2和COVID-19疫苗免疫应答的影响

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-01-25 DOI: 10.1002/cti2.70023

Nicole L Messina, Susie Germano, Amy W Chung, Carolien E van de Sandt, Natalie E Stevens, Lilith F Allen, Rhian Bonnici, Julio Croda, Claudio Counoupas, Branka Grubor-Bauk, Ebene R Haycroft, Katherine Kedzierska, Ellie McDonald, Rebecca McElroy, Mihai G Netea, Boris Novakovic, Kirsten P Perrett, Laure F Pittet, Ruth A Purcell, Kanta Subbarao, James A Triccas, David J Lynn, Nigel Curtis, the BRACE Trial Consortium Group

Objectives

Bacille Calmette–Guérin (BCG) vaccination has off-target effects on disease risk for unrelated infections and immune responses to vaccines. This study aimed to determine the immunomodulatory effects of BCG vaccination on immune responses to vaccines against SARS-CoV-2.

Methods

Blood samples, from a subset of 275 SARS-CoV-2-naïve healthcare workers randomised to BCG vaccination (BCG group) or no BCG vaccination (Control group) in the BRACE trial, were collected before and 28 days after the primary course (two doses) of ChAdOx1-S (Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) vaccination. SARS-CoV-2-specific antibodies were measured using ELISA and multiplex bead array, whole blood cytokine responses to γ-irradiated SARS-CoV-2 (iSARS) stimulation were measured by multiplex bead array, and SARS-CoV-2-specific T-cell responses were measured by activation-induced marker and intracellular cytokine staining assays.

Results

After randomisation (mean 11 months) but prior to COVID-19 vaccination, the BCG group had lower cytokine responses to iSARS stimulation than the Control group. After two doses of ChAdOx1-S, differences in iSARS-induced cytokine responses between the BCG group and Control group were found for three cytokines (CTACK, TRAIL and VEGF). No differences were found between the groups after BNT162b2 vaccination. There were also no differences between the BCG and Control groups in COVID-19 vaccine-induced antigen-specific antibody responses, T-cell activation or T-cell cytokine production.

Conclusion

BCG vaccination induced a broad and persistent reduction in ex vivo cytokine responses to SARS-CoV-2. Following COVID-19 vaccination, this effect was abrogated, and BCG vaccination did not influence adaptive immune responses to COVID-19 vaccine antigens.

目的：卡介苗（BCG）疫苗接种对非相关感染的疾病风险和疫苗免疫反应具有脱靶效应。本研究旨在确定卡介苗接种对SARS-CoV-2疫苗免疫应答的免疫调节作用。方法：在BRACE试验中随机分为接种卡介苗组（BCG组）或未接种卡介苗组（对照组）的275名SARS-CoV-2-naïve医护人员的血液样本，在接种ChAdOx1-S（牛津-阿斯利康）或BNT162b2（辉瑞- biontech）疫苗的初级疗程（两剂）之前和之后28天收集。采用ELISA和多重头阵列法检测SARS-CoV-2特异性抗体，采用多重头阵列法检测γ辐照SARS-CoV-2 （iSARS）刺激下的全血细胞因子反应，采用活化诱导标记和细胞内细胞因子染色法检测SARS-CoV-2特异性t细胞反应。结果：随机化后（平均11个月），但在COVID-19疫苗接种之前，BCG组对iSARS刺激的细胞因子反应低于对照组。两剂量ChAdOx1-S后，卡介苗组和对照组在isars诱导的细胞因子反应中发现了三种细胞因子（CTACK、TRAIL和VEGF）的差异。接种BNT162b2疫苗后各组间无差异。卡介苗组和对照组在COVID-19疫苗诱导的抗原特异性抗体反应、t细胞活化或t细胞细胞因子产生方面也没有差异。结论：卡介苗接种诱导了对SARS-CoV-2的体外细胞因子反应的广泛和持续的降低。接种COVID-19疫苗后，这种效应消失，接种卡介苗不影响对COVID-19疫苗抗原的适应性免疫应答。

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引用次数: 0