Clinical & Translational Immunology最新文献_第4页

The role of immunochemotherapy maintenance in metastatic nasopharyngeal carcinoma: insights from a cohort study in an endemic region 免疫化疗维持在转移性鼻咽癌中的作用：来自一个流行地区队列研究的见解

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-07-02 DOI: 10.1002/cti2.70043

Zhuoying Luo, Yue Xia, Yuping Zhao, Haoyang Huang, Ying Deng, Zejiang Zhan, Yingying Huang, Xun Cao, Xi Chen, Jiayu Zhou, Chixiong Liang, Weixiong Xia, Liangru Ke, Xuehua Wei, Jinling Duan, Xing Lv, Hu Liang

Objectives

Metastatic nasopharyngeal carcinoma (mNPC) following palliative chemotherapy has high incidence and mortality rates. While maintenance therapy shows promising potential, the optimal strategy remains undefined. This study aimed to evaluate the therapeutic efficacy of immunochemotherapy maintenance in patients with mNPC.

Methods

This cohort study evaluated the therapeutic efficacy of combined maintenance therapy with capecitabine and anti-PD-1 antibodies in mNPC patients, using a prospectively maintained database. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival and safety profile. Furthermore, stratification analysis and sensitivity analysis were performed.

Results

The study included 300 mNPC patients treated at Sun Yat-sen University Cancer Center from 2018 to 2023. Two hundred and thirty-four patients (78.0%) were male, and the median age was 45 years [interquartile range (IQR): 36–54]. At median follow-up of 43.6 months (IQR: 31.8–57.8), combination maintenance significantly improved PFS compared to single-drug maintenance [weighted hazard ratio (HR) 0.580, 95% confidence interval (95% CI) 0.387–0.872, P = 0.009; E-value, 2.27]. Stratification analysis revealed enhanced efficacy of immunochemotherapy maintenance in patients without prior local treatment (HR 0.414, 95% CI 0.224–0.767, P = 0.005) or with elevated premaintenance Epstein–Barr virus (EBV) DNA levels (HR 0.063, 95% CI 0.007–0.548, P = 0.012). No significant difference in PFS was observed between the capecitabine and anti-PD-1 single-agent groups. Notably, combination therapy yielded significantly longer PFS than either single-drug regimen. The safety profile was similar between combination maintenance and single-drug groups.

Conclusions

Combined maintenance therapy with anti-PD-1 antibodies and capecitabine may be a feasible treatment strategy for mNPC patients.

目的姑息性化疗后转移性鼻咽癌（mNPC）的发病率和死亡率较高。虽然维持治疗显示出良好的潜力，但最佳策略仍未确定。本研究旨在评价免疫化疗维持治疗mNPC患者的疗效。方法本队列研究使用前瞻性维护的数据库，评估卡培他滨和抗pd -1抗体联合维持治疗mNPC患者的疗效。主要终点是无进展生存期（PFS），次要终点包括总生存期和安全性。并进行分层分析和敏感性分析。该研究纳入了2018年至2023年在中山大学癌症中心接受治疗的300例mNPC患者。男性234例（78.0%），中位年龄45岁[四分位间距（IQR）： 36-54岁]。中位随访43.6个月（IQR: 31.8 ~ 57.8），联合维持较单药维持显著改善PFS[加权风险比（HR） 0.580, 95%可信区间（95% CI） 0.387 ~ 0.872, P = 0.009；创造价值,2.27]。分层分析显示，未接受过局部治疗的患者（HR 0.414, 95% CI 0.244 - 0.767, P = 0.005）或维持前eb病毒（EBV） DNA水平升高的患者（HR 0.063, 95% CI 0.007-0.548, P = 0.012）维持免疫化疗的疗效增强。卡培他滨与抗pd -1单药组间PFS无显著差异。值得注意的是，联合治疗的PFS明显长于单药治疗。联合维持组和单药组的安全性相似。结论抗pd -1抗体联合卡培他滨维持治疗可能是mNPC患者的一种可行的治疗策略。

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引用次数: 0

Cellular hierarchy for understanding heterogeneity of acute myeloid leukaemia with t(8;21)/RUNX1-RUNX1T1 细胞层级对t(8;21)/RUNX1-RUNX1T1急性髓系白血病异质性的认识

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-07-02 DOI: 10.1002/cti2.70042

Yibo Wu, Xiaolin Yuan, Xiaoyu Lai, Lizhen Liu, Yue Liang, Lihong Ni, Luxin Yang, Shanshan Hu, Jimin Shi, Jian Yu, Yanmin Zhao, Weiyan Zheng, Jie Sun, Yuanyuan Zhu, Wenjun Wu, Zhen Cai, He Huang, Shanshan Pei, Yi Luo

Objectives

Differentiation hierarchies in myeloid malignancies influence therapeutic response and prognosis. Acute myeloid leukaemia (AML) with t(8;21) is one of the most recurrent genetic subtypes of AML and is considered a distinct entity with shared characteristics. However, clinical outcomes remain markedly heterogeneous. This study aimed to investigate the relationship between leukaemic arrest at specific differentiation stages, genomic profiles and clinical outcomes in t(8;21) AML.

Methods

We conducted a retrospective study involving 338 patients with t(8;21) AML from three clinical centres in China. Patients received either chemotherapy alone (49.11%, n = 166) or chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT; 41.72%, n = 141). Immunophenotypic profiling classified patients into progenitor subgroups: MPP (20.12%, n = 68), lymphoid-primed multi-potent progenitor (14.50%, n = 49), CMP (12.72%, n = 43), GMP (24.85%, n = 84) and GP/MP (10.36%, n = 35). Based on differentiation stage, patients were categorised as primitive (Immuno-Prim; 47.34%, n = 160) or monocytic (Immuno-Mono; 35.21%, n = 119).

Results

The Immuno-Mono group was associated with lower 2-year overall survival (OS) and a higher 2-year cumulative incidence of relapse (CIR) compared to the Immuno-Prim group. Patients with a KIT mutation had poorer 2-year OS and higher 2-year CIR than those without the mutation. In the allo-HSCT cohort, the Immuno-Mono group continued to show lower 2-year OS and higher 2-year CIR relative to the Immuno-Prim group. Neither gene mutations (aside from KIT) nor chromosomal losses significantly affected OS or CIR.

Conclusions

Leukaemic differentiation stage independently predicts post-treatment outcomes in t(8;21) AML. Arrest at specific myeloid stages correlates significantly with genetic aberrations, clinical presentation, therapeutic response and survival.

目的髓系恶性肿瘤的分化等级影响治疗效果和预后。急性髓性白血病（AML）伴t（8;21）是AML最常复发的遗传亚型之一，被认为是具有共同特征的独特实体。然而，临床结果仍然存在明显的异质性。本研究旨在探讨t(8;21) AML在特定分化阶段白血病骤停、基因组谱和临床结局之间的关系。方法我们对来自中国三个临床中心的338例t(8;21) AML患者进行了回顾性研究。患者接受单独化疗（49.11%,n = 166）或化疗后异体造血干细胞移植(alloo - hsct；41.72%, n = 141)。免疫表型分析将患者分为祖细胞亚组：MPP （20.12%, n = 68）、淋巴细胞引发的多能祖细胞（14.50%,n = 49）、CMP （12.72%, n = 43）、GMP （24.85%, n = 84）和GP/MP （10.36%, n = 35）。根据分化阶段，将患者分为原始（immune - prim）；47.34%, n = 160)或单核细胞(immune - mono；35.21%, n = 119)。结果与免疫- prim组相比，免疫- mono组的2年总生存期（OS）较低，2年累积复发发生率（CIR）较高。与没有突变的患者相比，KIT突变患者的2年OS较差，2年CIR较高。在同种hsct队列中，相对于免疫- prim组，免疫- mono组继续显示较低的2年OS和较高的2年CIR。基因突变（KIT除外）和染色体缺失均未显著影响OS或CIR。结论白血病分化阶段独立预测t(8;21) AML治疗后预后。在特定的髓细胞阶段的阻滞与基因畸变、临床表现、治疗反应和生存显著相关。

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引用次数: 0

Long-term immune changes after COVID-19 and the effect of BCG vaccination and latent infections on disease severity COVID-19后长期免疫变化及卡介苗接种和潜伏感染对疾病严重程度的影响

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-06-27 DOI: 10.1002/cti2.70041

Kamila Bendíčková, Ioanna Papatheodorou, Gabriela Blažková, Martin Helán, Michaela Haláková, Petr Bednář, Erin Spearing, Lucie Obermannová, Julie Štíchová, Monika Dvořáková Heroldová, Tomáš Tomáš, Roman Panovský, Vladimír Šrámek, Marco De Zuani, Marcela Vlková, Daniel Růžek, Marcela Hortová-Kohoutková, Jan Frič

Objectives

Several years after the COVID-19 pandemic, the impact of SARS-CoV-2 on immunity and the potential protective role of Bacillus Calmette–Guérin (BCG) vaccination through trained immunity remain a subject of investigation. This study aimed to determine the long-term impact of SARS-CoV-2 on immune cells and the association between BCG vaccination, latent infections and COVID-19 severity and sepsis progression.

Methods

We conducted a prospective analysis of patients who recovered from mild/severe/critical COVID-19 (n = 97, 3–17 months after COVID-19) and sepsis patients (n = 64). First, we assessed the impact of COVID-19 and its severity on immune cell frequencies and expression of functional markers. Further, we analysed plasma titres of anti-Toxoplasma gondii/cytomegalovirus/BCG antibodies and their association with COVID-19 severity and sepsis outcome. To examine monocyte responses to secondary challenge, monocytes isolated from COVID-19 convalescent patients, BCG vaccinated and unvaccinated volunteers were stimulated with SARS-CoV-2 and LPS.

Results

Post-COVID-19 patients showed immune dysregulation regardless of disease severity characterised by altered expression of activation and functional markers in myeloid (CD39, CD64, CD85d, CD11b) and lymphoid cells (CD39, CD57, TIGIT). Strikingly, post-critical COVID-19 patients showed elevated expression of CD57 in CD8⁺ T cells compared to other severity groups. A trend toward improved outcomes in BCG-seropositive COVID-19/sepsis patients was observed, although this may be confounded by age differences between groups. In contrast, the monocyte response to stimulation appeared unaffected by COVID-19 severity.

Conclusion

These findings highlight the long-term alterations of immune cells in post-COVID-19 patients, emphasising the substantial impact of COVID-19 on immune function.

在COVID-19大流行几年后，SARS-CoV-2对免疫的影响以及通过训练免疫接种卡介苗的潜在保护作用仍是一个研究课题。本研究旨在确定SARS-CoV-2对免疫细胞的长期影响，以及卡介苗接种、潜伏感染与COVID-19严重程度和败血症进展之间的关系。方法前瞻性分析轻/重/危重型COVID-19患者（n = 97， COVID-19后3-17个月）和败血症患者（n = 64）。首先，我们评估了COVID-19及其严重程度对免疫细胞频率和功能标志物表达的影响。此外，我们分析了血浆抗刚地弓形虫/巨细胞病毒/卡介苗抗体滴度及其与COVID-19严重程度和败血症结局的关系。为了检测单核细胞对继发性攻击的反应，我们用SARS-CoV-2和LPS刺激从COVID-19恢复期患者、卡介苗接种者和未接种者中分离的单核细胞。结果无论疾病严重程度如何，covid -19后患者均表现出免疫失调，其特征是髓细胞（CD39、CD64、CD85d、CD11b）和淋巴样细胞（CD39、CD57、TIGIT）的活化和功能标志物表达改变。引人注目的是，与其他严重程度组相比，危重后的COVID-19患者CD8+ T细胞中CD57的表达升高。观察到bcg血清阳性的COVID-19/败血症患者预后改善的趋势，尽管这可能与组间年龄差异相混淆。相反，单核细胞对刺激的反应似乎不受COVID-19严重程度的影响。结论这些发现突出了COVID-19后患者免疫细胞的长期改变，强调了COVID-19对免疫功能的实质性影响。

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引用次数: 0

Functional characterisation of CD8+ T cells mobilised with acute supramaximal high-intensity interval exercise: implications for immune surveillance CD8+ T细胞在急性超极大期高强度间歇运动中动员的功能特征：对免疫监测的影响

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-06-20 DOI: 10.1002/cti2.70037

Anna Strömberg, Mirko Mandić, Brennan J Wadsworth, Sebastian Proschinger, Seher Alam, Lisa MJ Eriksson, Laura Barbieri, Eric Rullman, Helene Rundqvist

Objectives

The beneficial influence of exercise on outcomes such as infection control and cancer prevention has been attributed partly to the immune system response during physical exertion. CD8⁺ T cells play a crucial role in immune surveillance, and in this study, we performed an in-depth analysis of the impact of supramaximal high-intensity exercise (HIIT) on CD8⁺ T-cell dynamics and function, which are currently lacking in the literature.

Methods

CD8⁺ T cells obtained from healthy human subjects before and after 3 × 30 s of HIIT were analysed ex vivo for viability and expansion properties, metabolic function using SeaHorse, IFN-gamma release using EliSpot, phenotype using RNA-seq and flow cytometry, and cytotoxic capacity by co-culture with HEK293T cells.

Results

Exercise led to a threefold increase in CD8⁺ T-cell count, and CD8⁺ T cells obtained after exercise had a more cytotoxic profile. Post-exercise CD8⁺ T cells had a lower glycolytic capacity than pre-exercise cells, and incubation of pre-exercise CD8⁺ T cells with post-exercise serum replicated this metabolic shift, suggesting a systemic effect of exercise on CD8⁺ T-cell metabolism. Importantly, CD8⁺ T cells maintained their viability and expansion properties despite the metabolic challenges induced by exercise. Functionally, post-exercise CD8⁺ T cells showed increased release of IFN-gamma and an enhanced unspecific cell killing capacity as demonstrated by co-culture with the immortalised cell line HEK293T.

Conclusion

The pronounced increase in the total number of circulating CD8⁺ T-cells with an increased cytotoxic capacity suggests a potential improvement in immune surveillance after acute HIIT.

运动对感染控制和癌症预防等结果的有益影响部分归因于运动时的免疫系统反应。CD8+ T细胞在免疫监视中起着至关重要的作用，在本研究中，我们深入分析了超极大高强度运动（HIIT）对CD8+ T细胞动力学和功能的影响，这是目前文献所缺乏的。方法对健康人HIIT前后3 × 30 s的CD8+ T细胞进行体外活力和扩增特性、代谢功能分析（SeaHorse）、ifn - γ释放分析（EliSpot）、表型分析（RNA-seq和流式细胞术）和细胞毒能力分析（HEK293T细胞共培养）。结果运动导致CD8+ T细胞计数增加三倍，运动后获得的CD8+ T细胞具有更强的细胞毒性。运动后的CD8+ T细胞比运动前的细胞具有更低的糖酵解能力，运动前的CD8+ T细胞与运动后的血清一起培养可以复制这种代谢变化，这表明运动对CD8+ T细胞代谢有全身性影响。重要的是，尽管运动引起代谢挑战，CD8+ T细胞仍保持其活力和扩增特性。功能上，运动后CD8+ T细胞表现出ifn - γ释放增加和非特异性细胞杀伤能力增强，与永生化细胞系HEK293T共培养证实了这一点。结论急性HIIT后循环CD8+ t细胞总数明显增加，细胞毒能力增加，提示免疫监测可能有所改善。

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引用次数: 0

Long-lasting changes in circulating dendritic cell and monocyte subsets, and altered expression of EMR2, CD97 and EMR3 on these cells in the posttraumatic course 循环树突状细胞和单核细胞亚群的长期变化，以及创伤后这些细胞上EMR2、CD97和EMR3表达的改变

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-06-17 DOI: 10.1002/cti2.70040

Leyu Zheng, Carolin Fuchs, Christian Kleber, Georg Osterhoff, Gabriela Aust

Objectives

Traumatic injury triggers the rapid release of damage-associated patterns (DAMPs). Dendritic cells (DCs) and monocytes play key roles in sensing, processing, and presenting DAMPs to naïve T cells. These heterogeneous immune cells express the adhesion GPCR EMR2/ADGRE2, which is likely regulated by DAMPs.

Methods

We analysed the various blood DC and monocyte subsets in trauma patients and uninjured volunteers using flow cytometry. EMR2 and its closest relatives, CD97/ADGRE5 and EMR3/ADGRE3, were quantified on these subsets to gain insights into their (patho)physiological regulation.

Results

Following trauma, conventional and plasmocytoid DCs nearly disappeared from the circulation, which is inversely correlated with injury severity and adverse clinical parameters 120–240 h post injury. Alterations in EMR2 and CD97 on DCs were relatively minor. Classical monocytes increased, while non-classical monocytes showed a sustained decline in both absolute number and percentage, in a manner dependent on injury severity after trauma. EMR2 expression increased across all monocyte subsets, whereas CD97 showed little change. EMR3 expression decreased and remained low in classical monocytes, while it markedly increased in non-classical monocytes. These temporal patterns in adhesion GPRC expression were largely independent of injury severity and were observed in all injured patients.

Conclusion

Circulating DC and monocyte subsets underwent significant compositional changes after trauma, often correlating with injury severity and other clinical parameters. Despite structural similarities, EMR2, CD97, and EMR3 showed distinct regulatory patterns on monocyte subsets, suggesting different functional roles in the immune response to injury.

目的创伤性损伤触发损伤相关模式（DAMPs）的快速释放。树突状细胞（dc）和单核细胞在感知、处理和向naïve T细胞呈递DAMPs中发挥关键作用。这些异质免疫细胞表达粘附GPCR EMR2/ADGRE2，可能受DAMPs调控。方法采用流式细胞术对创伤患者和未受伤志愿者血液DC和单核细胞亚群进行分析。EMR2及其近亲CD97/ADGRE5和EMR3/ADGRE3在这些亚群上被量化，以深入了解它们的（病理）生理调节。结果外伤后，常规dc和浆细胞dc几乎从循环中消失，与损伤严重程度和损伤后120 ~ 240 h的不良临床参数呈负相关。DCs的EMR2和CD97的改变相对较小。经典单核细胞增加，而非经典单核细胞的绝对数量和百分比持续下降，其方式取决于创伤后损伤的严重程度。EMR2的表达在所有单核细胞亚群中均有所增加，而CD97的表达变化不大。EMR3表达在经典单核细胞中降低并保持在低水平，而在非经典单核细胞中显著升高。这些粘附GPRC表达的时间模式在很大程度上与损伤严重程度无关，并且在所有损伤患者中都观察到。结论创伤后循环DC和单核细胞亚群发生了显著的组成变化，通常与损伤严重程度和其他临床参数相关。尽管结构相似，但EMR2、CD97和EMR3对单核细胞亚群表现出不同的调节模式，这表明它们在损伤免疫反应中具有不同的功能作用。

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引用次数: 0

Allogeneic ‘off-the-shelf’ SARS-CoV-2-specific adoptive T-cell therapy for refractory viral infection and end organ disease 同种异体“现成”sars - cov -2特异性过继t细胞疗法治疗难治性病毒感染和终末器官疾病

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-06-10 DOI: 10.1002/cti2.70038

Andrea S Henden, Katie E Lineburg, Archana Panikkar, Arushi Mahajan, Ricky Nelles, Emma Wright, Pauline Crooks, Jyothy Raju, Laetitia Le Texier, Srividhya Swaminathan, Leone Beagley, Shannon Best, Matthew Solomon, Hilary Reddiex, Glen Kennedy, Siok-Keen Tey, Michelle A Neller, Rajiv Khanna, Corey Smith

Objectives

Despite the effective roll-out of COVID-19 vaccines, immunocompromised patients have a higher risk of morbidity and mortality following SARS-CoV-2 infection. Allogeneic adoptive T-cell immunotherapy is now established as an effective approach to treat viral diseases in immunocompromised patients. The objective of this study was to assess the safety of allogeneic virus-specific T-cell therapy in patients with COVID-19.

Methods

Using a repository of SARS-CoV-2-specific T cells generated from healthy exposed volunteers, we conducted an open-label phase I trial to assess the feasibility and safety of allogeneic SARS-CoV-2-specific T cells in immune-compromised cancer patients with COVID-19.

Results

Six participants at risk of severe COVID-19 were enrolled and received SARS-CoV-2-specific T-cell therapy within 4 days of recruitment. The first five participants who received two infusions of allogeneic SARS-CoV-2-specific T-cell therapy experienced no adverse events following treatment. Four of the six participants showed improvement in viral load following treatment and were alive at 12-week follow-up. One participant died 6 days after their second infusion, because of established pulmonary parenchymal damage following prolonged COVID infection. Another, who had underlying lupus nephritis, developed cytokine release syndrome and diffuse alveolar haemorrhage following a single infusion and was withdrawn from the study. They subsequently recovered from this serious adverse event.

Conclusion

Allogeneic SARS-CoV-2-specific T-cell therapy provides a platform to rapidly administer T cells to high-risk COVID-19 patients. It was associated with a reduced viral load and increased SARS-CoV-2-specific T-cell responses in the majority of treated patients.

尽管COVID-19疫苗已得到有效推广，但免疫功能低下患者在感染SARS-CoV-2后发病和死亡的风险更高。同种异体过继性t细胞免疫疗法现已被确定为治疗免疫功能低下患者病毒性疾病的有效方法。本研究的目的是评估同种异体病毒特异性t细胞治疗COVID-19患者的安全性。方法利用健康暴露志愿者产生的sars - cov -2特异性T细胞库，进行了一项开放标签的I期试验，以评估异体sars - cov -2特异性T细胞用于免疫功能低下的COVID-19癌症患者的可行性和安全性。结果6名有严重COVID-19风险的参与者在招募后4天内接受了sars - cov -2特异性t细胞治疗。前五名接受两次异体sars - cov -2特异性t细胞治疗的参与者在治疗后没有出现不良事件。6名参与者中的4名在治疗后病毒载量有所改善，并在12周的随访中存活。一名参与者在第二次输注后6天死亡，原因是长期感染COVID后肺实质损伤。另一名患有狼疮肾炎的患者在单次输注后出现细胞因子释放综合征和弥漫性肺泡出血，并退出了研究。他们随后从这一严重不良事件中恢复过来。结论同种异体sars - cov -2特异性T细胞治疗为快速给药高危患者提供了平台。在大多数接受治疗的患者中，它与病毒载量降低和sars - cov -2特异性t细胞反应增加有关。

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引用次数: 0

Loss of CXCR5 expression and monocyte epithelial–mesenchymal transition are blood-borne signatures of sterile granulomatous diseases CXCR5表达缺失和单核细胞上皮-间质转化是无菌肉芽肿疾病的血源性特征

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-06-03 DOI: 10.1002/cti2.70039

Yuwei Hao, Anthea Anantharajah, Jane M Wells, Lyndell L Lim, Anthony JH Hall, Gary YJ Chew, Matthew C Cook

Objectives

Sarcoidosis is the exemplar sterile granulomatous disease and can affect any organ system. Tattoo uveitis (TU) resembles sarcoidosis clinically and histologically but is distinguished by the absence of systemic lymphadenopathy, with inflammation restricted to skin and eyes. In this study, our objectives were, first, to resolve whether TU is a subset of sarcoidosis or a different antigen-driven condition and, second, by comparing TU and sarcoidosis, to identify blood-borne signatures of active and quiescent sterile granulomatous diseases.

Methods

We recruited patients with active and inactive TU, sarcoidosis and healthy controls on whom we performed blood cell phenotyping and transcriptomics.

Results

Unlike sarcoidosis, active TU is characterised by marked CXCR5 down-regulation on B cells and CD4⁺ T cells that normalises on remission. TCR-VDJ sequencing reveals an antigen-driven response in sarcoidosis, but not in TU, with clonally expanded cytotoxic and terminally differentiated CD8⁺ effectors. Both active TU and sarcoidosis exhibit gene signatures of epithelial-to-mesenchymal transition (EMT) in circulating monocytes, whereas epithelioid macrophages are a hallmark of active granulomas.

Conclusion

We have identified both shared and specific phenotypes in TU and sarcoidosis. Marked CXCR5 down-regulation occurs in active TU and could explain the unique absence of lymphadenopathy. Both TU and sarcoidosis are characterised by inflammatory monocyte phenotypes and transcriptional signatures of EMT.

目的结节病是典型的无菌肉芽肿性疾病，可累及任何器官系统。纹身葡萄膜炎（TU）在临床和组织学上类似于结节病，但其特点是没有全身性淋巴结病，炎症仅限于皮肤和眼睛。在这项研究中，我们的目标是，首先，确定TU是结节病的一个子集还是不同的抗原驱动病症，其次，通过比较TU和结节病，确定活动性和静止性无菌肉芽肿疾病的血源性特征。方法我们招募了活动性和非活动性TU患者、结节病患者和健康对照者，我们对他们进行了血细胞表型和转录组学研究。结果与结节病不同，活动性TU的特征是B细胞和CD4+ T细胞的CXCR5显著下调，并在缓解后恢复正常。TCR-VDJ测序揭示了结节病中抗原驱动的反应，但在TU中没有，具有克隆扩增的细胞毒性和终末分化的CD8+效应物。活动性TU和结节病都表现出循环单核细胞上皮-间质转化（EMT）的基因特征，而上皮样巨噬细胞是活动性肉芽肿的标志。结论我们已经确定了TU和结节病的共同表型和特异性表型。显著的CXCR5下调发生在活跃的TU中，这可以解释淋巴结病的独特缺失。TU和结节病都以炎性单核细胞表型和EMT的转录特征为特征。

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引用次数: 0

Enhancing CAR T-cell therapy manufacturing efficiency through semi-automated bioprocessing 通过半自动生物加工提高CAR - t细胞疗法的生产效率

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-06-02 DOI: 10.1002/cti2.70025

Jason Isaacson, Prajakta Bhanap, Nicholas Putnam, Jasmine Padilla, Nujhat Fatima, Max Dotson, Danny Hayoun, Moloud Ahmadi, Gertrude Nonterah, Yongchang Ji

<div> <section> <h3> Objectives</h3> <p>Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the treatment of blood-based malignancies. The use of manual CAR T-cell manufacturing methods is one of the challenges that contributes to these delays. As CAR T therapy emerges as a potential first- or second-line treatment option for these cancers, the demand for these therapies continues to rise. However, challenges persist in ensuring that the patients who need these therapies receive them in a timely manner. Automated CAR T-cell manufacturing methods that use software to control the equipment used in the process can help overcome the roadblocks associated with manual manufacturing, ultimately enabling a reduction in variability, increased efficiency, improved product quality and better data management. This paper aims to present an end-to-end semi-automated methodology for manufacturing CAR T cells using the Cell Therapy Systems (CTS™) Cellmation software – an off-the-shelf software solution – to control physically connected modular cell therapy instruments that eliminates the roadblocks associated with manual manufacturing.</p> </section> <section> <h3> Methods</h3> <p>T cells from healthy donors were isolated and processed into CAR T cells using a semi-automated, connected, multi-instrument setup that leveraged electroporation and a CRISPR/Cas system for delivering the CD19-CAR construct to the T cells. Flow cytometry was used to assess cell type composition, cell viability and expression of T-cell activation markers throughout the process. We also measured exhaustion marker expression on T cells, T-cell receptor (TCR) knock-out, CAR knock-in and cytotoxic activity against NALM6 cells.</p> </section> <section> <h3> Results</h3> <p>The results demonstrated the successful generation of functional CAR T cells using a semi-automated instrument workflow. The results were similar to the results from CAR T cells manufactured using non-automated processes; however, the successful connection and control of the instruments using automated software present an exciting opportunity for process developers and manufacturers who want to reduce manual touchpoints in their cell therapy manufacturing process.</p> </section> <section> <h3> Conclusion</h3> <p>The method that we describe in this paper could be beneficial to process development and manufacturing teams that might require flexibility in their CAR T cell manufacturing workflow and want to take advantage of modular systems that can be automated using the Cellmation software to reduce the proble

嵌合抗原受体（CAR） t细胞疗法已经彻底改变了血液恶性肿瘤的治疗。使用手工CAR - t细胞制造方法是导致这些延迟的挑战之一。随着CAR - T疗法成为这些癌症潜在的一线或二线治疗选择，对这些疗法的需求持续上升。然而，在确保需要这些治疗的患者及时得到治疗方面仍然存在挑战。自动化CAR - t细胞制造方法使用软件控制过程中使用的设备，可以帮助克服人工制造相关的障碍，最终实现减少可变性，提高效率，提高产品质量和更好的数据管理。本文旨在介绍一种端到端的半自动化方法，用于使用细胞治疗系统（CTS™）cellation软件（一种现成的软件解决方案）来控制物理连接的模块化细胞治疗仪器，从而消除与手工制造相关的障碍。来自健康供体的T细胞被分离并加工成CAR - T细胞，使用半自动、连接的多仪器装置，利用电穿孔和CRISPR/Cas系统将CD19-CAR构建体递送到T细胞。流式细胞术检测细胞类型组成、细胞活力和t细胞活化标志物的表达。我们还测量了T细胞上的衰竭标志物表达、T细胞受体（TCR）敲除、CAR敲入和对NALM6细胞的细胞毒活性。结果表明，使用半自动仪器工作流程成功生成功能性CAR - T细胞。结果与使用非自动化过程制造的CAR - T细胞的结果相似；然而，使用自动化软件成功连接和控制仪器为希望减少细胞治疗制造过程中人工接触点的工艺开发人员和制造商提供了一个令人兴奋的机会。我们在本文中描述的方法可能有利于工艺开发和制造团队，他们可能需要灵活的CAR - T细胞制造工作流程，并希望利用模块化系统，可以使用cellation软件自动化，以减少与人工处理相关的问题。

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引用次数: 0

Data standards for single-cell RNA-sequencing of paediatric cancer 儿童癌症单细胞rna测序数据标准

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-05-23 DOI: 10.1002/cti2.70033

Xiaohan Xu, John Saxon, Megan Sioe Fei Soon, Colin YC Lee, Zewen Kelvin Tuong

Single-cell RNA sequencing (scRNA-seq) is a powerful tool for investigating paediatric cancers, but individual studies often profile a small number of individuals. It is now the standard practice to upload the scRNA-seq data to data repositories to support scientific reproducibility. Public data deposition is a cost-effective and sustainability-conscious solution that allows any researcher to download and analyse existing scRNA-seq data to develop new ideas. This is incredibly valuable, especially in the context of paediatric cancer research, where access to funding and to patient cohorts may be prohibitive. However, standards for data deposition are absent, leading to significant issues that may slow progress. As a consequence, it is difficult, even impossible, for other researchers to validate findings or utilise these data for tailored analyses. Here, we systematically accessed and reviewed publicly available scRNA-seq data sets from various paediatric cancer studies, covering over 1.3 million cells across 488 clinical samples. We highlight striking inconsistencies with study design and data availability across several levels, which hinder downstream analyses and data reproducibility. To address these challenges, we propose a recommendations framework to improve data deposition practices that promote more effective use of scRNA-seq data sets deposited on public repositories and accelerate discoveries in paediatric cancer research and beyond. We urge data standards institutes and repositories, such as NCBI Gene Expression Omnibus (GEO) and European Genome-Phenome Archive (EGA), to strictly enforce these standardised data practices.

单细胞RNA测序（scRNA-seq）是研究儿科癌症的有力工具，但个体研究通常只涉及少数个体。现在，将scRNA-seq数据上传到数据存储库以支持科学可重复性已成为标准做法。公共数据沉积是一种具有成本效益和可持续性意识的解决方案，允许任何研究人员下载和分析现有的scRNA-seq数据以开发新的想法。这是非常有价值的，特别是在儿科癌症研究的背景下，在那里获得资金和患者队列可能是令人望而却步的。然而，缺乏数据存储的标准，导致可能减缓进展的重大问题。因此，其他研究人员很难，甚至不可能验证这些发现或利用这些数据进行量身定制的分析。在这里，我们系统地访问和审查了来自各种儿科癌症研究的公开可用的scRNA-seq数据集，涵盖了488个临床样本中的130多万个细胞。我们强调了研究设计和数据可用性在几个层面上的显著不一致，这阻碍了下游分析和数据可重复性。为了应对这些挑战，我们提出了一个建议框架，以改进数据存储实践，促进更有效地使用存储在公共存储库中的scRNA-seq数据集，并加速儿科癌症研究及其他领域的发现。我们敦促数据标准机构和存储库，如NCBI基因表达综合数据库（GEO）和欧洲基因组-表型档案（EGA），严格执行这些标准化的数据实践。

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引用次数: 0

High-dimensional flow cytometry reveals lymphocyte subset populations predictive of chronic lung allograft dysfunction 高维流式细胞术显示淋巴细胞亚群预测慢性肺移植功能障碍

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2025-05-23 DOI: 10.1002/cti2.70035

Rohia Farighi, Steven Hiho, Thomas Ashhurst, Emily SJ Edwards, Lucy Sullivan, Menno C van Zelm, Greg Snell, Glen Westall, David M Tarlinton, Dimitra Zotos

Objectives

Despite cellular and antibody-mediated rejection being clinically relevant drivers of chronic lung allograft dysfunction (CLAD), there are few studies describing the T- and B-cell dynamics inherent to such alloreactive responses. We conducted a longitudinal immunophenotyping study of B- and T-cell subsets from pre- to 12 months post-lung transplant, focussing on patients who subsequently developed either donor specific antibodies to human leukocyte antigen class II (HLA-DSA) or CLAD within 3 years.

Methods

In a single centre, comparative study, we used high-dimensional flow cytometry clustering analysis to assess the B- and T-cell populations in blood from lung allograft recipients prior to transplantation and at 0.5, 1.5, 3, 6, 9 and 12 months post-transplantation. Recipients who developed de novo HLA-DSA at 3 months post-transplantation (n = 18) and those in whom CLAD was diagnosed within 3 years post-transplantation (n = 13) were compared to matched, DSA-negative (n = 15) or CLAD-free recipients (n = 26), respectively.

Results

This longitudinal study provided a detailed analysis of B- and T-cell lineage subsets, including both cell frequencies and cell counts. There were no statistically significant differences in lymphocyte populations between graft recipients with and without HLA-DSA. However, patients that developed CLAD had a mean threefold deficit in the absolute number of B cells and had significantly fewer T regulatory cells than CLAD-free patients. Strikingly, these differences existed prior to and persisted post-transplantation.

Conclusions

Utilising high-dimensional flow cytometry, a new putative association was identified between two peripheral blood lymphocyte populations and the subsequent development of CLAD.

尽管细胞和抗体介导的排斥反应是慢性肺同种异体移植功能障碍（CLAD）的临床相关驱动因素，但很少有研究描述这种同种异体反应反应所固有的T细胞和b细胞动力学。我们对肺移植前至12个月的B细胞和t细胞亚群进行了纵向免疫表型研究，重点关注在3年内出现供体特异性人白细胞抗原II类（HLA-DSA）或CLAD抗体的患者。方法在一项单中心比较研究中，我们使用高维流式细胞术聚类分析来评估移植前和移植后0.5、1.5、3、6、9和12个月肺同种异体移植受者血液中的B细胞和t细胞群。在移植后3个月发生HLA-DSA的受者（n = 18）和在移植后3年内诊断为CLAD的受者（n = 13）分别与匹配的、dsa阴性（n = 15）或无CLAD的受者（n = 26）进行比较。这项纵向研究提供了B细胞和t细胞谱系亚群的详细分析，包括细胞频率和细胞计数。在接受HLA-DSA和不接受HLA-DSA的受者之间，淋巴细胞群没有统计学上的显著差异。然而，与无CLAD的患者相比，发生CLAD的患者B细胞的绝对数量平均减少三倍，T调节细胞明显减少。引人注目的是，这些差异在移植前就存在，移植后也持续存在。结论利用高维流式细胞术，确定了两种外周血淋巴细胞群与随后的CLAD发展之间的新的假定关联。

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引用次数: 0