Clinical & Translational Immunology最新文献

Pulmonary complications post allogeneic haematopoietic stem cell transplant in children 儿童异基因造血干细胞移植后的肺部并发症

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-09-17 DOI: 10.1002/cti2.70003

Hannah Walker, Joanne Abbotsford, Gabrielle M Haeusler, Daniel Yeoh, Shanti Ramachandran, Michelle Ng, Jonathan Holzmann, Shivanthan Shanthikumar, Heather Weerdenburg, Diane Hanna, Melanie R Neeland, Theresa Cole

Objectives

Haematopoietic stem cell transplant (HCT) is a cellular therapy that, whilst curative for a child's underlying disease, carries significant risk of mortality, including because of pulmonary complications. The aims of this study were to describe the burden of pulmonary complications post-HCT in a cohort of Australian children and identify risk factors for the development of these complications.

Methods

Patients were identified from the HCT databases at two paediatric transplant centres in Australia. Medical records were reviewed, and demographics, HCT characteristics and pulmonary complications documented. Relative risk ratio was used to identify risk factors for developing pulmonary complications prior to first transplant episode, and survival analysis performed to determine hazard ratio.

Results

In total, 243 children underwent transplant during the study period, and pulmonary complications occurred in 48% (117/243) of children. Infectious complications were more common (55%) than non-infective complications (18%) and 26% of patients developed both. Risk factors for the development of pulmonary complications included the following: diagnoses of MPAL (RR 2.16, P = 0.02), matched unrelated donor (RR1.34, P = 0.03), peripheral blood (RR 1.36, P = 0.028) or cord blood (RR 1.73, P = 0.012) as the stem cell source and pre-existing lung disease (RR1.72, P < 0.0001). Children with a post-HCT lung complication had a significantly increased risk of mortality compared with those who did not (HR 3.9, P < 0.0001).

Conclusion

This study demonstrates pulmonary complications continue to occur frequently in children post-HCT and contribute significantly to mortality. Highlighting the need for improved strategies to identify patients at risk pre-transplant and enhanced treatments for those who develop lung disease.

目的造血干细胞移植（HCT）是一种细胞疗法，虽然可以治愈儿童的潜在疾病，但却有很大的死亡风险，包括肺部并发症。本研究旨在描述澳大利亚儿童组群中造血干细胞移植后肺部并发症的负担，并确定这些并发症发生的风险因素。方法从澳大利亚两家儿科移植中心的 HCT 数据库中确定患者。审查病历，记录人口统计学特征、HCT特征和肺部并发症。采用相对风险比确定首次移植前出现肺部并发症的风险因素，并进行生存分析以确定危险比。结果在研究期间，共有 243 名儿童接受了移植手术，其中 48% 的儿童（117/243）出现了肺部并发症。感染性并发症（55%）比非感染性并发症（18%）更常见，26%的患者同时出现感染性并发症和非感染性并发症。出现肺部并发症的风险因素包括：诊断为MPAL（RR 2.16，P = 0.02），匹配的非亲属捐赠者（RR 1.34，P = 0.03），干细胞来源为外周血（RR 1.36，P = 0.028）或脐带血（RR 1.73，P = 0.012），以及原有肺部疾病（RR 1.72，P <0.0001）。造血干细胞移植后出现肺部并发症的儿童与未出现并发症的儿童相比，死亡风险明显增加（HR 3.9，P < 0.0001）。结论本研究表明，儿童造血干细胞移植后肺部并发症仍会频繁发生，并严重影响死亡率。因此需要改进策略，在移植前识别高危患者，并加强对肺部疾病患者的治疗。

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引用次数: 0

Biomarkers to predict and diagnose pulmonary complications in children post haematopoietic stem cell transplant 预测和诊断造血干细胞移植后儿童肺部并发症的生物标志物

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-09-17 DOI: 10.1002/cti2.70002

Hannah Walker, Gabrielle M Haeusler, Theresa Cole, Melanie Neeland, Diane Hanna, Shivanthan Shanthikumar

Objectives. Haematopoietic cell transplant (HCT) is a cellular therapy for a group of high-risk children with cancer, immunodeficiency and metabolic disorders. Whilst curative for a child's underlying condition, HCT has significant risks associated, including lung injury. These complications are associated with increased post HCT mortality and require improved methods of risk stratification, diagnosis and treatment. Methods. Biomarkers measured in bronchoalveolar fluid and peripheral blood have been identified for both acute and chronic lung injury post HCT.This review evaluates the current research available investigating the use of these biomarkers to improve clinical care, with a focus on the paediatric cohort. Results. Elevated levels of cytokines such as IL-6, IL-8, G-CSF and TNF were identified as potential predictive biomarkers for the development of post HCT lung disease. The pulmonary microbiome was found to have strong potential as a biomarker pre and post HCT for the development of pulmonary complications. General limitations of the studies identified were study design, retrospective or single centre and not exclusively performed in the paediatric population. Conclusion. To translate biomarker discovery into clinical implementation further research is required, utilising larger cohorts of children in prospective trials to validate these biomarkers and determine how they can be translated into better outcomes for children post HCT.

目的。造血细胞移植（HCT）是一种细胞疗法，适用于患有癌症、免疫缺陷和代谢紊乱的高危儿童。造血干细胞移植虽然能治愈儿童的潜在疾病，但也有很大的风险，包括肺损伤。这些并发症与 HCT 后死亡率的增加有关，因此需要改进风险分层、诊断和治疗方法。方法。在支气管肺泡液和外周血中测量的生物标志物已被确定为 HCT 后急性和慢性肺损伤的标志物。本综述评估了目前利用这些生物标志物改善临床护理的研究，重点是儿科人群。结果IL-6、IL-8、G-CSF 和 TNF 等细胞因子水平升高被确定为 HCT 后肺部疾病发生的潜在预测性生物标志物。研究发现，肺微生物组作为 HCT 前后肺部并发症发生的生物标志物具有很强的潜力。所发现的研究存在一些局限性，如研究设计、回顾性研究或单中心研究，以及并非仅在儿科人群中进行。结论要将生物标志物的发现转化为临床应用，还需要进一步的研究，在前瞻性试验中利用更大的儿童群体来验证这些生物标志物，并确定如何将它们转化为 HCT 后儿童更好的治疗效果。

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引用次数: 0

The Omega-6 Lipid pathway shift is associated with neutrophil influx and structural lung damage in early cystic fibrosis lung disease 在早期囊性纤维化肺病中，Omega-6 脂质通路的转变与中性粒细胞涌入和肺结构损伤有关

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-09-16 DOI: 10.1002/cti2.70000

Lisa JM Slimmen, Jelle Y Broos, Badies HAN Manaï, Silvia C Estevão, Martin Giera, Gijs Kooij, Wendy WJ Unger, Hettie M Janssens

Objectives

In cystic fibrosis (CF), an imbalanced lipid metabolism is associated with lung inflammation. Little is known about the role that specific lipid mediators (LMs) exert in CF lung inflammation, and whether their levels change during early disease progression. Therefore, we measured airway LM profiles of young CF patients, correlating these with disease-associated parameters.

Methods

Levels of omega (ω)-3/6 PUFAs and their LM derivatives were determined in bronchoalveolar lavage fluid (BALF) of children with CF ages 1–5 using a targeted high-performance liquid chromatography–tandem mass spectrometry approach. Hierarchical clustering analysis was performed on relative LM levels. Individual relative LM levels were correlated with neutrophilic inflammation (BALF %Neu) and structural lung damage (PRAGMA-CF %Disease). Significant correlations were included in a backward multivariate linear regression model to identify the LMs that are best related to disease progression.

Results

A total of 65 BALF samples were analysed for ω-3/6 lipid content. LM profiles clustered into an arachidonic acid (AA)-enriched and a linoleic acid (LA)-enriched sample cluster. AA derivatives like 17-OH-DH-HETE, 5-HETE, 5,15-diHETE, 15-HETE, 15-KETE, LTB₄ and 6-trans-LTB₄ positively correlated with BALF %Neu and/or PRAGMA %Dis. Contrastingly, 9-HoTrE and the LA derivatives 9-HoDE, 9(10)-EpOME, 9(10)-DiHOME, 13-HoDE, 13-oxoODE and 12(13)-EpOME negatively correlated with BALF %Neu and/or PRAGMA %Dis. 6-trans-LTB₄ was the strongest predictor for BALF %Neu. 5-HETE and 15-KETE contributed most to PRAGMA %Dis prediction.

Conclusions

Our data provide more insight into the lung lipidome of infants with CF, and show that a shift from LA derivatives to AA derivatives in BALF associates with early CF lung disease progression.

囊性纤维化（CF）患者的脂质代谢失衡与肺部炎症有关。人们对特定脂质介质（LMs）在 CF 肺部炎症中所起的作用，以及它们的水平在疾病早期是否会发生变化知之甚少。因此，我们测量了年轻 CF 患者的气道脂质介质谱，并将其与疾病相关参数联系起来。方法采用靶向高效液相色谱-串联质谱法测定了1-5岁CF患儿支气管肺泡灌洗液（BALF）中ω (ω)-3/6 PUFAs及其LM衍生物的水平。对相对 LM 水平进行了层次聚类分析。单个相对 LM 水平与中性粒细胞炎症（BALF %Neu）和肺结构损伤（PRAGMA-CF %Disease）相关。显著相关性被纳入后向多变量线性回归模型，以确定与疾病进展关系最密切的 LMs。结果共分析了 65 份 BALF 样本中的ω-3/6 脂质含量。LM特征分为富含花生四烯酸（AA）和富含亚油酸（LA）的样本群。AA衍生物如17-OH-DH-HETE、5-HETE、5,15-diHETE、15-HETE、15-KETE、LTB4和6-反式-LTB4与BALF %Neu和/或PRAGMA %Dis呈正相关。相反，9-HoTrE 和 LA 衍生物 9-HoDE、9(10)-EpOME、9(10)-DiHOME、13-HoDE、13-oxoODE 和 12(13)-EpOME 与 BALF %Neu 和/或 PRAGMA %Dis 呈负相关。6-trans-LTB4 是预测 BALF %Neu 的最强指标。5-HETE 和 15-KETE 对 PRAGMA %Dis 预测的贡献最大。结论我们的数据让我们对 CF 婴儿的肺脂质组有了更深入的了解，并表明 BALF 中从 LA 衍生物到 AA 衍生物的转变与 CF 肺部疾病的早期进展有关。

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引用次数: 0

Siglec-7 and Siglec-9 expression in primary triple negative and oestrogen receptor positive breast cancer and in vitro signalling 原发性三阴性和雌激素受体阳性乳腺癌中 Siglec-7 和 Siglec-9 的表达及体外信号传导

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-09-06 DOI: 10.1002/cti2.1524

Eline JH van Houtum, Anne HC Valk, Daniel Granado, Jasper Lok, Lune van den Bogaard, Naomi Remkes, Jesper van Eck van der Sluijs, Paul N Span, Lenneke AM Cornelissen, Gosse J Adema

Objectives

PD-1/PD-L1 immune checkpoint blockade can be an effective treatment for advanced breast cancer patients. However, patients with oestrogen receptor positive (ER+) tumors often display only low lymphocyte infiltration, while a large part of triple negative (TN) breast tumors does not generate an effective immunotherapy response. Therefore, new treatment strategies have to be developed. Here, we investigate Siglec-7 and Siglec-9 as novel ITIM-bearing inhibitory immune checkpoint receptors similar to PD-1, but expressed on a broader range of immune cells.

Methods

We assessed Siglec-7 and Siglec-9 (ligand) expression in TN and ER+ breast cancer tumors and their breast cancer cell line-induced signalling.

Results

We report that Siglec-7 and Siglec-9 are highly expressed in TN tumors, and to a low extent in ER+ tumors. Siglec-7 was observed on myeloid cells, T cells, and NK cells and Siglec-9 preferentially on myeloid cells. Expression of sialoglycans, including Siglec-7 and Siglec-9 ligands, was observed in both TN and ER+ breast cancer tissue sections. Expression levels of Siglec-7 and Siglec-9 ligands were higher on in vitro cultured TN cell lines than ER+ cell lines. Importantly, by applying chimeric Siglec-7 reporter cells, we showed the induction of Siglec-7 signalling by multiple TN cell lines, but only by one ER+ cell line. Moreover, Siglec-7 signalling is directly related to Siglec-7 ligand expression levels of breast cancer cell lines.

Conclusion

These data imply that immunotherapy targeting Siglec receptors may be particularly interesting for TN breast cancer patients not responding to current treatment strategies with tumors displaying high immune cell infiltration.

目的 PD-1/PD-L1 免疫检查点阻断疗法是治疗晚期乳腺癌患者的有效方法。然而，雌激素受体阳性（ER+）肿瘤患者往往只有少量淋巴细胞浸润，而大部分三阴性（TN）乳腺肿瘤患者不会产生有效的免疫治疗反应。因此，必须开发新的治疗策略。在此，我们研究了 Siglec-7 和 Siglec-9，它们是新型的 ITIM 抑制性免疫检查点受体，类似于 PD-1，但在更广泛的免疫细胞上表达。方法我们评估了 Siglec-7 和 Siglec-9（配体）在 TN 和 ER+ 乳腺癌肿瘤中的表达及其乳腺癌细胞系诱导的信号传导。结果我们发现，Siglec-7 和 Siglec-9 在 TN 肿瘤中高表达，而在 ER+ 肿瘤中低表达。髓系细胞、T 细胞和 NK 细胞中均可观察到 Siglec-7 的表达，而髓系细胞中则优先观察到 Siglec-9。在TN和ER+乳腺癌组织切片中都观察到了包括Siglec-7和Siglec-9配体在内的硅聚糖的表达。体外培养的 TN 细胞系中 Siglec-7 和 Siglec-9 配体的表达水平高于 ER+ 细胞系。重要的是，通过应用嵌合 Siglec-7 报告细胞，我们发现多个 TN 细胞系诱导了 Siglec-7 信号，但只有一个 ER+ 细胞系诱导了 Siglec-7 信号。此外，Siglec-7 信号与乳腺癌细胞系的 Siglec-7 配体表达水平直接相关。结论这些数据表明，针对 Siglec 受体的免疫疗法对目前治疗策略无效且肿瘤显示高免疫细胞浸润的 TN 乳腺癌患者尤为有效。

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引用次数: 0

Schistosoma excretory/secretory products: an untapped library of tolerogenic immunotherapeutics against food allergy 血吸虫排泄物/分泌物：尚未开发的抗食物过敏耐受性免疫疗法库

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-08-29 DOI: 10.1002/cti2.70001

Madeleine Rogers, Sandip Kamath, Donald McManus, Malcolm Jones, Catherine Gordon, Severine Navarro

Food allergy (FA) is considered the ‘second wave’ of the allergy epidemic in developed countries after asthma and allergic rhinitis with a steadily growing burden of 40%. The absence of early childhood pathogen stimulation embodied by the hygiene hypothesis is one explanation, and in particular, the eradication of parasitic helminths could be at play. Infections with parasites Schistosoma spp. have been found to have a negative correlation with allergic diseases. Schistosomes induce regulatory responses to evade immune detection and ensure their long-term survival. This is achieved via excretory/secretory (E/S) products, consisting of proteins, lipids, metabolites, nucleic acids and extracellular vesicles, representing an untapped therapeutic avenue for the treatment of FA without the unpleasant side-effects and risks associated with live infection. Schistosome-derived immunotherapeutic development is in its infancy and novel discoveries are heavily technology dependent; thus, it is essential to better understand how newly identified molecules interact with host immune systems to ensure safety and successful translation. This review will outline the identified Schistosoma-derived E/S products at all life cycle stages and discuss known mechanisms of action and their ability to suppress FA.

在发达国家，食物过敏（FA）被认为是继哮喘和过敏性鼻炎之后的 "第二波 "过敏流行病，其发病率持续上升，达到 40%。卫生假说所体现的儿童早期缺乏病原体刺激是一种解释，特别是寄生蠕虫的根除可能是其中的原因。研究发现，寄生虫血吸虫感染与过敏性疾病呈负相关。血吸虫会诱导调节反应，以躲避免疫检测并确保其长期存活。这是通过排泄/分泌（E/S）产物实现的，这些产物由蛋白质、脂类、代谢物、核酸和细胞外囊泡组成，是一种尚未开发的治疗 FA 的途径，而且不会产生令人不快的副作用，也没有与活体感染相关的风险。血吸虫衍生免疫疗法的开发正处于起步阶段，新发现在很大程度上依赖于技术；因此，必须更好地了解新发现的分子如何与宿主免疫系统相互作用，以确保安全性和成功转化。本综述将概述已确定的各生命周期阶段的血吸虫衍生 E/S 产品，并讨论已知的作用机制及其抑制 FA 的能力。

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引用次数: 0

Anti-signal recognition particle antibodies induce cardiac diastolic dysfunction via oxidative stress injury 抗信号识别颗粒抗体通过氧化应激损伤诱发心脏舒张功能障碍

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-08-13 DOI: 10.1002/cti2.1525

Hao Zhang, Yunjing Shi, Yingze Fan, Dehao Zhu, Zeping Qiu, Huihui Chi, Qiongyi Hu, Liangzhe Xie, Yue Sun, Honglei Liu, Xiaobing Cheng, Junna Ye, Hui Shi, Zhuochao Zhou, Jianfen Meng, Jialin Teng, Chengde Yang, Wei Jin, Yutong Su

Objectives

Anti-signal recognition particle (SRP) antibodies, markers of immune-mediated necrotising myopathy, are reportedly related to cardiac involvement; however, whether they are pathogenic to the myocardium remains unclear. We aimed, therefore, to explore the pathogenicity of anti-SRP antibodies against the myocardium through in vivo and in vitro studies.

Methods

Total immunoglobulin G (IgG), purified from patients with positive anti-SRP antibodies, was passively transferred into C57BL/6 mice. Cardiac function was evaluated via echocardiography and the ventricular pressure–volume loop; cardiac histological changes were analysed using haematoxylin–eosin staining, picrosirius red staining, immunofluorescence and immunohistochemistry. Additionally, reactive oxygen species (ROS) formation was evaluated by dihydroethidium (DHE) staining; mitochondrial morphology and function were evaluated using transmission electron microscopy and seahorse mitochondrial respiration assay, respectively. The myositis cohort at our centre was subsequently reviewed in terms of cardiac assessments.

Results

After the passive transfer of total IgG from patients with positive anti-SRP antibodies, C57BL/6 mice developed significant left ventricular diastolic dysfunction (LVDD). Transcriptomic analysis and corresponding experiments revealed increased oxidative stress and mitochondrial damage in the hearts of the experimental mice. Cardiomyocytes exposed to anti-SRP-specific IgG, however, recovered normal mitochondrial metabolism after treatment with N-acetylcysteine, an ROS scavenger. Moreover, patients positive for anti-SRP antibodies manifested worse diastolic but equivalent systolic function compared to their counterparts after propensity score matching.

Conclusion

Anti-SRP antibodies may play a pathogenic role in the development of LVDD by promoting ROS production and subsequent myocardial mitochondrial impairment. The inhibition of oxidative stress was effective in reversing anti-SRP antibody-induced LVDD.

目的抗信号识别颗粒（SRP）抗体是免疫介导的坏死性肌病的标志物，据报道与心脏受累有关；但它们是否对心肌具有致病性仍不清楚。因此，我们旨在通过体内和体外研究探讨抗 SRP 抗体对心肌的致病性。方法将从抗 SRP 抗体阳性患者体内纯化的总免疫球蛋白 G（IgG）被动转移到 C57BL/6 小鼠体内。通过超声心动图和心室压力-容积环路评估心脏功能；使用血红素-伊红染色法、苦参红染色法、免疫荧光法和免疫组化法分析心脏组织学变化。此外，还采用二氢乙锭（DHE）染色法评估活性氧（ROS）的形成；分别采用透射电子显微镜和海马线粒体呼吸测定法评估线粒体形态和功能。随后对本中心的肌炎患者进行了心脏评估。结果 C57BL/6小鼠在被动转移抗SRP抗体阳性患者的总IgG后，出现了明显的左心室舒张功能障碍（LVDD）。转录组分析和相应的实验显示，实验小鼠心脏的氧化应激和线粒体损伤增加。然而，暴露于抗 SRP 特异性 IgG 的心肌细胞在接受 ROS 清除剂 N-乙酰半胱氨酸治疗后，线粒体代谢恢复正常。此外，抗 SRP 抗体阳性患者的舒张功能较差，但与倾向评分匹配后的收缩功能相当。结论抗 SRP 抗体可能通过促进 ROS 生成和随后的心肌线粒体损伤，在 LVDD 的发病过程中起到致病作用。抑制氧化应激能有效逆转抗 SRP 抗体诱导的 LVDD。

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引用次数: 0

Primary SARS-CoV-2 infection in children and adults results in similar Fc-mediated antibody effector function patterns 儿童和成人原发性 SARS-CoV-2 感染导致相似的 Fc 介导抗体效应器功能模式

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-26 DOI: 10.1002/cti2.1521

Anne T Gelderloos, Anke J Lakerveld, Rutger M Schepp, Mioara Alina Nicolaie, Josine van Beek, Lisa Beckers, Robert S van Binnendijk, Nynke Y Rots, Puck B van Kasteren

Objectives

Increasing evidence suggests that Fc-mediated antibody effector functions have an important role in protection against respiratory viruses, including SARS-CoV-2. However, limited data are available on the potential differences in the development, heterogeneity and durability of these responses in children compared to adults.

Methods

Here, we assessed the development of spike S1-specific serum antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD) and natural killer cell activation (ADNKA), alongside specific antibody binding concentrations (IgG, IgA and IgM) and IgG avidity in healthy adults (n = 38, 18–56 years) and children (n = 21, 5–16 years) following primary SARS-CoV-2 infection, with a 10-month longitudinal follow-up. Differences between groups were assessed using a nonparametric Kruskal–Wallis test with Dunn's multiple comparisons test.

Results

We found similar (functional) antibody responses in children compared to adults, with a tendency for increased durability in children, which was statistically significant for ADCD (P < 0.05). While ADNKA was strongly reduced in both adults (P < 0.001) and children (P < 0.05) at the latest time point, ADCP remained relatively stable over time, possibly relating to an increase in avidity of the spike-specific antibodies (P < 0.001). Finally, the ADNKA capacity relative to antibody concentration appeared to decrease over time in both children and adults.

Conclusion

In conclusion, our data provide novel insights into the development of SARS-CoV-2-specific antibody Fc-mediated effector functions in children and adults. An increased understanding of these characteristics in specific age populations is valuable for the future design of novel and improved vaccination strategies for respiratory viruses such as SARS-CoV-2.

目的越来越多的证据表明，Fc 介导的抗体效应器功能在抵御呼吸道病毒（包括 SARS-CoV-2 ）方面发挥着重要作用。然而，关于儿童与成人相比在这些反应的发展、异质性和持久性方面的潜在差异的数据却很有限。方法在此，我们评估了健康成人（n = 38，18-56 岁）和儿童（n = 21，5-16 岁）在原发性 SARS-CoV-2 感染后尖峰 S1 特异性血清抗体依赖性细胞吞噬（ADCP）、补体沉积（ADCD）和自然杀伤细胞激活（ADNKA）的发展情况，以及特异性抗体结合浓度（IgG、IgA 和 IgM）和 IgG 阳性，并进行了为期 10 个月的纵向随访。采用非参数 Kruskal-Wallis 检验和 Dunn's 多重比较检验对组间差异进行评估。成人和儿童的 ADNKA 在最近的时间点均显著降低（P <0.001），而 ADCP 随着时间的推移保持相对稳定，这可能与尖峰特异性抗体的亲和力增加有关（P <0.001）。最后，在儿童和成人中，相对于抗体浓度的 ADNKA 能力似乎随着时间的推移而降低。进一步了解特定年龄段人群的这些特征，对于今后设计新型和改良的呼吸道病毒（如 SARS-CoV-2 ）疫苗接种策略很有价值。

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引用次数: 0

Serological responses and clinical outcomes following a three-dose primary COVID-19 vaccine schedule in kidney transplant recipients and people on dialysis 肾移植受者和透析患者接种三剂 COVID-19 疫苗后的血清反应和临床结果。

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-25 DOI: 10.1002/cti2.1523

Dhakshayini Tharmaraj, Irene Boo, Jessie O'Hara, Shir Sun, Kevan R Polkinghorne, Claire Dendle, Stephen J Turner, Menno C van Zelm, Heidi E Drummer, Gabriela Khoury, William R Mulley

Objectives

Despite vaccination strategies, people with chronic kidney disease, particularly kidney transplant recipients (KTRs), remained at high risk of poor COVID-19 outcomes. We assessed serological responses to the three-dose COVID-19 vaccine schedule in KTRs and people on dialysis, as well as seroresponse predictors and the relationship between responses and breakthrough infection.

Methods

Plasma from 30 KTRs and 17 people receiving dialysis was tested for anti-Spike receptor binding domain (RBD) IgG and neutralising antibodies (NAb) to the ancestral and Omicron BA.2 variant after Doses 2 and 3 of vaccination.

Results

After three doses, KTRs achieved lower anti-Spike RBD IgG levels (P < 0.001) and NAb titres than people receiving dialysis (P = 0.002). Seropositive cross-reactive Omicron neutralisation levels were achieved in 11/27 (40.7%) KTRs and 11/14 (78.6%) dialysis recipients. ChAdOx1/viral-vector vaccine type, higher mycophenolate dose (> 1 g per day) and lower absolute B-cell counts predicted poor serological responses in KTRs. ChAdOx-1 vaccine type and higher monocyte counts were negative predictors in dialysis recipients. Among ancestral NAb seroresponders, higher NAb levels positively correlated with higher Omicron neutralisation (R = 0.9, P < 0.001). More KTRs contracted SARS-CoV-2 infection (14/30; 47%) than dialysis recipients (5/17; 29%) and had more severe disease. Those with breakthrough infections had significantly lower median interdose incremental change in anti-Spike RBD IgG and ancestral NAb titres.

Conclusion

Serological responses to COVID-19 vaccines in KTRs lag behind their dialysis counterparts. KTRs remained at high risk of breakthrough infection after their primary vaccination schedule underlining their need for booster doses, strict infection prevention measures and close surveillance.

目标：尽管采取了疫苗接种策略，但慢性肾脏病患者，尤其是肾移植受者（KTR）仍面临COVID-19不良后果的高风险。我们评估了 KTR 和透析患者对三剂 COVID-19 疫苗计划的血清反应，以及血清反应预测因子和反应与突破性感染之间的关系：方法：在接种第二剂和第三剂疫苗后，对 30 名 KTR 和 17 名透析患者的血浆进行抗史派克受体结合域（RBD）IgG 和祖先抗体及 Omicron BA.2 变异体中和抗体（NAb）检测：接种三剂疫苗后，KTR 的抗史派克 RBD IgG 水平较低（P = 0.002）。11/27（40.7%）名 KTR 和 11/14（78.6%）名透析受者的血清交叉反应性 Omicron 中和水平呈阳性。ChAdOx1/ 病毒载体疫苗类型、较高的霉酚酸酯剂量（> 1 克/天）和较低的 B 细胞绝对计数预示着 KTR 的血清反应较差。ChAdOx-1 疫苗类型和较高的单核细胞计数对透析受者的血清学反应呈负向预测。在祖先 NAb 血清应答者中，较高的 NAb 水平与较高的 Omicron 中和度呈正相关（R = 0.9，P 结论：在祖先 NAb 血清应答者中，较高的 NAb 水平与较高的 Omicron 中和度呈正相关：KTR 对 COVID-19 疫苗的血清反应落后于透析受者。KTR 在完成初级疫苗接种后仍面临突破性感染的高风险，这表明他们需要加强剂量、严格的感染预防措施和密切监测。

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引用次数: 0

Spatial proteomic profiling of tumor and stromal compartments in non-small-cell lung cancer identifies signatures associated with overall survival 非小细胞肺癌肿瘤和基质区的空间蛋白质组学分析确定了与总生存率相关的特征。

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-18 DOI: 10.1002/cti2.1522

Vahid Yaghoubi Naei, James Monkman, Habib Sadeghirad, Ahmed Mehdi, Tony Blick, William Mullally, Ken O'Byrne, Majid Ebrahimi Warkiani, Arutha Kulasinghe

Objectives

Non-small-cell lung carcinoma (NSCLC) is the most prevalent and lethal form of lung cancer. The need for biomarker-informed stratification of targeted therapies has underpinned the need to uncover the underlying properties of the tumor microenvironment (TME) through high-plex quantitative assays.

Methods

In this study, we profiled resected NSCLC tissues from 102 patients by targeted spatial proteomics of 78 proteins across tumor, immune activation, immune cell typing, immune-oncology, drug targets, cell death and PI3K/AKT modules to identify the tumor and stromal signatures associated with overall survival (OS).

Results

Survival analysis revealed that stromal CD56 (HR = 0.384, P = 0.06) and tumoral TIM3 (HR = 0.703, P = 0.05) were associated with better survival in univariate Cox models. In contrast, after adjusting for stage, BCLXL (HR = 2.093, P = 0.02) and cleaved caspase 9 (HR = 1.575, P = 0.1) negatively influenced survival. Delta testing indicated the protective effect of TIM-3 (HR = 0.614, P = 0.04) on OS. In multivariate analysis, CD56 (HR = 0.172, P = 0.001) was associated with better survival in the stroma, while B7.H3 (HR = 1.72, P = 0.008) was linked to poorer survival in the tumor.

Conclusions

Deciphering the TME using high-plex spatially resolved methods is giving us new insights into compartmentalised tumor and stromal protein signatures associated with clinical endpoints in NSCLC.

研究目的非小细胞肺癌（NSCLC）是发病率最高、致死率最高的肺癌。由于需要根据生物标志物对靶向疗法进行分层，因此需要通过高倍定量检测来揭示肿瘤微环境（TME）的基本特性：在这项研究中，我们通过对肿瘤、免疫激活、免疫细胞分型、免疫肿瘤学、药物靶点、细胞死亡和PI3K/AKT模块中的78种蛋白质进行靶向空间蛋白质组学研究，对102例患者切除的NSCLC组织进行了分析，以确定与总生存期（OS）相关的肿瘤和基质特征：结果：生存分析表明，在单变量Cox模型中，基质CD56（HR=0.384，P=0.06）和肿瘤TIM3（HR=0.703，P=0.05）与较好的生存率相关。相反，在调整分期后，BCLXL（HR = 2.093，P = 0.02）和裂解的caspase 9（HR = 1.575，P = 0.1）对生存率有负面影响。德尔塔测试表明，TIM-3（HR = 0.614，P = 0.04）对 OS 有保护作用。在多变量分析中，CD56（HR = 0.172，P = 0.001）与基质中较高的生存率相关，而B7.H3（HR = 1.72，P = 0.008）与肿瘤中较低的生存率相关：结论：利用高倍空间分辨方法对TME进行解密，让我们对与NSCLC临床终点相关的分区肿瘤和基质蛋白特征有了新的认识。

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引用次数: 0

Endogenous bystander killing mechanisms enhance the activity of novel FAP-specific CAR-T cells against glioblastoma 内源性旁观者杀伤机制增强了新型 FAP 特异性 CAR-T 细胞对抗胶质母细胞瘤的活性

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-05 DOI: 10.1002/cti2.1519

Wenbo Yu, Nga TH Truong, Ruhi Polara, Tessa Gargett, Melinda N Tea, Stuart M Pitson, Michaelia P Cockshell, Claudine S Bonder, Lisa M Ebert, Michael P Brown

Objectives

CAR-T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR-T cells targeting FAP have never been investigated as a therapy for glioblastoma.

Methods

We generated a novel FAP targeting CAR with CD3ζ and CD28 signalling domains and tested the resulting CAR-T cells for their lytic activity and cytokine secretion function in vitro (using real-time impedance, flow cytometry, imaging and bead-based cytokine assays), and in vivo (using a xenograft mimicking the natural heterogeneity of human glioblastoma).

Results

FAP-CAR-T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient-derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co-culture assays, we confirmed FAP-CAR-T cells mediate bystander killing of antigen-negative tumor cells, but only after activation by FAP-positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL-2 which activated the non-transduced fraction of the CAR-T product. Finally, a low dose of intravenously administered FAP-CAR-T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen-negative and antigen-positive glioblastoma cells.

Conclusions

Our findings advance FAP as a leading candidate for clinical CAR-T therapy of glioblastoma and highlight under-recognised antigen nonspecific mechanisms that may contribute meaningfully to the antitumor activity of CAR-T cells.

目的 CAR-T 细胞作为一种治疗胶质母细胞瘤的新型免疫疗法正在接受研究，但临床成功率有限。我们最近描述了成纤维细胞活化蛋白（FAP），它是胶质母细胞瘤免疫疗法的理想靶抗原，在肿瘤细胞和肿瘤血管上都有表达。然而，以 FAP 为靶点的 CAR-T 细胞从未作为胶质母细胞瘤的疗法进行过研究。方法我们生成了一种带有 CD3ζ 和 CD28 信号结构域的新型 FAP 靶向 CAR，并在体外（使用实时阻抗、流式细胞仪、成像和基于微珠的细胞因子测定）和体内（使用模拟人类胶质母细胞瘤天然异质性的异种移植）测试了所生成的 CAR-T 细胞的溶解活性和细胞因子分泌功能。结果 FAP-CAR-T 细胞对模型细胞系具有靶向特异性，对源自患者的胶质瘤神经干细胞具有强大的细胞毒性，即使只有亚群表达 FAP，这表明存在旁观者杀伤机制。通过共培养试验，我们证实了 FAP-CAR-T 细胞对抗原阴性肿瘤细胞的旁观者杀伤作用，但只有在 FAP 阳性靶细胞激活后才能起作用。这种旁观者杀伤作用至少部分由可溶性因子介导，并由 IL-2 激活 CAR-T 产物的非转化部分而放大。最后，静脉注射低剂量的 FAP-CAR-T 细胞可控制使用抗原阴性和抗原阳性胶质母细胞瘤细胞混合物生成的皮下肿瘤的生长，且无明显毒性。结论我们的研究结果推动了 FAP 成为胶质母细胞瘤临床 CAR-T 疗法的主要候选者，并强调了未被充分认识的抗原非特异性机制，这种机制可能会对 CAR-T 细胞的抗肿瘤活性做出有意义的贡献。

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引用次数: 0