Seasonal influenza viruses continue to cause severe medical and financial complications annually. Although there are many licenced influenza vaccines, there are billions of cases of influenza infection every year, resulting in the death of over half a million individuals. Furthermore, these figures can rise in the event of a pandemic, as seen throughout history, like the 1918 Spanish influenza pandemic (50 million deaths) and the 1968 Hong Kong influenza pandemic (~4 million deaths). In this review, we have summarised many of the currently licenced influenza vaccines available across the world and current vaccines in clinical trials. We then briefly discuss the important role of CD8+ T cells during influenza infection and why future influenza vaccines should consider targeting CD8+ T cells. Finally, we assess the current landscape of known immunogenic CD8+ T-cell epitopes and highlight the knowledge gaps required to be filled for the design of rational future influenza vaccines that incorporate CD8+ T cells.
季节性流感病毒每年都会引发严重的医疗和经济并发症。尽管有许多获得许可的流感疫苗，但每年仍有数十亿例流感感染病例，导致 50 多万人死亡。此外，在流感大流行的情况下，这些数字还会上升，这在历史上也曾发生过，如 1918 年西班牙流感大流行（5000 万人死亡）和 1968 年香港流感大流行（约 400 万人死亡）。在这篇综述中，我们总结了目前全球许多获得许可的流感疫苗以及正在进行临床试验的疫苗。然后，我们简要讨论了 CD8+ T 细胞在流感感染过程中的重要作用，以及为什么未来的流感疫苗应考虑以 CD8+ T 细胞为靶标。最后，我们对目前已知的免疫原性 CD8+ T 细胞表位进行了评估，并强调了在设计包含 CD8+ T 细胞的合理未来流感疫苗时需要填补的知识空白。
{"title":"Fighting flu: novel CD8+ T-cell targets are required for future influenza vaccines","authors":"Samuel Liwei Leong, Stephanie Gras, Emma J Grant","doi":"10.1002/cti2.1491","DOIUrl":"https://doi.org/10.1002/cti2.1491","url":null,"abstract":"<p>Seasonal influenza viruses continue to cause severe medical and financial complications annually. Although there are many licenced influenza vaccines, there are billions of cases of influenza infection every year, resulting in the death of over half a million individuals. Furthermore, these figures can rise in the event of a pandemic, as seen throughout history, like the 1918 Spanish influenza pandemic (50 million deaths) and the 1968 Hong Kong influenza pandemic (~4 million deaths). In this review, we have summarised many of the currently licenced influenza vaccines available across the world and current vaccines in clinical trials. We then briefly discuss the important role of CD8<sup>+</sup> T cells during influenza infection and why future influenza vaccines should consider targeting CD8<sup>+</sup> T cells. Finally, we assess the current landscape of known immunogenic CD8<sup>+</sup> T-cell epitopes and highlight the knowledge gaps required to be filled for the design of rational future influenza vaccines that incorporate CD8<sup>+</sup> T cells.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1491","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139739129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nataly Stylianou, Ismail Sebina, Nicholas Matigian, James Monkman, Hadeel Doehler, Joan Röhl, Mark Allenby, Andy Nam, Liuliu Pan, Anja Rockstroh, Habib Sadeghirad, Kimberly Chung, Thais Sobanski, Ken O'Byrne, Ana Clara Simoes Florido Almeida, Patricia Zadorosnei Rebutini, Cleber Machado-Souza, Emanuele Therezinha Schueda Stonoga, Majid E Warkiani, Carlos Salomon, Kirsty Short, Lana McClements, Lucia de Noronha, Ruby Huang, Gabrielle T Belz, Fernando Souza-Fonseca-Guimaraes, Vicki Clifton, Arutha Kulasinghe
Objectives
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a ‘preeclampsia-like syndrome’. However, the mechanisms underpinning SARS-CoV-2-induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS-CoV-2 infection.
Methods
We utilised whole-transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS-CoV-2 in the third trimester of their pregnancy (n = 7) and those collected prior to the start of the coronavirus disease 2019 (COVID-19) pandemic (n = 9).
Results
Through comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified SARS-CoV-2 to promote signatures associated with hypoxia and placental dysfunction. Notably, genes associated with vasodilation (NOS3), oxidative stress (GDF15, CRH) and preeclampsia (FLT1, EGFR, KISS1, PAPPA2) were enriched with SARS-CoV-2. Pathways related to increased nutrient uptake, vascular tension, hypertension and inflammation were also enriched in SARS-CoV-2 samples compared to uninfected controls.
Conclusions
Our findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS-CoV-2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS-CoV-2 infection.
{"title":"Whole transcriptome profiling of placental pathobiology in SARS-CoV-2 pregnancies identifies placental dysfunction signatures","authors":"Nataly Stylianou, Ismail Sebina, Nicholas Matigian, James Monkman, Hadeel Doehler, Joan Röhl, Mark Allenby, Andy Nam, Liuliu Pan, Anja Rockstroh, Habib Sadeghirad, Kimberly Chung, Thais Sobanski, Ken O'Byrne, Ana Clara Simoes Florido Almeida, Patricia Zadorosnei Rebutini, Cleber Machado-Souza, Emanuele Therezinha Schueda Stonoga, Majid E Warkiani, Carlos Salomon, Kirsty Short, Lana McClements, Lucia de Noronha, Ruby Huang, Gabrielle T Belz, Fernando Souza-Fonseca-Guimaraes, Vicki Clifton, Arutha Kulasinghe","doi":"10.1002/cti2.1488","DOIUrl":"10.1002/cti2.1488","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a ‘preeclampsia-like syndrome’. However, the mechanisms underpinning SARS-CoV-2-induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS-CoV-2 infection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We utilised whole-transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS-CoV-2 in the third trimester of their pregnancy (<i>n</i> = 7) and those collected prior to the start of the coronavirus disease 2019 (COVID-19) pandemic (<i>n</i> = 9).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Through comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified SARS-CoV-2 to promote signatures associated with hypoxia and placental dysfunction. Notably, genes associated with vasodilation (<i>NOS3</i>), oxidative stress (<i>GDF15</i>, <i>CRH</i>) and preeclampsia (<i>FLT1</i>, <i>EGFR</i>, <i>KISS1</i>, <i>PAPPA2</i>) were enriched with SARS-CoV-2. Pathways related to increased nutrient uptake, vascular tension, hypertension and inflammation were also enriched in SARS-CoV-2 samples compared to uninfected controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS-CoV-2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS-CoV-2 infection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10846628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139696582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Infiltrating characteristics and prognostic value of tertiary lymphoid structures in resected gastric neuroendocrine neoplasm patients","authors":"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","doi":"10.1002/cti2.1489","DOIUrl":"https://doi.org/10.1002/cti2.1489","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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<sup>+</sup> TANs and FOXP3<sup>+</sup> 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1489","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139695182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"SARS-CoV-2-associated T-cell infiltration in the central nervous system","authors":"Malte Mohme, Christoph Schultheiß, Andras Piffko, Antonia Fitzek, Lisa Paschold, Benjamin Thiele, Klaus Püschel, Markus Glatzel, Manfred Westphal, Katrin Lamszus, Jakob Matschke, Mascha Binder","doi":"10.1002/cti2.1487","DOIUrl":"10.1002/cti2.1487","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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<sup>+</sup> T-cell infiltration with a perivascular infiltration pattern.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1487","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139657271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"γδ T cells mediate robust anti-HIV functions during antiretroviral therapy regardless of immune checkpoint expression","authors":"Kirsty R Field, Kathleen M Wragg, Stephen J Kent, Wen Shi Lee, Jennifer A Juno","doi":"10.1002/cti2.1486","DOIUrl":"https://doi.org/10.1002/cti2.1486","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Utilising a cohort of ART-treated PLWH, we assessed the frequency and phenotype, characterised <i>in vitro</i> 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 <i>in vitro</i> expansion of Vδ2 T cells from PLWH on ART and the mechanisms by which such expanded cells may sense and kill HIV-infected targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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<sup>−1</sup> 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1486","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139643901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Multi-omics integration reveals a nonlinear signature that precedes progression of lung fibrosis","authors":"Céline Pattaroni, Christina Begka, Bailey Cardwell, Jade Jaffar, Matthew Macowan, Nicola L Harris, Glen P Westall, Benjamin J Marsland","doi":"10.1002/cti2.1485","DOIUrl":"10.1002/cti2.1485","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10807351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139544817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"A phase II study to evaluate the safety and efficacy of anlotinib combined with toripalimab for advanced biliary tract cancer","authors":"Mingzhen Zhou, Yuncheng Jin, Sihui Zhu, Chen Xu, Lin Li, Baorui Liu, Jie Shen","doi":"10.1002/cti2.1483","DOIUrl":"https://doi.org/10.1002/cti2.1483","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>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).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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 (<i>P</i> = 0.0397).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1483","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139435088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"Graft CD8 T-cell-based risk system predicts survival in antithymocyte globulin-based myeloablative haploidentical peripheral blood stem cell transplantation","authors":"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","doi":"10.1002/cti2.1484","DOIUrl":"https://doi.org/10.1002/cti2.1484","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study investigated the cellular composition of peripheral blood grafts for anti-thymocyte globulin (ATG)-based myeloablative haploidentical haematopoietic stem cell transplantation (haplo-HSCT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A higher dose of graft CD8<sup>+</sup> T cells (≥ 0.85 × 10<sup>8</sup> kg<sup>−1</sup>) was significantly improved overall survival (OS; hazard ratio [HR], 1.750; <i>P</i> = 0.002) and disease-free survival (DFS; HR, 1.751; <i>P</i> < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; <i>P</i> = 0.038) and DFS (HR, 1.532; <i>P</i> = 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<sup>+</sup> T-cell risk system based on graft CD8<sup>+</sup> 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<sup>+</sup> T-cell dose was negatively correlated with donor age (<i>P</i> < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (<i>P</i> < 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>A higher CD8<sup>+</sup> 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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1484","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139435089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Cellular models in autoinflammatory disease research","authors":"Başak Şen, Banu Balcı-Peynircioğlu","doi":"10.1002/cti2.1481","DOIUrl":"10.1002/cti2.1481","url":null,"abstract":"<p>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.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10784111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"CD14 down-modulation as a real-time biomarker in Kawasaki disease","authors":"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","doi":"10.1002/cti2.1482","DOIUrl":"10.1002/cti2.1482","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1482","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139069630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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