The most successful immunotherapies for solid malignancies to date, immune checkpoint inhibitors, target the essential role of T cells in antitumor immunity. However, T-cell dysfunction presents a major hindrance to treatment efficacy, warranting research into combined treatment strategies for improving outcomes. The use of radiotherapy for this purpose has garnered much interest. Preclinical study has established that radiotherapy activates various immune mechanisms to improve T-cell activation, localisation and function within tumors, which improves response to immune checkpoint inhibitors. However, so far, these strategies have not been successfully translated into the clinic. Here, we briefly reflect on the development of immune checkpoint inhibitors and the mechanistic insights revealed by an evolving understanding of T-cell dysfunction in cancer, before providing an overview of the immunomodulatory effects of radiotherapy in the context of the T-cell-mediated antitumor immune response. We discuss the mixed results of clinical trials, comment on various factors that may preclude immuno-radiotherapy responses in the clinic, and highlight priorities for preclinical and clinical study. Finally, we discuss the role of emerging combinations of radiotherapy and immunotherapy to potentially provide additional treatment options and improve outcomes for patients.
迄今为止，治疗实体恶性肿瘤最成功的免疫疗法--免疫检查点抑制剂--针对的是 T 细胞在抗肿瘤免疫中的重要作用。然而，T 细胞功能障碍是影响疗效的主要障碍，因此有必要研究改善疗效的综合治疗策略。为此，放疗的应用引起了广泛关注。临床前研究证实，放疗可激活各种免疫机制，改善肿瘤内 T 细胞的活化、定位和功能，从而改善对免疫检查点抑制剂的反应。然而，迄今为止，这些策略尚未成功应用于临床。在此，我们简要回顾了免疫检查点抑制剂的发展历程，以及对癌症中 T 细胞功能障碍不断发展的认识所揭示的机理，然后概述了放疗在 T 细胞介导的抗肿瘤免疫反应中的免疫调节作用。我们讨论了临床试验喜忧参半的结果，评论了可能阻碍临床免疫放疗反应的各种因素，并强调了临床前和临床研究的重点。最后，我们讨论了新出现的放疗和免疫疗法组合的作用，它们有可能提供更多的治疗选择并改善患者的预后。
{"title":"Leveraging radiotherapy to improve immunotherapy outcomes: rationale, progress and research priorities","authors":"Faith Hartley, Martin Ebert, Alistair M Cook","doi":"10.1002/cti2.70030","DOIUrl":"https://doi.org/10.1002/cti2.70030","url":null,"abstract":"<p>The most successful immunotherapies for solid malignancies to date, immune checkpoint inhibitors, target the essential role of T cells in antitumor immunity. However, T-cell dysfunction presents a major hindrance to treatment efficacy, warranting research into combined treatment strategies for improving outcomes. The use of radiotherapy for this purpose has garnered much interest. Preclinical study has established that radiotherapy activates various immune mechanisms to improve T-cell activation, localisation and function within tumors, which improves response to immune checkpoint inhibitors. However, so far, these strategies have not been successfully translated into the clinic. Here, we briefly reflect on the development of immune checkpoint inhibitors and the mechanistic insights revealed by an evolving understanding of T-cell dysfunction in cancer, before providing an overview of the immunomodulatory effects of radiotherapy in the context of the T-cell-mediated antitumor immune response. We discuss the mixed results of clinical trials, comment on various factors that may preclude immuno-radiotherapy responses in the clinic, and highlight priorities for preclinical and clinical study. Finally, we discuss the role of emerging combinations of radiotherapy and immunotherapy to potentially provide additional treatment options and improve outcomes for patients.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 4","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793580","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}
Jiafu Wang, Song Li, Xianling Zhou, Hongxing Wu, Xiaolan Ouyang, Zhuoshan Huang, Long Peng, Qian Chen, Yuman Wu, Zhitong Li, Ziyi Peng, Yi Yang, Yan Lu, Xixiang Tang, Yue Li, Suhua Li
Objectives
Myocardial ischaemia and remodelling are major contributors to the progression and mortality of coronary artery disease (CAD). Previous studies have shown immune cell alterations in CAD patients, but their characteristics and associations with myocardial ischaemia and remodelling remain unclear.
Methods
We compared immune cell changes among patients without CAD, those with CAD and those with CAD and heart failure (HF).
Results
We found a progressive reduction in circulating mucosal-associated invariant T (MAIT) cells across the three patient groups. MAIT cells exhibited increased expression of activation markers (CD69 and PD-1) and cytotoxic molecules (such as granzyme B). The features of MAIT cells were correlated positively with worsening clinical indicators of myocardial ischaemia and remodelling, including the Gensini score, cTnI, NT-proBNP, LVEF and E/e′. Additionally, the reduction, activation and cytotoxicity of MAIT cells were associated with indicators of myocardial fibrosis (sST2, Gal-3, PICP and PIIINP), a central pathological mechanism of myocardial remodelling. Finally, we preliminarily explored potential triggers for MAIT cell abnormalities in CAD patients and found that impaired intestinal barrier function and increased circulating bacterial antigens may contribute to these changes.
Conclusions
During CAD progression, we observed a decrease in circulating MAIT cells. Enhanced activation and cytotoxicity of MAIT cells are associated with myocardial ischaemia and remodelling in CAD patients with heart failure, potentially triggered by gut microbial leakage. Our findings suggest a novel strategy for monitoring and intervention in disease progression.
{"title":"Mucosal-associated invariant T cells correlate with myocardial ischaemia and remodelling in coronary artery disease","authors":"Jiafu Wang, Song Li, Xianling Zhou, Hongxing Wu, Xiaolan Ouyang, Zhuoshan Huang, Long Peng, Qian Chen, Yuman Wu, Zhitong Li, Ziyi Peng, Yi Yang, Yan Lu, Xixiang Tang, Yue Li, Suhua Li","doi":"10.1002/cti2.70029","DOIUrl":"https://doi.org/10.1002/cti2.70029","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Myocardial ischaemia and remodelling are major contributors to the progression and mortality of coronary artery disease (CAD). Previous studies have shown immune cell alterations in CAD patients, but their characteristics and associations with myocardial ischaemia and remodelling remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compared immune cell changes among patients without CAD, those with CAD and those with CAD and heart failure (HF).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found a progressive reduction in circulating mucosal-associated invariant T (MAIT) cells across the three patient groups. MAIT cells exhibited increased expression of activation markers (CD69 and PD-1) and cytotoxic molecules (such as granzyme B). The features of MAIT cells were correlated positively with worsening clinical indicators of myocardial ischaemia and remodelling, including the Gensini score, cTnI, NT-proBNP, LVEF and E/e′. Additionally, the reduction, activation and cytotoxicity of MAIT cells were associated with indicators of myocardial fibrosis (sST2, Gal-3, PICP and PIIINP), a central pathological mechanism of myocardial remodelling. Finally, we preliminarily explored potential triggers for MAIT cell abnormalities in CAD patients and found that impaired intestinal barrier function and increased circulating bacterial antigens may contribute to these changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>During CAD progression, we observed a decrease in circulating MAIT cells. Enhanced activation and cytotoxicity of MAIT cells are associated with myocardial ischaemia and remodelling in CAD patients with heart failure, potentially triggered by gut microbial leakage. Our findings suggest a novel strategy for monitoring and intervention in disease progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 3","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690104","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}
Faisal Alagrafi, Arwen Stikvoort, Ahmed Gaballa, Martin Solders, Olle Ringden, Thomas Poiret, Lucas CM Arruda, Michael Uhlin
Objectives
The clinical outcome after allogeneic haematopoietic stem cell transplantation (aHCT) relies greatly on the efficient recovery of T cells. Several studies have investigated the short-term γδ T cell reconstitution and their role in clinical outcomes following haematopoietic stem cell transplantation. Nevertheless, their long-term characteristics and impact have remained largely unknown.
Methods
We analysed γδ T cells from 20 recipient/donor pairs at phenotypic, clonotypic and functional levels to assess their reconstitution ≥ 8 years (median 18 years) post-transplantation using high-parameter flow cytometry and next-generation sequencing of the TCR γ-chain.
Results
γδ T cells displayed comparable phenotypic characteristics between recipients and matching donors. The Vδ2+ subset showed a more activated phenotype and cytokine production, while the Vδ1+ and non-Vδ2 T cells maintained long-term CMV control. TCR γ-chain composition in long-term survivors was largely restored, with no significant differences in gene segment usage or diversity. A small cohort of recipients with severe chronic graft-versus-host disease (GVHD) showed overrepresented donor-derived private clonotypes. Furthermore, we also found elevated HLA-DR+Vδ1+ T cells in recipients with severe chronic GVHD.
Conclusion
Overall, γδ T cells reconstitute with a normalised repertoire, high functional capacity and sustained CMV control ability. An increased proportion of activated Vδ1+ T cells correlates with chronic GVHD severity, indicating a potential therapeutic target.
{"title":"γδ T cell characterisation in the long term after haematopoietic stem cell transplantation and its impact on CMV control and cGVHD severity","authors":"Faisal Alagrafi, Arwen Stikvoort, Ahmed Gaballa, Martin Solders, Olle Ringden, Thomas Poiret, Lucas CM Arruda, Michael Uhlin","doi":"10.1002/cti2.70027","DOIUrl":"https://doi.org/10.1002/cti2.70027","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The clinical outcome after allogeneic haematopoietic stem cell transplantation (aHCT) relies greatly on the efficient recovery of T cells. Several studies have investigated the short-term γδ T cell reconstitution and their role in clinical outcomes following haematopoietic stem cell transplantation. Nevertheless, their long-term characteristics and impact have remained largely unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed γδ T cells from 20 recipient/donor pairs at phenotypic, clonotypic and functional levels to assess their reconstitution ≥ 8 years (median 18 years) post-transplantation using high-parameter flow cytometry and next-generation sequencing of the TCR γ-chain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>γδ T cells displayed comparable phenotypic characteristics between recipients and matching donors. The Vδ2<sup>+</sup> subset showed a more activated phenotype and cytokine production, while the Vδ1<sup>+</sup> and non-Vδ2 T cells maintained long-term CMV control. TCR γ-chain composition in long-term survivors was largely restored, with no significant differences in gene segment usage or diversity. A small cohort of recipients with severe chronic graft-versus-host disease (GVHD) showed overrepresented donor-derived private clonotypes. Furthermore, we also found elevated HLA-DR<sup>+</sup>Vδ1<sup>+</sup> T cells in recipients with severe chronic GVHD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall, γδ T cells reconstitute with a normalised repertoire, high functional capacity and sustained CMV control ability. An increased proportion of activated Vδ1<sup>+</sup> T cells correlates with chronic GVHD severity, indicating a potential therapeutic target.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 3","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565227","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}
Johanna Emgård, Iva Filipovic, Christian Unge, Laura M Palma Medina, Åsa Parke, Helena Bergsten, Kirsten Moll, Majda Dzidic, Helena Alpkvist, Hong Fang, Volkan Özenci, Niklas K Björkström, Mattias Svensson, Johan K Sandberg, Kristoffer Strålin, Anna Norrby-Teglund
Objectives
Rapid diagnosis and intervention are critical for sepsis patient outcomes. However, diagnosis is challenging because of a heterogenic patient group as well as sometimes vague symptoms when the patient presents at the emergency department. Mucosal-associated invariant T (MAIT) cells are rapid responders to infection, but their role and characteristics in the early course of sepsis remain unknown. Here, we evaluate the early MAIT cell characteristics in the blood of patients triggering a clinical sepsis alert system at the emergency department.
Methods
Peripheral blood mononuclear cells were isolated from freshly drawn blood and immediately stained. MAIT cell phenotyping analyses were conducted using multiparameter flow cytometry. All analyses were completed prior to the stratification of patients into sepsis or non-sepsis groups. Soluble factors in plasma were measured using a multiplex assay.
Results
Unsupervised high-dimensional phenotyping identified distinct MAIT cell activation profiles in sepsis and non-sepsis groups. Among sepsis patients, hierarchical clustering of MAIT cell phenotypes separated clinical endotypes into three groups with different infection focus, severity and aetiology. A prominent characteristic of sepsis severity was high expression of CD69 on MAIT cells, which was associated with organ dysfunction, lymphopenia and poor outcome. Plasma levels of IL-12, IL-15, TNF, IFNγ and CXCL10 correlated with the magnitude of MAIT cell activation in sepsis patients.
Conclusions
These clinical endotype-specific MAIT cell phenotypes presenting already in the emergency department are of interest for early patient identification and prognostication in sepsis.
{"title":"Distinct MAIT cell phenotypes associated with sepsis clinical outcome in emergency department patients","authors":"Johanna Emgård, Iva Filipovic, Christian Unge, Laura M Palma Medina, Åsa Parke, Helena Bergsten, Kirsten Moll, Majda Dzidic, Helena Alpkvist, Hong Fang, Volkan Özenci, Niklas K Björkström, Mattias Svensson, Johan K Sandberg, Kristoffer Strålin, Anna Norrby-Teglund","doi":"10.1002/cti2.70028","DOIUrl":"https://doi.org/10.1002/cti2.70028","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Rapid diagnosis and intervention are critical for sepsis patient outcomes. However, diagnosis is challenging because of a heterogenic patient group as well as sometimes vague symptoms when the patient presents at the emergency department. Mucosal-associated invariant T (MAIT) cells are rapid responders to infection, but their role and characteristics in the early course of sepsis remain unknown. Here, we evaluate the early MAIT cell characteristics in the blood of patients triggering a clinical sepsis alert system at the emergency department.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Peripheral blood mononuclear cells were isolated from freshly drawn blood and immediately stained. MAIT cell phenotyping analyses were conducted using multiparameter flow cytometry. All analyses were completed prior to the stratification of patients into sepsis or non-sepsis groups. Soluble factors in plasma were measured using a multiplex assay.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Unsupervised high-dimensional phenotyping identified distinct MAIT cell activation profiles in sepsis and non-sepsis groups. Among sepsis patients, hierarchical clustering of MAIT cell phenotypes separated clinical endotypes into three groups with different infection focus, severity and aetiology. A prominent characteristic of sepsis severity was high expression of CD69 on MAIT cells, which was associated with organ dysfunction, lymphopenia and poor outcome. Plasma levels of IL-12, IL-15, TNF, IFNγ and CXCL10 correlated with the magnitude of MAIT cell activation in sepsis patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These clinical endotype-specific MAIT cell phenotypes presenting already in the emergency department are of interest for early patient identification and prognostication in sepsis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 3","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554605","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}
Björn Österberg, Sara Falck-Jones, Sindhu Vangeti, Eric Åhlberg, Meng Yu, Diana Granja, Marijn E Snik, Ryan Falck-Jones, Guilherme WF Barros, Afandi Charles, Rico Lepzien, Niclas Johansson, Tyson H Holmes, Holden Maecker, Paulo Czarnewski, Max Bell, Anna Färnert, Anna Smed-Sörensen
Objectives
Monocytes and dendritic cells (DCs) are essential players in the immune response to infections, involved in shaping innate and adaptive immunity. However, a complete understanding of their specific roles in respiratory infections, including SARS-CoV-2, remains elusive.
Methods
To investigate the dynamics of monocytes and DCs in blood as well as the upper and lower airways, we sampled 147 patients with varying degree of COVID-19 severity longitudinally during the spring of 2020.
Results
Using flow cytometry, proteomics and in vitro TLR stimulation, we found differences in the distribution and function of monocytes and DCs in patients compared with controls, and importantly, reduced levels of DCs in both blood and airways. In fact, lower frequencies of cDC2s (Lin− HLA-DR+ CD1c+) early after symptom onset predicted subsequent severe disease, and depletion of DC subsets lasted longer in patients with more severe disease. In contrast, severe COVID-19 was associated with increased frequencies of activated monocytes in the lower, but not the upper, airways. Proteomic analysis showed that monocyte and DC-related cytokines in plasma and airways associated with disease severity. During convalescence, cell frequencies and responses to TLR ligands normalised in blood, except for persistently low plasmacytoid DCs.
Conclusion
Our study reveals a distinct pattern of recruitment of monocytes but not DCs to the airways during severe COVID-19. Instead, decreased levels of DCs in both blood and airways were found, possibly contributing to more severe COVID-19. The connection between low blood DCs early in disease course and more severe outcomes provides insight into COVID-19 immunopathology, with possible therapeutic implications.
{"title":"Decreased levels and function of dendritic cells in blood and airways predict COVID-19 severity","authors":"Björn Österberg, Sara Falck-Jones, Sindhu Vangeti, Eric Åhlberg, Meng Yu, Diana Granja, Marijn E Snik, Ryan Falck-Jones, Guilherme WF Barros, Afandi Charles, Rico Lepzien, Niclas Johansson, Tyson H Holmes, Holden Maecker, Paulo Czarnewski, Max Bell, Anna Färnert, Anna Smed-Sörensen","doi":"10.1002/cti2.70026","DOIUrl":"https://doi.org/10.1002/cti2.70026","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Monocytes and dendritic cells (DCs) are essential players in the immune response to infections, involved in shaping innate and adaptive immunity. However, a complete understanding of their specific roles in respiratory infections, including SARS-CoV-2, remains elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To investigate the dynamics of monocytes and DCs in blood as well as the upper and lower airways, we sampled 147 patients with varying degree of COVID-19 severity longitudinally during the spring of 2020.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Using flow cytometry, proteomics and <i>in vitro</i> TLR stimulation, we found differences in the distribution and function of monocytes and DCs in patients compared with controls, and importantly, reduced levels of DCs in both blood and airways. In fact, lower frequencies of cDC2s (Lin<sup>−</sup> HLA-DR<sup>+</sup> CD1c<sup>+</sup>) early after symptom onset predicted subsequent severe disease, and depletion of DC subsets lasted longer in patients with more severe disease. In contrast, severe COVID-19 was associated with increased frequencies of activated monocytes in the lower, but not the upper, airways. Proteomic analysis showed that monocyte and DC-related cytokines in plasma and airways associated with disease severity. During convalescence, cell frequencies and responses to TLR ligands normalised in blood, except for persistently low plasmacytoid DCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study reveals a distinct pattern of recruitment of monocytes but not DCs to the airways during severe COVID-19. Instead, decreased levels of DCs in both blood and airways were found, possibly contributing to more severe COVID-19. The connection between low blood DCs early in disease course and more severe outcomes provides insight into COVID-19 immunopathology, with possible therapeutic implications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 3","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530404","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}
Despite great strides of progress, at least 60% of the responding patients relapse to CAR therapy across the blood malignancies. Off-tumor toxicity apart from functional deficits, cytopenia and infection are the major unfavourable effect of CAR therapy. Models, which faithfully recapitulate the physiology and complexities of immunocompetent tumor microenvironment (TME), paused challenges in capturing potential off-tumor effects of CAR therapy. Importantly, a landmark change in the legislation allows US Food and Drug Administration and New Drugs and Clinical Trial Rules in India encourages researchers to replace animal testing with cell culture approaches relevant to human system. Organ-on-chip (OOC) based on microfluidics technology can potentially emulate multiple biochemical and biophysical intricacies of blood and lymph flow at microscale. Nonetheless, how the evolving microfluidics technology can be enabling to real-time testing of cell and gene is yet to be realised.
{"title":"Organ-on-chip for advancing CAR therapy","authors":"Lightson Ngashangva, Sunil Martin","doi":"10.1002/cti2.70024","DOIUrl":"https://doi.org/10.1002/cti2.70024","url":null,"abstract":"<p>Despite great strides of progress, at least 60% of the responding patients relapse to CAR therapy across the blood malignancies. Off-tumor toxicity apart from functional deficits, cytopenia and infection are the major unfavourable effect of CAR therapy. Models, which faithfully recapitulate the physiology and complexities of immunocompetent tumor microenvironment (TME), paused challenges in capturing potential off-tumor effects of CAR therapy. Importantly, a landmark change in the legislation allows US Food and Drug Administration and New Drugs and Clinical Trial Rules in India encourages researchers to replace animal testing with cell culture approaches relevant to human system. Organ-on-chip (OOC) based on microfluidics technology can potentially emulate multiple biochemical and biophysical intricacies of blood and lymph flow at microscale. Nonetheless, how the evolving microfluidics technology can be enabling to real-time testing of cell and gene is yet to be realised.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 2","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489966","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}
Nicole L Messina, Susie Germano, Amy W Chung, Carolien E van de Sandt, Natalie E Stevens, Lilith F Allen, Rhian Bonnici, Julio Croda, Claudio Counoupas, Branka Grubor-Bauk, Ebene R Haycroft, Katherine Kedzierska, Ellie McDonald, Rebecca McElroy, Mihai G Netea, Boris Novakovic, Kirsten P Perrett, Laure F Pittet, Ruth A Purcell, Kanta Subbarao, James A Triccas, David J Lynn, Nigel Curtis, the BRACE Trial Consortium Group
Objectives
Bacille Calmette–Guérin (BCG) vaccination has off-target effects on disease risk for unrelated infections and immune responses to vaccines. This study aimed to determine the immunomodulatory effects of BCG vaccination on immune responses to vaccines against SARS-CoV-2.
Methods
Blood samples, from a subset of 275 SARS-CoV-2-naïve healthcare workers randomised to BCG vaccination (BCG group) or no BCG vaccination (Control group) in the BRACE trial, were collected before and 28 days after the primary course (two doses) of ChAdOx1-S (Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) vaccination. SARS-CoV-2-specific antibodies were measured using ELISA and multiplex bead array, whole blood cytokine responses to γ-irradiated SARS-CoV-2 (iSARS) stimulation were measured by multiplex bead array, and SARS-CoV-2-specific T-cell responses were measured by activation-induced marker and intracellular cytokine staining assays.
Results
After randomisation (mean 11 months) but prior to COVID-19 vaccination, the BCG group had lower cytokine responses to iSARS stimulation than the Control group. After two doses of ChAdOx1-S, differences in iSARS-induced cytokine responses between the BCG group and Control group were found for three cytokines (CTACK, TRAIL and VEGF). No differences were found between the groups after BNT162b2 vaccination. There were also no differences between the BCG and Control groups in COVID-19 vaccine-induced antigen-specific antibody responses, T-cell activation or T-cell cytokine production.
Conclusion
BCG vaccination induced a broad and persistent reduction in ex vivo cytokine responses to SARS-CoV-2. Following COVID-19 vaccination, this effect was abrogated, and BCG vaccination did not influence adaptive immune responses to COVID-19 vaccine antigens.
{"title":"Effect of Bacille Calmette–Guérin vaccination on immune responses to SARS-CoV-2 and COVID-19 vaccination","authors":"Nicole L Messina, Susie Germano, Amy W Chung, Carolien E van de Sandt, Natalie E Stevens, Lilith F Allen, Rhian Bonnici, Julio Croda, Claudio Counoupas, Branka Grubor-Bauk, Ebene R Haycroft, Katherine Kedzierska, Ellie McDonald, Rebecca McElroy, Mihai G Netea, Boris Novakovic, Kirsten P Perrett, Laure F Pittet, Ruth A Purcell, Kanta Subbarao, James A Triccas, David J Lynn, Nigel Curtis, the BRACE Trial Consortium Group","doi":"10.1002/cti2.70023","DOIUrl":"10.1002/cti2.70023","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Bacille Calmette–Guérin (BCG) vaccination has off-target effects on disease risk for unrelated infections and immune responses to vaccines. This study aimed to determine the immunomodulatory effects of BCG vaccination on immune responses to vaccines against SARS-CoV-2.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Blood samples, from a subset of 275 SARS-CoV-2-naïve healthcare workers randomised to BCG vaccination (BCG group) or no BCG vaccination (Control group) in the BRACE trial, were collected before and 28 days after the primary course (two doses) of ChAdOx1-S (Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) vaccination. SARS-CoV-2-specific antibodies were measured using ELISA and multiplex bead array, whole blood cytokine responses to γ-irradiated SARS-CoV-2 (iSARS) stimulation were measured by multiplex bead array, and SARS-CoV-2-specific T-cell responses were measured by activation-induced marker and intracellular cytokine staining assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After randomisation (mean 11 months) but prior to COVID-19 vaccination, the BCG group had lower cytokine responses to iSARS stimulation than the Control group. After two doses of ChAdOx1-S, differences in iSARS-induced cytokine responses between the BCG group and Control group were found for three cytokines (CTACK, TRAIL and VEGF). No differences were found between the groups after BNT162b2 vaccination. There were also no differences between the BCG and Control groups in COVID-19 vaccine-induced antigen-specific antibody responses, T-cell activation or T-cell cytokine production.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>BCG vaccination induced a broad and persistent reduction in <i>ex vivo</i> cytokine responses to SARS-CoV-2. Following COVID-19 vaccination, this effect was abrogated, and BCG vaccination did not influence adaptive immune responses to COVID-19 vaccine antigens.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051099","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}
Eleni Tiniakou, Livia Casciola-Rosen, Mekha A Thomas, Yuka Manabe, Annukka AR Antar, Mahendra Damarla, Paul M Hassoun, Li Gao, Zitong Wang, Scott Zeger, Antony Rosen
Objectives
CD209L and its homologous protein CD209 act as alternative entry receptors for the SARS-CoV-2 virus and are highly expressed in the virally targeted tissues. We tested for the presence and clinical features of autoantibodies targeting these receptors and compared these with autoantibodies known to be associated with COVID-19.
Methods
Using banked samples (n = 118) from Johns Hopkins patients hospitalised with COVID-19, we defined autoantibodies against CD209 and CD209L by enzyme-linked immunosorbent assay (ELISA). Clinical associations of these antibodies were compared with those of patients with anti-interferon (IFN) and anti-angiotensin-converting enzyme-2 (ACE2) autoantibodies.
Results
Amongst patients hospitalised with COVID-19, 19.5% (23/118) had IgM autoantibodies against CD209L and were more likely to have coronary artery disease (44% vs 19%, P = 0.03). Antibodies against CD209 were present in 5.9% (7/118); interestingly, all 7 were male (P = 0.02). In our study, the presence of either antibody was positively associated with disease severity [OR 95% confidence interval (95% CI): 1.80 (0.69–5.03)], but the association did not reach statistical significance. In contrast, 10/118 (8.5%) had IgG autoantibodies against IFNα, and 21 (17.8%) had IgM antibodies against ACE2. These patients had significantly worse prognosis (intubation or death) and prolonged hospital stays. However, when adjusting for patient characteristics on admission, only the presence of anti-ACE2 IgM remained significant [pooled common OR (95% CI), 4.14 (1.37, 12.54)].
Conclusion
We describe IgM autoantibodies against CD209 and CD209L amongst patients hospitalised with COVID-19. These were not associated with disease severity. Conversely, patients with either anti-ACE2 IgM or anti-IFNα IgG antibodies had worse outcomes. Due to the small size of the study cohort, conclusions drawn should be considered cautiously.
{"title":"Autoantibodies in hospitalised patients with COVID-19","authors":"Eleni Tiniakou, Livia Casciola-Rosen, Mekha A Thomas, Yuka Manabe, Annukka AR Antar, Mahendra Damarla, Paul M Hassoun, Li Gao, Zitong Wang, Scott Zeger, Antony Rosen","doi":"10.1002/cti2.70019","DOIUrl":"10.1002/cti2.70019","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>CD209L and its homologous protein CD209 act as alternative entry receptors for the SARS-CoV-2 virus and are highly expressed in the virally targeted tissues. We tested for the presence and clinical features of autoantibodies targeting these receptors and compared these with autoantibodies known to be associated with COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using banked samples (<i>n</i> = 118) from Johns Hopkins patients hospitalised with COVID-19, we defined autoantibodies against CD209 and CD209L by enzyme-linked immunosorbent assay (ELISA). Clinical associations of these antibodies were compared with those of patients with anti-interferon (IFN) and anti-angiotensin-converting enzyme-2 (ACE2) autoantibodies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Amongst patients hospitalised with COVID-19, 19.5% (23/118) had IgM autoantibodies against CD209L and were more likely to have coronary artery disease (44% vs 19%, <i>P</i> = 0.03). Antibodies against CD209 were present in 5.9% (7/118); interestingly, all 7 were male (<i>P</i> = 0.02). In our study, the presence of either antibody was positively associated with disease severity [OR 95% confidence interval (95% CI): 1.80 (0.69–5.03)], but the association did not reach statistical significance. In contrast, 10/118 (8.5%) had IgG autoantibodies against IFNα, and 21 (17.8%) had IgM antibodies against ACE2. These patients had significantly worse prognosis (intubation or death) and prolonged hospital stays. However, when adjusting for patient characteristics on admission, only the presence of anti-ACE2 IgM remained significant [pooled common OR (95% CI), 4.14 (1.37, 12.54)].</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We describe IgM autoantibodies against CD209 and CD209L amongst patients hospitalised with COVID-19. These were not associated with disease severity. Conversely, patients with either anti-ACE2 IgM or anti-IFNα IgG antibodies had worse outcomes. Due to the small size of the study cohort, conclusions drawn should be considered cautiously.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902525","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}
Dan Wang, Liuyang Wang, Shuai Liu, Jianjun Tong, Honglin Zhu, Man Xu, Xiancai Li, Zhiqiang Xiang, Qinghua Sun, Hengcai Wang, Yuli Wang, Shuyang Wang, Liming Yang
Objectives
To evaluate the manufacturability, efficacy and safety of allogeneic CD19 chimeric antigen receptor double-negative T cells (CD19-CAR-DNTs) as an off-the-shelf therapeutic cell product.
Methods
A membrane proteome array was used to assess the off-target binding of CD19-CAR. DNTs derived from healthy donors were transduced with lentiviral vectors encoding the CD19-CAR. The manufacture of the CD19-CAR-DNTs was under GMP conditions, and their surface molecule expression patterns were characterised using flow cytometry. We investigated the off-the-shelf potential of CD19-CAR-DNTs by evaluating the cryopreserved CD19-CAR-DNTs in terms of cell viability as well as their cytotoxicity against various CD19+ target cell lines and primary patient blasts in vitro. We evaluated the persistence and safety of the cryopreserved CD19-CAR-DNTs in xenograft models in vivo.
Results
GMP-grade CD19-CAR-DNTs were manufactured and cryopreserved for use in advance. The cryopreserved CD19-CAR-DNTs maintain their viability and antitumor activity against various CD19+ target cell lines and primary patient blasts. These cells significantly prolonged the survival in Raji-Luc-xenografted NOG mice. Multiple infusions of the cells can further augment their efficacy. Remarkably, following a single infusion in mice, CD19-CAR-DNTs rapidly got distributed among well-perfused organs initially, and progressively spread to most tissues, peaking at Day 43. In toxicity studies, CD19-CAR-DNTs significantly reduced tumor burden and ameliorated tissue damage in tumor-bearing NOG mice. Critically, no immunotoxicity or graft versus host disease was observed in non-tumor-bearing NOG mice.
Conclusions
The allogeneic CD19-CAR-DNTs fulfil the requirements of an off-the-shelf therapeutic cell product, offering a promising new approach to the treatment of haematological malignancies.
目的：评价同种异体CD19嵌合抗原受体双阴性T细胞（CD19- car - dnts）作为一种现成的治疗细胞产品的可制造性、有效性和安全性。方法：采用膜蛋白质组阵列检测CD19-CAR的脱靶结合。用编码CD19-CAR的慢病毒载体转导来自健康供体的dnt。在GMP条件下制备CD19-CAR-DNTs，并使用流式细胞术表征其表面分子表达模式。我们通过在体外评估冷冻保存的CD19- car - dnts的细胞活力以及它们对各种CD19+靶细胞系和原代患者细胞的细胞毒性，研究了CD19- car - dnts的现成潜力。我们评估了冷冻保存的CD19-CAR-DNTs在体内异种移植模型中的持久性和安全性。结果：制备出gmp级CD19-CAR-DNTs并冷冻保存。冷冻保存的CD19- car - dnts对各种CD19+靶细胞系和原代患者原细胞保持活性和抗肿瘤活性。这些细胞显著延长了raji - luc异种移植NOG小鼠的存活时间。多次输注细胞可进一步增强其功效。值得注意的是，在小鼠体内单次输注后，CD19-CAR-DNTs最初迅速分布在灌注良好的器官中，并逐渐扩散到大多数组织，在第43天达到峰值。在毒性研究中，CD19-CAR-DNTs显著减轻了荷瘤NOG小鼠的肿瘤负荷并改善了组织损伤。关键的是，在非荷瘤NOG小鼠中没有观察到免疫毒性或移植物抗宿主病。结论：同种异体CD19-CAR-DNTs满足了一种现成的治疗细胞产品的要求，为治疗血液系统恶性肿瘤提供了一种有希望的新方法。
{"title":"A preclinical study of allogeneic CD19 chimeric antigen receptor double-negative T cells as an off-the-shelf immunotherapy drug against B-cell malignancies","authors":"Dan Wang, Liuyang Wang, Shuai Liu, Jianjun Tong, Honglin Zhu, Man Xu, Xiancai Li, Zhiqiang Xiang, Qinghua Sun, Hengcai Wang, Yuli Wang, Shuyang Wang, Liming Yang","doi":"10.1002/cti2.70022","DOIUrl":"10.1002/cti2.70022","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To evaluate the manufacturability, efficacy and safety of allogeneic CD19 chimeric antigen receptor double-negative T cells (CD19-CAR-DNTs) as an off-the-shelf therapeutic cell product.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A membrane proteome array was used to assess the off-target binding of CD19-CAR. DNTs derived from healthy donors were transduced with lentiviral vectors encoding the CD19-CAR. The manufacture of the CD19-CAR-DNTs was under GMP conditions, and their surface molecule expression patterns were characterised using flow cytometry. We investigated the off-the-shelf potential of CD19-CAR-DNTs by evaluating the cryopreserved CD19-CAR-DNTs in terms of cell viability as well as their cytotoxicity against various CD19<sup>+</sup> target cell lines and primary patient blasts <i>in vitro.</i> We evaluated the persistence and safety of the cryopreserved CD19-CAR-DNTs in xenograft models <i>in vivo</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GMP-grade CD19-CAR-DNTs were manufactured and cryopreserved for use in advance. The cryopreserved CD19-CAR-DNTs maintain their viability and antitumor activity against various CD19<sup>+</sup> target cell lines and primary patient blasts. These cells significantly prolonged the survival in Raji-Luc-xenografted NOG mice. Multiple infusions of the cells can further augment their efficacy. Remarkably, following a single infusion in mice, CD19-CAR-DNTs rapidly got distributed among well-perfused organs initially, and progressively spread to most tissues, peaking at Day 43. In toxicity studies, CD19-CAR-DNTs significantly reduced tumor burden and ameliorated tissue damage in tumor-bearing NOG mice. Critically, no immunotoxicity or graft versus host disease was observed in non-tumor-bearing NOG mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The allogeneic CD19-CAR-DNTs fulfil the requirements of an off-the-shelf therapeutic cell product, offering a promising new approach to the treatment of haematological malignancies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884898","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}
Daniel Álvarez, Hephzibah E Winter, Carlos J Velasquez Franco, Aleida Susana Castellanos Gutierrez, Núria Baños, Udo R Markert, Ángela P Cadavid, Diana M Morales-Prieto
Objectives
Antiphospholipid syndrome (APS) is an autoimmune disease driven by antiphospholipid antibodies (aPL). Currently, APS diagnosis requires a combination of clinical manifestations (thrombosis and/or obstetric morbidity) and the persistent presence of at least one criteria aPL: anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2GPI) or lupus anticoagulant (LA). Patients with suggestive obstetric symptoms but lacking criteria aPL face diagnostic challenges. Non-criteria aPL screening may enhance discrimination. This study proposes a classification incorporating both criteria and non-criteria antibodies to improve obstetric APS diagnosis.
Methods
Blood samples from non-pregnant women (n = 68) with a history of vascular, obstetric, or vascular and obstetric manifestations were analysed. Among them, 30 had previous diagnosis of APS. Healthy women with proven gestational success were included as controls (n = 16). Criteria and non-criteria (anti-phosphatidylglycerol, anti-phosphatidylethanolamine, anti-phosphatidylinositol, anti-phosphatidylserine and anti-phosphatidic acid) IgG aPL were evaluated by ELISA and coagulation tests. Based on the resulting aPL profile, patients were reclassified. Responsiveness to treatment was obtained from medical records.
Results
Criteria aPL levels marginally differentiated women previously managed as obstetric APS from unexplained/other causes of obstetric morbidity. Including non-criteria aPL improved separation. The proposed classification identified an obstetric APS group that exhibits non-criteria aPL and aβ2GPI titres below the cut-off but higher than healthy women (7.88 vs. 2.47 SGU, P = 0.006). Compared to cases of other causes of obstetric morbidity, these patients retrospectively responded better to aspirin and/or heparin treatment (71.43% vs. 11.11%, P = 0.035).
Conclusions
Assessing non-criteria antibodies may identify isolated obstetric APS cases benefiting from established therapies.
目的：抗磷脂综合征（APS）是一种由抗磷脂抗体（aPL）驱动的自身免疫性疾病。目前，APS的诊断需要结合临床表现（血栓形成和/或产科发病）和至少一种标准aPL的持续存在：抗心磷脂抗体（aCL）、抗β2-糖蛋白I抗体（a -β 2gpi）或狼疮抗凝剂（LA）。有暗示性产科症状但缺乏标准aPL的患者面临诊断挑战。非标准aPL筛查可能增强歧视。本研究提出了一种结合标准和非标准抗体的分类，以改善产科APS诊断。方法：对有血管、产科病史或血管和产科表现的非妊娠妇女（n = 68）的血液样本进行分析。其中30例既往诊断为APS。经证实妊娠成功的健康妇女作为对照组（n = 16）。采用ELISA和凝血试验评价标准和非标准（抗磷脂酰甘油、抗磷脂酰乙醇胺、抗磷脂酰肌醇、抗磷脂酰丝氨酸和抗磷脂酸）IgG aPL。根据结果的aPL谱，对患者进行重新分类。从医疗记录中获得对治疗的反应性。结果：标准aPL水平将以前作为产科APS管理的妇女与不明原因/其他原因的产科发病率区分开来。包括非标准api改善了分离。建议的分类确定了一个产科APS组，其显示非标准aPL和aβ2GPI滴度低于临界值，但高于健康妇女（7.88 vs 2.47 SGU, P = 0.006）。与其他原因的产科发病病例相比，这些患者对阿司匹林和/或肝素治疗的回顾性反应更好（71.43%比11.11%,P = 0.035）。结论：评估非标准抗体可以识别孤立的产科APS病例受益于既定的治疗。
{"title":"Improving diagnosis in patients with obstetric antiphospholipid syndrome through the evaluation of non-criteria antibodies","authors":"Daniel Álvarez, Hephzibah E Winter, Carlos J Velasquez Franco, Aleida Susana Castellanos Gutierrez, Núria Baños, Udo R Markert, Ángela P Cadavid, Diana M Morales-Prieto","doi":"10.1002/cti2.70021","DOIUrl":"10.1002/cti2.70021","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Antiphospholipid syndrome (APS) is an autoimmune disease driven by antiphospholipid antibodies (aPL). Currently, APS diagnosis requires a combination of clinical manifestations (thrombosis and/or obstetric morbidity) and the persistent presence of at least one criteria aPL: anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2GPI) or lupus anticoagulant (LA). Patients with suggestive obstetric symptoms but lacking criteria aPL face diagnostic challenges. Non-criteria aPL screening may enhance discrimination. This study proposes a classification incorporating both criteria and non-criteria antibodies to improve obstetric APS diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Blood samples from non-pregnant women (<i>n</i> = 68) with a history of vascular, obstetric, or vascular and obstetric manifestations were analysed. Among them, 30 had previous diagnosis of APS. Healthy women with proven gestational success were included as controls (<i>n</i> = 16). Criteria and non-criteria (anti-phosphatidylglycerol, anti-phosphatidylethanolamine, anti-phosphatidylinositol, anti-phosphatidylserine and anti-phosphatidic acid) IgG aPL were evaluated by ELISA and coagulation tests. Based on the resulting aPL profile, patients were reclassified. Responsiveness to treatment was obtained from medical records.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Criteria aPL levels marginally differentiated women previously managed as obstetric APS from unexplained/other causes of obstetric morbidity. Including non-criteria aPL improved separation. The proposed classification identified an obstetric APS group that exhibits non-criteria aPL and aβ2GPI titres below the cut-off but higher than healthy women (7.88 vs. 2.47 SGU, <i>P</i> = 0.006). Compared to cases of other causes of obstetric morbidity, these patients retrospectively responded better to aspirin and/or heparin treatment (71.43% vs. 11.11%, <i>P</i> = 0.035).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Assessing non-criteria antibodies may identify isolated obstetric APS cases benefiting from established therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826958","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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