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1.
Type 2 immunity is characterized by expression of the cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13, which can function in mediating protective immunity in the host or possess a pathogenic role. T helper (Th) 2 cells have emerged to play a beneficial role in mediating anti-parasitic immunity and are also known to be key players in mediating allergic diseases. In addition to the Th2 cells, recent studies have identified T follicular helper (Tfh) cells as an alternative source of IL-4 to regulate type 2 humoral immune responses, indicating that Th2 and Tfh cells exhibit overlapping phenotypical and functional characteristics. Th2 and Tfh cells appear to utilize distinct mechanisms for regulation of IL-4 expression; however unlike Th2 cells, the regulation and function of Tfh-derived IL-4 is not yet fully understood. Understanding of the molecular mechanisms for IL-4 expression and function in both cell subsets will be beneficial for the development of future therapeutic interventions. 相似文献
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Katherine M. Littlefield Rene O. Watson Jennifer M. Schneider Charles P. Neff Eiko Yamada Min Zhang Thomas B. Campbell Michael T. Falta Sarah E. Jolley Andrew P. Fontenot Brent E. Palmer 《PLoS pathogens》2022,18(5)
As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden. 相似文献
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新型冠状病毒的全球大流行,给人类的生命健康和社会秩序带来了巨大的危害。疫苗、小分子药物及各类抗体药物的研发在遏制新型冠状病毒感染传播、降低重症率和死亡风险上发挥了积极的作用。然而,由于新冠病毒庞大的感染基数及自身易突变的特征,当前已经演化出多种能逃逸疫苗及中和抗体的变异株,显著削弱了抗体的保护效果。研发新型冠状病毒广谱甚至泛β冠状病毒广谱的中和抗体对于未来新冠变异株及其他高致病性β冠状病毒的防治具有重要意义。本文从新型冠状病毒中和抗体的筛选制备策略、作用机制、中和效果及广谱性等方面进行了系统综述,并对当前面临的挑战和未来的发展方向进行了讨论和展望,以期为后续相关研究提供参考。 相似文献
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Archana Panikkar Katie E. Lineburg Jyothy Raju Keng Yih Chew George R. Ambalathingal Sweera Rehan Srividhya Swaminathan Pauline Crooks Laetitia Le Texier Leone Beagley Shannon Best Matthew Solomon Katherine K. Matthews Sriganesh Srihari Michelle A. Neller Kirsty R. Short Rajiv Khanna Corey Smith 《PLoS pathogens》2022,18(2)
Adoptive T-cell immunotherapy has provided promising results in the treatment of viral complications in humans, particularly in the context of immunocompromised patients who have exhausted all other clinical options. The capacity to expand T cells from healthy immune individuals is providing a new approach to anti-viral immunotherapy, offering rapid off-the-shelf treatment with tailor-made human leukocyte antigen (HLA)-matched T cells. While most of this research has focused on the treatment of latent viral infections, emerging evidence that SARS-CoV-2-specific T cells play an important role in protection against COVID-19 suggests that the transfer of HLA-matched allogeneic off-the-shelf virus-specific T cells could provide a treatment option for patients with active COVID-19 or at risk of developing COVID-19. We initially screened 60 convalescent individuals and based on HLA typing and T-cell response profile, 12 individuals were selected for the development of a SARS-CoV-2-specific T-cell bank. We demonstrate that these T cells are specific for up to four SARS-CoV-2 antigens presented by a broad range of both HLA class I and class II alleles. These T cells show consistent functional and phenotypic properties, display cytotoxic potential against HLA-matched targets and can recognize HLA-matched cells infected with different SARS-CoV-2 variants. These observations demonstrate a robust approach for the production of SARS-CoV-2-specific T cells and provide the impetus for the development of a T-cell repository for clinical assessment. 相似文献
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Dan Fu Guangshun Zhang Yuhui Wang Zheng Zhang Hengrui Hu Shu Shen Jun Wu Bo Li Xin Li Yaohui Fang Jia Liu Qiao Wang Yunjiao Zhou Wei Wang Yufeng Li Zhonghua Lu Xiaoxiao Wang Cui Nie Yujie Tian Da Chen Yuan Wang Xingdong Zhou Qisheng Wang Feng Yu Chen Zhang Changjing Deng Liang Zhou Guangkuo Guan Na Shao Zhiyong Lou Fei Deng Hongkai Zhang Xinwen Chen Manli Wang Louis Liu Zihe Rao Yu Guo 《PLoS biology》2021,19(5)
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.This study characterizes novel neutralizing antibodies against the SARS-CoV-2 spike protein. Co-crystal structures of the spike protein receptor-binding domain and humanised mouse antibodies identify novel epitopes on the spike protein; binding to these epitopes competes with the ACE2 receptor, and one of the antibodies provides protection against SARS-CoV-2 infection in a mouse model of COVID-19. 相似文献
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由严重急性呼吸系统综合征冠状病毒2型(severe acute respiratory syndrome coronavirus-2,SARS-CoV-2)引起的疾病被命名为新型冠状病毒肺炎(coronavirus disease 2019,COVID-19),是一种具有强传染性、高易感性、长潜伏期的传染病。病毒刺突蛋白受体结合结构域(receptor binding domain,RBD)和细胞血管紧张素转换酶2(angiotensin-converting enzyme 2,ACE2)之间的相互作用使得SARS-CoV-2顺利进入细胞。本文对SARS-CoV-2与ACE2的相关作用机制进行了简单概述,对目前针对SARS-CoV-2中和单克隆抗体、纳米抗体的最新研究进展进行了总结,探讨了新冠肺炎的发展过程和抗体药物的研究方向,以期为包括新冠肺炎在内的新发、突发传染病中和抗体药物的研发提供参考。 相似文献
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Milne K Barnes RO Girardin A Mawer MA Nesslinger NJ Ng A Nielsen JS Sahota R Tran E Webb JR Wong MQ Wick DA Wray A McMurtrie E Köbel M Kalloger SE Gilks CB Watson PH Nelson BH 《PloS one》2008,3(10):e3409
Background
Tumor-infiltrating CD8+ T cells are correlated with prolonged progression-free and overall survival in epithelial ovarian cancer (EOC). A significant fraction of EOC patients mount autoantibody responses to various tumor antigens, however the relationship between autoantibodies and tumor-infiltrating T cells has not been investigated in EOC or any other human cancer. We hypothesized that autoantibody and T cell responses may be correlated in EOC and directed toward the same antigens.Methodology and Principal Findings
We obtained matched serum and tumor tissue from 35 patients with high-grade serous ovarian cancer. Serum samples were assessed by ELISA for autoantibodies to the common tumor antigen NY-ESO-1. Tumor tissue was examined by immunohistochemistry for expression of NY-ESO-1, various T cell markers (CD3, CD4, CD8, CD25, FoxP3, TIA-1 and Granzyme B) and other immunological markers (CD20, MHC class I and MHC class II). Lymphocytic infiltrates varied widely among tumors and included cells positive for CD3, CD8, TIA-1, CD25, FoxP3 and CD4. Twenty-six percent (9/35) of patients demonstrated serum IgG autoantibodies to NY-ESO-1, which were positively correlated with expression of NY-ESO-1 antigen by tumor cells (r = 0.57, p = 0.0004). Autoantibodies to NY-ESO-1 were associated with increased tumor-infiltrating CD8+, CD4+ and FoxP3+ cells. In an individual HLA-A2+ patient with autoantibodies to NY-ESO-1, CD8+ T cells isolated from solid tumor and ascites were reactive to NY-ESO-1 by IFN-γ ELISPOT and MHC class I pentamer staining.Conclusion and Significance
We demonstrate that tumor-specific autoantibodies and tumor-infiltrating T cells are correlated in human cancer and can be directed against the same target antigen. This implies that autoantibodies may collaborate with tumor-infiltrating T cells to influence clinical outcomes in EOC. Furthermore, serological screening methods may prove useful for identifying clinically relevant T cell antigens for immunotherapy. 相似文献11.
Antibody therapeutics and vaccines for coronavirus disease 2019(COVID-19) have been approved in many countries, with most being developed based on the original strain of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2). SARS-Co V-2has an exceptional ability to mutate under the pressure of host immunity, especially the immune-dominant spike protein of the virus, which is the target of both antibody drugs and vaccines. Given the continuous evolution of the virus and the identification ... 相似文献
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Daniel Asarnow Bei Wang Wen-Hsin Lee Yuanyu Hu Ching-Wen Huang Bryan Faust Patricia Miang Lon Ng Eve Zi Xian Ngoh Markus Bohn David Bulkley Andrés Pizzorno Beatrice Ary Hwee Ching Tan Chia Yin Lee Rabiatul Adawiyah Minhat Olivier Terrier Mun Kuen Soh Frannie Jiuyi Teo Cheng-I Wang 《Cell》2021,184(12):3192-3204.e16
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Dongyan Zhou Jasper Fuk-Woo Chan Biao Zhou Runhong Zhou Shuang Li Sisi Shan Li Liu Anna Jinxia Zhang Serena J. Chen Chris Chung-Sing Chan Haoran Xu Vincent Kwok-Man Poon Shuofeng Yuan Cun Li Kenn Ka-Heng Chik Chris Chun-Yiu Chan Jianli Cao Chun-Yin Chan Zhiwei Chen 《Cell host & microbe》2021,29(4):551-563.e5
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Juerg Richner Edward P. Ambinder Kenneth Hoffmann Eric J. Feuer George Bekesi 《Cancer immunology, immunotherapy : CII》1991,34(2):138-142
Summary Mononuclear cells from 12 normal controls (co), 10 advanced untreated (c1), and 6 advanced treated cancer patients (c2) have been isolated. The numbers of mononuclear cells bearing Leu1, Leu2, Leu3, Leu2/HLA-DR and LeuM3 were measured with a fluorescence-activated cell sorter. Only the quantity of helper T cells (Leu3) was decreased in cancer patients (co: 0.89, c1: 0.32, c2: 0.44 × 109/1). Expression of all other markers, including activated suppressor T cells (Leu2/HLA-DR), did not differ significantly from the control. The proliferation of the lymphocytes was determined in a phytohemagglutininculture assay. The cancer groups showed a significantly decreased response (co: 95.8 × 109, cl: 28.7 × 109, c2: 25.7 × 109 cpm). These values correlated with the number of helper T cells but not with the suppressor T cells. Monocytes of cancer patients adsorbed significantly more immunoglobulins than the monocytes of controls. The addition of indomethacin or isoprinosine to phytohemagglutinin-culture assay increased the proliferation of lymphocytes from both the cancer patients and normal controls.Supported by the Swiss National Science Foundation 相似文献
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Nicola Cotugno Alessandra Ruggiero Francesco Bonfante Maria Raffaella Petrara Sonia Zicari Giuseppe Rubens Pascucci Paola Zangari Maria Antonietta De Ioris Veronica Santilli E.C. Manno Donato Amodio Alessio Bortolami Matteo Pagliari Carlo Concato Giulia Linardos Andrea Campana Daniele Donà Carlo Giaquinto 《Cell reports》2021,34(11):108852
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Lynch JB Nduati R Blish CA Richardson BA Mabuka JM Jalalian-Lechak Z John-Stewart G Overbaugh J 《Journal of virology》2011,85(11):5252-5261
Although a major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is to elicit broad and potent neutralizing antibodies (NAbs), there are no data that directly demonstrate a role for such NAbs in protection from HIV-1 infection in exposed humans. The setting of mother-to-child transmission provides an opportunity to examine whether NAbs provide protection from HIV-1 infection because infants acquire passive antibodies from their mothers prior to exposure to HIV-1 through breastfeeding. We evaluated the characteristics of HIV-1-specific NAbs in 100 breast-fed infants of HIV-1-positive mothers who were HIV-1 negative at birth and monitored them until age 2. A panel of eight viruses that included variants representative of those in the study region as well as more diverse strains was used to determine the breadth of the infant NAbs. From their mothers, infants acquired broad and potent NAbs that were capable of recognizing heterologous circulating HIV-1 variants of diverse subtypes, but the presence of NAbs of broad HIV-1 specificity was not associated with transmission risk. There was also no correlation between responses to any particular virus tested, which included a range of diverse variants that demonstrated different neutralization profiles, including recognition by specific antibodies with known epitope targets. The eight viruses tested exhibited neutralization profiles to a variety of monoclonal antibodies (2F5, PG9, and VRC01) similar to those of viruses present in pregnant women in the cohort. These results suggest that the breadth and potency of the heterologous antibody response in exposed infants, measured against a virus panel comprised of variants typical of those circulating in the population, does not predict protection. 相似文献
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Markus Hoffmann Prerna Arora Rüdiger Groß Alina Seidel Bojan F. Hörnich Alexander S. Hahn Nadine Krüger Luise Graichen Heike Hofmann-Winkler Amy Kempf Martin S. Winkler Sebastian Schulz Hans-Martin Jäck Bernd Jahrsdörfer Hubert Schrezenmeier Martin Müller Alexander Kleger Jan Münch Stefan Pöhlmann 《Cell》2021,184(9):2384-2393.e12
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Nitesh Mishra Sanjeev Kumar Swarandeep Singh Tanu Bansal Nishkarsh Jain Sumedha Saluja Rajesh Kumar Sankar Bhattacharyya Jayanth Kumar Palanichamy Riyaz Ahmad Mir Subrata Sinha Kalpana Luthra 《PLoS pathogens》2021,17(9)
Cross-reactive epitopes (CREs) are similar epitopes on viruses that are recognized or neutralized by same antibodies. The S protein of SARS-CoV-2, similar to type I fusion proteins of viruses such as HIV-1 envelope (Env) and influenza hemagglutinin, is heavily glycosylated. Viral Env glycans, though host derived, are distinctly processed and thereby recognized or accommodated during antibody responses. In recent years, highly potent and/or broadly neutralizing human monoclonal antibodies (bnAbs) that are generated in chronic HIV-1 infections have been defined. These bnAbs exhibit atypical features such as extensive somatic hypermutations, long complementary determining region (CDR) lengths, tyrosine sulfation and presence of insertions/deletions, enabling them to effectively neutralize diverse HIV-1 viruses despite extensive variations within the core epitopes they recognize. As some of the HIV-1 bnAbs have evolved to recognize the dense viral glycans and cross-reactive epitopes (CREs), we assessed if these bnAbs cross-react with SARS-CoV-2. Several HIV-1 bnAbs showed cross-reactivity with SARS-CoV-2 while one HIV-1 CD4 binding site bnAb, N6, neutralized SARS-CoV-2. Furthermore, neutralizing plasma antibodies of chronically HIV-1 infected children showed cross neutralizing activity against SARS-CoV-2 pseudoviruses. Collectively, our observations suggest that human monoclonal antibodies tolerating extensive epitope variability can be leveraged to neutralize pathogens with related antigenic profile. 相似文献