INTRODUCTIONGranzyme B is a serine protease extensively studied for its implication in cytotoxic lymphocyte-mediated apoptosis. In recent years, the paradigm that the role of granzyme B is restricted to immune cell-mediated killing has been challenged as extracellular roles for the protease have emerged. While mostly absent from healthy tissues, granzyme B levels are elevated in several autoimmune and/or chronic inflammatory conditions. In the skin, its accumulation significantly impairs proper wound healing.AREAS COVEREDAfter an overview of the current knowledge on granzyme B, a description of newly identified functions will be presented, focussing on granzyme B ability to promote cell-cell and dermal-epidermal junction disruption, extracellular matrix degradation, vascular permeabilization, and epithelial barrier dysfunction. Progress in granzyme B inhibition, as well as the use of granzyme B inhibitors for the treatment of tissue damage, will be discussed.EXPERT OPINIONThe absence of endogenous extracellular inhibitors renders extracellular granzyme B accumulation deleterious for the proper healing of chronic wounds due to sustained proteolytic activity. Consequently, specific granzyme B inhibitors have been developed as new therapeutic approaches. Beyond applications in wound healing, other autoimmune and/or chronic inflammatory conditions related to exacerbated granzyme B activity may also benefit from the development of these inhibitors.

2022-01-01·Clinical Rheumatology3区 · 医学

The role of CD8+ Granzyme B+ T cells in the pathogenesis of Takayasu’s arteritis

3区 · 医学

Article

作者: Zhu, Junming ; Gao, Na ; Pan, Lili ; Guo, Shichao ; Qiao, Zhiyu ; Cui, Wei ; Shi, Xuemei ; Li, Taotao ; Zhao, Limin ; Du, Juan

OBJECTIVET cell-mediated immune response plays a key role in Takayasu arteritis (TAK). Although previous studies have showed the roles of CD4⁺T cell and its subsets in TAK, the change of CD8⁺ T cell subsets remains unclear. This study investigated the role of CD8⁺ T cell subsets in TAK.METHODSThe study consisted of 56 TA patients and 51 healthy controls. The percentages of CD8⁺T cells, CD8⁺GranzymeB⁺ T cells, CD8⁺Perforin⁺ T cells, and CD8⁺IFN-γ⁺ T cells in blood samples were analyzed by flow cytometry.RESULTSWe found that the percentages of CD8⁺GranzymeB⁺ T cells (P = 0.030), CD8⁺Perforin⁺ T cells (P = 0.000), and CD8⁺IFN-γ⁺ T cells (P = 0.002) in CD8⁺T cells were higher in TAK patients compared to control group. After 6 months of treatment, the proportion of CD8⁺T cells in lymphocytes were significantly lower in TAK patients than the baseline assessment (P = 0.033). A lower ratio of CD8⁺GranzymeB⁺ T cells/CD8⁺ T cells were showed in TAK patents after treatment compared with TAK patients before treatments (P = 0.011). The change of CD8⁺GranzymeB⁺ T cells/CD8⁺ T cells ratio was positively correlated with the change of ITAS (r = 0.721, P = 0.002) and ITAS-A (r = 0.637, P = 0.008). Finally, the immunofluorescence staining showed the infiltration of CD8⁺ Granzyme B ⁺ cells in the aortic tissue of TAK patients.CONCLUSIONOur results disclose that the CD8⁺ T lymphocytes may play a role in TAK pathogenesis. Targeting CD8⁺GranzymeB⁺ T lymphocytes or Granzyme B inhibitors could be a potential therapeutic approach for the treatment of TAK. Key Points • Our study investigated role the of CD8⁺ T cell subsets in TAK. • We found the percentages of CD8⁺GranzymeB⁺ T cells, CD8⁺Perforin⁺ T cells, and CD8⁺IFN-γ⁺ T cells in CD3⁺CD8⁺T cells were higher in TAK patients. • The proportion of CD8⁺T cells in lymphocytes and the ratio of CD8⁺GranzymeB⁺ T cells/CD8⁺ T cells were significantly lower in TAK patients after treatment.

2021-11-01·International Journal of Biological Macromolecules1区 · 化学

Granzyme B and perforin produced by SEC2 mutant-activated human CD4+ T cells and CD8+ T cells induce apoptosis of K562 leukemic cells by the mitochondrial apoptotic pathway

1区 · 化学

Article

作者: Zhang, Guojun ; Jiang, Fengli ; Wu, Tianyi ; Zheng, Guoliang ; Wu, Lizhao

Staphylococcal enterotoxin C2 (SEC2), a classical representative of superantigens, activates T cells that produce massive cytokines. This characteristic makes SEC2 a promising candidate drug for cancer immunotherapy. Previous study showed that ST-4, a SEC2 mutant, enhanced recognition of mouse T-cell receptor Vβ regions, and activated the increased number of T cells that produced more cytokines. However, the underlying molecular mechanism for stimulation of human peripheral blood mononuclear cells (PBMCs) and antitumor effect on human tumor cells remains unknown. Herein, we showed that ST-4 significantly activated TCR Vβ 12, 13A, 14, 15, 17, and 20 CD4⁺ and CD8⁺ T cells, which produced substantial amounts of granzyme B and perforin. These cytokines exhibited antitumor effect on K562 cells by promoting apoptosis and inducing S-phase cell cycle arrest. Conversely, the granzyme B inhibitor or perforin inhibitor significantly weakened antitumor effect of ST-4, accompanied by a decrease of cleaved proapoptotic BAX and cytochrome c, and an increase of antiapoptotic BCL2. Taken together, these data suggest that granzyme B and perforin produced by ST-4-activated CD4⁺ T cells and CD8⁺ T cells play a pivotal role in inducing K562 cell apoptosis by the mitochondrial apoptotic pathway, and support ST-4 as a potential candidate for cancer immunotherapy.

项与 MRT-201 相关的新闻（医药）

2022-10-13

·生物制药小编

对抗病毒变异，疫苗研发不可或缺细胞免疫保护效果评价

近年来，新冠疫情几乎未曾间断，接种疫苗仍是阻挡新冠病毒强有力的武器。现有新冠疫苗种类包括灭活疫苗、减毒活疫苗、重组蛋白疫苗、病毒载体疫苗以及mRNA疫苗等。目前疫苗的研发困境在于，新冠病毒不断变异，逃逸性增强后，在预防新冠感染方面，现有疫苗的保护性在不断降低，但仍能有效地预防新冠引起的重症和病亡。疫苗是如何保护我们的呢？疫苗的原理是在病毒感染人体之前，就训练免疫系统认识这种病毒，从而具有预防感染的能力。适应性免疫反应包括体液免疫和细胞免疫，分别由B细胞（产生抗体）和T细胞介导。有效的疫苗不仅能够激发强烈的体液免疫，也能激发有效的细胞免疫，尤其是一些新型疫苗，通过激发细胞免疫应答，发挥更持久的保护效果。年初一篇《Cell》文章对比了几款不同类型新冠疫苗，包括RNA疫苗、腺病毒疫苗、重组蛋白疫苗是否交叉识别突变株后发现，接种疫苗后6个月的受试者中，84%的CD4+T细胞和85%的CD8+T细胞对omicron的应答被保留，而omicron RBD记忆B细胞识别率大幅降低至42%；这说明大多数T细胞反应的保留可能针对不同突变株的预防发挥了重要作用[1]。5月同一团队发表的另一篇《Cell》文章，系统性评价了mRNA-1273、BNT162b2、NVX-CoV2373和Ad26.COV2.S四种疫苗接种人群0-6个月体内中和抗体水平，CD4+T细胞，CD8+T细胞和记忆性B细胞的免疫应答，阐明了四种疫苗诱导细胞免疫和体液免疫之间的关联[2]。研究提示细胞免疫和体液免疫在机体对抗新冠病毒时同样重要。无论接受哪种疫苗，大多数人对SARS-CoV-2保持了一些免疫反应。这种免疫记忆可能无法预防感染，但它似乎有助于抵抗严重的疾病。评价疫苗T细胞免疫效果的新方法为了检测疫苗的细胞免疫保护效果，不论经典的EliSpot技术，还是流式细胞分析，往往一次只能检测T细胞分泌的1-2种或3-5种细胞因子，且手动操作流程繁琐，获得的数据指标少，无法进行更广泛、更深入的研究。利用领先的IsoPlexis单细胞分泌蛋白组技术，通过IsoCode单细胞芯片捕获、孵育单细胞，结合微流控技术+抗体条形码技术+自动液体处理和多重荧光蛋白检测+自动生信分析，实现对分泌不同细胞因子的T细胞亚群（Th1、Th2、Th17、调节性T细胞、细胞毒性T细胞等）在单细胞水平进行更全面的综合性分析，一次分析多达32种细胞因子/活细胞。IsoCode human单细胞分泌蛋白组检测panel其一通过独特的“细胞多功能指数（PSI）”更全面地分析抗原特异性T细胞的综合功能，找到在免疫应答反应中发挥超强作战能力的“超级英雄细胞”——多功能T细胞，指能同时分泌两种及以上细胞因子的细胞，它们往往比单功能细胞（只分泌一种细胞因子）介导更强烈的免疫反应，从而与疫苗的保护效果密切相关。举个例子，近日西北大学范伯格医学院发布其研究数据“Analysis of SARS-CoV-2-Specific T-Cell Responses Using Novel Single-Cell Multiplexed IsoLight in COVID-19 Convalescents”，利用IsoPlexis单细胞分泌蛋白组技术分析新冠恢复病人SARS-CoV-2特异性T细胞免疫反应，并希望进一步揭示缺乏抗体反应的器官移植者患新冠后的特异性细胞免疫应答[3]。IsoPlexis人PBMC单细胞分泌蛋白组检测流程研究发现，SARS-CoV-2 抗原刺激组与阳选对照（CD3/28刺激）和阴性对照（不刺激）相比，新冠恢复者的多功能T细胞亚群的比例上调，CD8+T和CD4+T细胞的PSI（细胞多功能指数）增高。CD8+T细胞分泌因子差异主要由效应因子（GranzymeB, IFN-γ, TNF-α, MIP-1a, perforin)和趋化因子(MIP-1b)驱动；CD4+T细胞分泌因子差异主要由效应因子(IFN-γ, GranzymeB, TNF-α)和刺激因子(GM-CSF, IL2)驱动。恢复期患者CD8+T和CD4+T细胞PSI分析图单细胞的细胞因子分泌谱多功能热图单细胞分泌因子谱PAT-PCA 主成分分析图IsoPlexis全自动单细胞功能蛋白组学检测，与EliSpot 或流式胞内染色分析相比，可更全面、更深入地研究疫苗接种对新冠感染提供有效保护的T细胞免疫特征，为发现疫苗有效保护作用的生物标志物提供数据基础，从而指导下一代疫苗研发，以应对不断出现的病毒变异。实验室参观预约火热报名中报名方法请戳以下链接：实验室参观预约正式开放啦，快来get预约方法！IsoPlexis公司总部位于美国的康涅狄格州，是一家专注于单细胞功能蛋白质组分析解决方案的领先供应商。作为单细胞多组学不可或缺的重要组成部分，IsoPlexis单细胞技术已被国内外用户广泛认可，包括全球顶尖高校科研机构、全球Top 20的制药企业、70%美国综合性癌症中心等，用于疾病发病和耐药性机制研究、药物前期开发、生物工艺优化、预测及评估病人临床疗效和免疫相关不良反应的新型生物标志物，在肿瘤免疫、细胞治疗、肿瘤学、抗感染免疫研究及疫苗开发、自身免疫病、移植免疫等方向取得了众多突破性成果，发表在Cell、Nature Medicine、Immunity、Journal of Clinical Oncology、Cancer Cell等全球知名的高影响力期刊上。参考来源：1.Tarke A, Coelho CH, Zhang Z, Dan JM, Yu ED, Methot N, Bloom NI, Goodwin B, Phillips E, Mallal S, Sidney J, Filaci G, Weiskopf D, da Silva Antunes R, Crotty S, Grifoni A, Sette A. SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron. Cell. 2022 Mar 3;185(5):847-859.e11. doi: 10.1016/j.cell.2022.01.015. Epub 2022 Jan 24. PMID: 35139340; PMCID: PMC8784649.2.Zhang Z, Mateus J, Coelho CH, Dan JM, Moderbacher CR, Gálvez RI, Cortes FH, Grifoni A, Tarke A, Chang J, Escarrega EA, Kim C, Goodwin B, Bloom NI, Frazier A, Weiskopf D, Sette A, Crotty S. Humoral and cellular immune memory to four COVID-19 vaccines. Cell. 2022 Jul 7;185(14):2434-2451.e17. doi: 10.1016/j.cell.2022.05.022. Epub 2022 May 27. PMID: 35764089; PMCID: PMC9135677.3.Analysis of SARS-CoV-2-Specific T-Cell Responses Using Novel Single Cell Multiplexed IsoLight in COVID-19 Convalescents

疫苗信使RNA抗体细胞疗法

100 项与 MRT-201 相关的药物交易

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