PELI1

该研究揭示了3次增强剂疫苗的独特特点，即在Omicron感染时通过“训练天然免疫”诱导单核细胞的活化和分化，从而提供保护性免疫。 截至2023年9月21日，全球新冠病毒SARS-CoV-2大流行已导致200多个国家和地区超过7.7亿例确诊病例及超过695万死亡病例，严重威胁了人类健康和公共卫生安全， 小范围的流行伴随新冠病毒进化和变异仍在不断发生。 一般认为，疫苗接种通过预先为宿主建立特异性抗病毒免疫记忆，从而起到预防病毒感染和病毒传播的作用。然而，新冠病毒（SARS-CoV-2） mRNA疫苗或/和灭活疫苗的免疫保护作用和免疫学机制尚未不明确。以往的研究关注新冠病毒mRNA疫苗或灭活病毒疫苗引发的针对Omicron变异株的特异性体液免疫和细胞免疫记忆的建立，灭活疫苗接种发挥的抗病毒作用是否涉及诱导“天然免疫记忆”，迄今为止尚不明确。 上海交通大学瑞金医院瞿介明教授、诸江教授、李庆云教授和陈赛娟院士合作，在 Cell 期刊发表了题为：Systemic immune profiling of Omicron-infected subjects inoculated with different doses of inactivated virus vaccine 的研究论文。 该研究以2022年春季上海Omicron变异株爆发为研究对象，建立了由接种了不同灭活病毒疫苗次数的感染者和未感染者组成的研究队列，通过整合质谱流式技术（CyTOF）、转录组测序（RNA-seq）和血浆微量蛋白的Olink检测技术和整合分析，揭示接种3次增强剂疫苗通过促进HLA-DRhigh经典单核细胞和非经典单核细胞的活化、Th1-like记忆效应性T细胞的极化，并抑制病理性调节性T细胞（Treg）的扩增等机制发挥免疫保护作用。相关性分析等研究提示：接种3次增强剂疫苗诱导了“训练天然免疫”，它会在Omicron感染时促进单核细胞的活化和成熟，而不是分化为髓源性抑制细胞（MDSCs）， 是一触发系例保护性免疫效应的核心事件。 该项研究首次系统性地描述了新冠病毒灭活疫苗接种对奥密克戎感染者免疫反应的影响，揭示了3次增强剂灭活疫苗通过诱导 “训练天然免疫”促进单核细胞的活化和成熟，从而发挥强有力抗病毒作用的分子机制。 通过CyTOF技术深入分析41个免疫细胞表面分子标志物的表达谱，鉴定了包括NK细胞、CD3+ T细胞、B细胞、树突状细胞、单核细胞和中性粒前体细胞在内共45个细胞亚群。在CD4+ T细胞亚群中，研究人员发现感染后3群naïve CD4+ T细胞的比例增加，而与未接种或接种2剂疫苗感染组相比，接种3剂疫苗感染组naïve CD4+ T细胞比例显著降低，提示3次增强剂疫苗可以促进CD4+ T细胞的活化。同时，Omicron感染后Treg细胞的比例及其TIM-3的表达增加，这一增加的趋势被3次增强剂疫苗接种所逆转。此外，感染后CD161hi效应记忆CD4+ T细胞和CD27int效应记忆CD4+ T细胞的比例下降，而接种3剂疫苗感染组与未接种或接种2剂疫苗感染组相比这两群细胞的比例上升。 这些结果表明，3次增强剂疫苗接种可以通过激活naïve CD4+ T细胞产生效应记忆CD4+ T细胞，而Omicron感染引起的Treg比例增加可能对此起到一定的限制作用。有趣的是，研究人员还通过实验证实3次增强剂疫苗接种在Omicron感染后促进CD4+ T细胞向功能性Th1方向极化，这已被证明对防止症状发生具有保护作用。在NK细胞亚群中，CD56hiCD16lo细胞因子分泌型NK亚群的比例在接种3剂疫苗感染组降低，而CD56intCD16hi细胞毒性NK亚群的比例在接种3剂疫苗感染组增加，提示3次增强剂疫苗可能会在Omicron感染后促进NK细胞成熟。 病毒感染的1-4天是一个主要由多种类型的天然免疫细胞的激活和功能主导的时期。在单核细胞方面，发现与健康对照组相比，Omicron感染者HLA-DRint经典单核细胞、HLA-DRhi经典单核细胞和非经典单核细胞的比例呈降低趋势。而与未接种组或接种2剂疫苗感染组相比，接种3剂疫苗感染组中HLA-DRhi经典单核细胞和非经典单核细胞的比例升高。同样地，Omicron感染后pDC细胞的比例降低同时及其PD-1和CTLA-4的表达增加，这一趋势被3次增强剂疫苗接种所部分逆转。由此可见，3次增强剂疫苗接种可以促进单核细胞/树突状细胞的活化和分化。 通过RNA-seq技术，进一步鉴定了一系列与免疫保护/免疫抑制密切相关的基因和信号通路。具体而言，单核/树突状细胞的功能激活而不是MDSC极化、Treg功能稳定性、记忆T细胞活化、Th1细胞分化、病毒复制抑制、低氧通路、TNF和NF-κB通路的活化，与接种3剂疫苗感染组正相关；而免疫缺陷、Th2细胞分化和线粒体代谢，与未接种组或接种2剂疫苗感染组相正相关。此外，与未接种组或接种2剂疫苗感染组相比，接种3剂疫苗感染组单核/巨噬细胞活或分化相关基因OSM、NAB2、THBS1、PLAUR、RAB20、ACSL1和TREM1，pDC激活基因SLC7A5和ICAM1，Treg功能稳定性基因DUSP5、SDC4、DUSP4、JAG1和PELI1，低氧通路基因JMJD6、VEGFA、HIF1A和NFIL3表达上调。相比之下，Treg增殖相关基因MCM3、CDC20和ZWINT，免疫抑制基因如T细胞免疫检查点受体BTLA以及NK细胞免疫检查点PVRIG和CISH，线粒体代谢基因LACTB2、ACADM、MRPS31和PYCR2在接种3剂疫苗感染组表达下调。这些结果表明，3次增强剂疫苗可能通过促进单核细胞/树突状细胞的活化和成熟，同时抑制致病性Treg的增殖，帮助宿主对抗Omicron感染。 BCG疫苗训练的天然免疫曾被提出作为增强对SARS-CoV-2感染的保护性免疫的可能手段。然而，灭活疫苗是否会诱导某些训练免疫通路，并在Omicron感染时再次发挥作用，这个问题尚未明确。研究人员分析了健康对照组和感染组中疫苗接种诱导的差异表达基因，发现在健康对照组中，大约1/5的疫苗接种诱导的基因在Omicron感染时也以相同的方向发生了差异表达，具有高度显著的相关性。为了筛选这33个同时上调和下调基因的核心基因，研究人员构建了这些基因的PPI网络，并揭示了排名前15的核心节点基因，其中包括调节单核细胞激活的基因如TREM1、C5AR1和FOSL1，其中TREM1已被证明是通过促进单核细胞活化从而发挥抗微生物感染的关键基因。有趣的是，这些同时上调和下调基因中的大多数（19/33），在外周血PBMC的26种免疫细胞类型中单核细胞中的表达最高。这些结果表明，在健康受试者接种疫苗后，通过预先训练，在Omicron感染后的某些关键单核细胞活化的驱动通路（如TREM1上调）可能会得到再次加强。 此外通过Olink技术系统检测了外周血血浆蛋白的变化，发现与与未接种组或接种2剂疫苗感染组相比，接种3剂疫苗感染组中细胞因子EN-RAGE、OSM和TGF-α水平上升，而CX3CL1水平显著下降。根据其他文献报道，EN-RAGE、OSM和TGF-α是促进单核细胞活化的关键细胞因子，而CX3CL1是促进免疫抑制性M2型巨噬细胞极化的趋化因子。此外，TNFSF14在接种3剂疫苗感染组中显著下降，而TNFSF14作为一种免疫共刺激分子，已被证明在抑制Treg积累和增殖方面发挥关键作用。 最后，研究团队对14个免疫细胞亚群（包括HLA-DRhi-经典单核细胞、非经典单核细胞、pDC、Treg、3群效应记忆CD4+ T细胞、3群naïve CD4+ T细胞、2群naïve-like T细胞、2群NK细胞）、13个基因（包含单核细胞激活和分化相关基因TREM1、ACSL1、CXCL16、PFKFB3、PLAUR、C15orf48、THBS1和NR4A3；Treg功能稳定性相关基因JAG1和LMNA；Treg扩增相关基因CDC20、ZWINT和MCM3）、3个基因集（2个与单核细胞活化相关和1个与Treg功能稳定性相关）、3种血浆蛋白（单核细胞活化相关蛋白OSM和EN-RAGE，Treg增殖相关蛋白TNFSF14）和9个临床参数（白细胞计数、中性粒细胞计数、抗RBD-总抗、抗RBD-IgG抗体、抗RBD-IgM抗体、抗WT或Omicron BA.2.2的中和抗体滴度、Ct值和尿素）进行Spearman聚类分析，所有这些因素在接种3剂疫苗感染组与未接种组或接种2剂疫苗感染组之间存在差异表达。根据它们之间的互相关系数，对这些组合因素（n=42）进行无监督聚类，形成了两个高度负相关的模块：其中较大的一个模块由三个子模块组成，富集了天然免疫激活、T细胞或NK细胞激活和体液免疫；较小的一个模块富集了Treg增殖。具体而言，在天然免疫激活子模块中，OSM、TNFSF14、白细胞和中性粒细胞计数、EN-RAGE、HLA-DRhi-经典单核细胞、非经典单核细胞和pDC之间的相关性更强，而与单核细胞活化和分化以及Treg功能稳定性有关的基因和通路之间的相关性更强。 总的来说，该研究揭示了3次增强剂疫苗的独特特点，即在Omicron感染时通过“训练天然免疫”诱导单核细胞的活化和分化，从而提供保护性免疫。 上海交通大学瑞金医院呼吸与危重症医学科瞿介明教授、瑞金医院上海血液学研究所诸江教授、呼吸与危重症医学科李庆云教授、转化医学国家重大科技基础设施（上海）陈赛娟院士为论文共同通讯作者。转化医学国家重大科技基础设施（上海）副研究员余山河，呼吸与危重症医学科主治医师林莹妮、副主任医师李勇；上海血液研究所博士研究生陈仕俊，呼吸与危重症医学科主治医师周丽娜、技师宋鹤杰为论文的共同第一作者。

Bridge to join as an industry member to advance the science of early detection and speed development of novel treatments SEONGNAM, South Korea and CAMBRIDGE, Mass., July 11, 2023 /PRNewswire/ -- Bridge Biotherapeutics (KQ288330), a South Korean clinical-stage biotech company developing novel drugs for fibrosis, cancer and inflammation, announced that it has joined PROLIFIC, the Prognostic Lung Fibrosis Consortium, an organization devoted to boosting scientific exploration and drug development in pulmonary fibrosis. PROLIFIC is a non-profit consortium of top-tier research institutions, academic medical centers, and pharmaceutical and biotech companies that are committed to developing treatments for pulmonary fibrosis. Members of PROLIFIC collaborate with each other to share expertise, technology, and data to develop precise and personalized treatments for patients with the fatal and progressive lung diseases. The near-term goal of PROLIFIC is to develop and validate tests for biomarkers indicative of pulmonary fibrosis in patients and to assess the biomarkers in predicting disease worsening or as suitable endpoints for clinical trials. "We are excited to join PROLIFIC and collaborate with other leaders in precision medicine to advance the understanding of pulmonary fibrosis and advance the science of biomarkers to detect this devastating disease," said Sujin Jung, Vice President of Clinical Development and Operations of Bridge Biotherapeutics. "As a member of PROLIFIC, we will be able to tap into a diverse range of expertise, technology, and data that will enable us to accelerate detection of pulmonary fibrosis, and speed the entire industry's development of new treatments." The group of industry members at PROLIFIC has selected 12 biomarkers based on peer-reviewed scientific reports showing their ability to predict the presence of the disease itself, and their potential ability to predict how well a drug candidate may work. The 12 biomarkers being studied include indicators of epithelial damage (CYFRA 21-1, SP-D, CA-19-9, KL-6), fibrosis (MMP-7, Tenascin C, periostin), inflammation (CCL18, CXCL13, slCAM1), and thrombosis (PAI-1). Having a validated panel of biomarkers could enable early detection of treatment response and comparison of drugs across clinical trials, which could speed regulatory approval. PROLIFIC also intends to partner with public health authorities worldwide to achieve the long-term goal of finding biomarkers that can predict which patients would benefit most from a particular treatment, bringing a precision medicine approach to the treatment of this chronic, often fatal condition. The consortium hopes to enable physicians to better tailor therapeutic treatments for patients. By joining PROLIFIC, Bridge Biotherapeutics will be able to collaborate with other pioneering companies in the area of pulmonary fibrosis. In addition to industry-wide advances, Bridge Biotherapeutics hopes to speed development of proprietary idiopathic pulmonary fibrosis pipeline and accelerate development of novel treatments for patients. Bridge Biotherapeutics is a clinical-stage biopharmaceutical company focused on developing innovative therapeutics for areas of high unmet medical needs. The company has three drugs in clinical trials for the treatment of fibrotic diseases such as idiopathic pulmonary fibrosis, as well as inflammatory diseases and cancers, and a robust pipeline of drug candidates in preclinical development. About PROLIFIC PROLIFIC, founded in 2020 by the Pulmonary Fibrosis Foundation and Bristol Myers Squibb, is a consortium of top-tier research institutions, academic medical centers, and biopharmaceutical companies that are committed to advancing precision medicine. The consortium aims to develop well-qualified assays to detect important peripheral blood protein biomarkers in patients with pulmonary fibrosis. Members of PROLIFIC collaborate to share expertise, technology, and data to develop more precise and personalized treatments for patients with devastating and progressive lung diseases. Industry members of PROLIFIC include BMS, Chiesi, Galapagos, Galecto, Genentech, Gilead, Lassen Therapeutics, Lung Therapeutics, NeRRe Therapeutics, Novartis, OptiKira, Pliant Therapeutics, Pulmonary Fibrosis Foundation, Three Lakes Foundation, Tvardi Therapeutics. About Bridge Biotherapeutics, Inc. Bridge Biotherapeutics Inc., based in the Republic of Korea and the U.S., is a publicly-traded, clinical-stage biotech company founded in 2015. Bridge Biotherapeutics is engaged in the discovery and development of novel therapeutics, focusing on therapeutic areas with high unmet needs, including ulcerative colitis, fibrotic diseases, and cancers. The company is developing BBT-401, a first-in-class Pellino-1 inhibitor for the treatment of ulcerative colitis, BBT-877, a novel autotaxin inhibitor for the treatment of fibrotic diseases including idiopathic pulmonary fibrosis (IPF), BBT-176 and BBT-207, potent targeted cancer therapies for non-small cell lung cancer (NSCLC) with EGFR C797S mutations. Learn more at . SOURCE Bridge Biotherapeutics, Inc.

SEONGNAM, South Korea and CAMBRIDGE, Mass., May 29, 2023 /PRNewswire/ -- Bridge Biotherapeutics Inc. (KQ288330), a South Korean clinical-stage biotechnology company focused on developing novel drugs for cancer, fibrosis and inflammation, is scheduled to give a company presentation on Tuesday, June 6 at the 2023 BIO International Convention taking place in Boston, Massachusetts, between June 5 - 8, 2023. Pavel Printsev, Director of Business Development, will provide an up-to-date company overview as well as an introduction to its clinical-stage assets: Oncology: BBT-176 and BBT-207 (Fourth-generation EGFR TKIs for non-small cell lung cancer active against C797S resistance mutations) Pulmonology: BBT-877 (Autotaxin inhibitor for idiopathic pulmonary fibrosis) Earlier this year, the company announced its acquisition of a diagnostics company with a novel biosensing technology. The company presentation is expected to include an introduction to the newly acquired biosensing technology and commercial prospects. "We are pleased to share the progress of clinical assets as well as new business activities through an in-person presentation at this year's BIO International conference, following last year's event. We look forward to advancing our novel research and development pipeline with a strong focus on oncology and pulmonology," stated Pavel Printsev, Director of Business Development of Bridge Biotherapeutics. To learn more about this session, please visit the events page on our website at . Date & Time: Tuesday, June 6th, 2023, 3:15 PM (ET) Place: Room 104B Therapeutic category: Multiple Therapeutics About Bridge Biotherapeutics Bridge Biotherapeutics Inc., based in the Republic of Korea and the U.S., is a publicly-traded, clinical-stage biotech company founded in 2015. Bridge Biotherapeutics is engaged in the discovery and development of novel therapeutics, focusing on therapeutic areas with high unmet needs, including ulcerative colitis, fibrotic diseases, and cancers. The company is developing BBT-401, a first-in-class Pellino-1 inhibitor for the treatment of ulcerative colitis, BBT-877, a novel autotaxin inhibitor for the treatment of fibrotic diseases including idiopathic pulmonary fibrosis (IPF), BBT-176 and BBT-207, potent targeted cancer therapies for non-small cell lung cancer (NSCLC) with EGFR C797S mutations. Learn more at . SOURCE Bridge Biotherapeutics, Inc.