High Dimensional Mass Cytometry Analysis of the Effects of Vedolizumab in Intestinal Cellular Subsets and its Correlation with Clinical Parameters

高维质量流式细胞仪分析维多珠单抗对肠细胞亚群的影响及其与临床参数的相关性

• 批准号: 9910384
• 负责人: Jesus Rivera-Nieves
• 金额: $ 17.81万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-08 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910384
• 关键词: Address; Affect; Algorithms; Antibodies; Biopsy; Blood Cells; CD3 Antigens; Cell Separation; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Cluster Analysis; Colonoscopy; Complex; Crohn' s disease; Cytometry; Data Analyses; Data Set; Development; Disease; Disease remission; Drug Targeting; Endothelium; Failure; Flow Cytometry; Genetic Transcription; Goals; Histologic; Homing; Human; Immune; Immunophenotyping; Industry; Inflammatory Bowel Diseases; Infrastructure; Integrin alpha Chains; Integrins; Intestinal Mucosa; Intestines; Isotopes; Label; Lamina Propria; Lead; Leukocytes; Ligands; Light; Logistics; Lymphocyte; Manuscripts; Mass Spectrum Analysis; Membrane; Metals; Methodology; Molecular; Mononuclear; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Population; Resolution; Sampling; Stains; Surface; Surrogate Markers; Suspensions; TNF gene; Techniques; Technology; Testing; Time; antibody conjugate; automated analysis; biobank; clinical practice; computerized tools; cytokine; data acquisition; drug efficacy; effective therapy; falls; healing; high dimensionality; infliximab; insight; mucosal addressin cell adhesion molecule-1; natalizumab; new therapeutic target; novel; peripheral blood; prospective; recruit; reduce symptoms; response; sample collection; success; targeted treatment; tool; transcription factor

Project Summary Our understanding of the specific cell subsets that are being depleted by vedolizumab and other effective agents within the intestine remains superficial. This is in part due to technical limitations which had hampered the unbiased interrogation of cellular and molecular composition of the human intestinal lamina propria. Recently, these technological challenges have been overcome by the development of mass cytometry, which enables the simultaneous quantification of up to 40 surface and/or intracellular markers on cell subsets. We have recently adapted existing mass cytometry methodology previously employed mainly for peripheral blood cell analyses, to allow for the interrogation of intestinal lamina propria cells. We have developed, tested and optimized a panel of 37 immune cell markers that allow us to simultaneously identify all major immune cell populations, as well as numerous sub-populations, intracellular cytokines and transcription factors. Here we will prospectively assess the effects of vedolizumab on the cellular composition of intestine by performing deep immunophenotyping of immune cell subsets, prior to and after the drug’s administration. We will then determine whether changes on cell subsets correlate with clinical, endoscopic or histologic parameters of disease activity. These studies will test the validity of mass cytometry outcomes as surrogate markers for the efficacy of drugs that target lymphocyte traffic (vedolizumab, etrolizumab, anti- MAdCAM-1, ozanimod) and may directly shed light on the specific mechanism of action of these traffic-targeted therapies.

项目摘要 我们对Vedolizumab和其他有效治疗药物消耗的特定细胞亚群的了解， 肠内的药剂保持浅表。这部分是由于技术限制， 对人体肠固有层的细胞和分子组成进行无偏见的调查。 最近，这些技术挑战已经被质谱细胞术的发展所克服， 能够同时定量细胞亚群上多达40种表面和/或细胞内标记物。我们 我最近采用了以前主要用于外周血的现有质量细胞计数方法 细胞分析，以允许询问肠固有层细胞。我们已经开发、测试和 优化了一组37个免疫细胞标记，使我们能够同时识别所有主要的免疫细胞， 群体以及许多亚群、细胞内细胞因子和转录因子。这里我们 将前瞻性评估Vedolizumab对肠道细胞组成的影响， 免疫细胞亚群的免疫表型，之前和之后的药物的管理。然后我们将 确定细胞亚群的变化是否与临床、内镜或组织学参数相关， 疾病活动。这些研究将测试质谱细胞计数结果作为替代标记物的有效性。 靶向淋巴细胞转运的药物（Vedolizumab、etrolizumab、抗MAdCAM-1、ozanimod）和 可以直接阐明这些交通靶向疗法的具体作用机制。