University of Pennsylvania Clinical Autoimmunity Center of Excellence

宾夕法尼亚大学临床自身免疫卓越中心

基本信息

批准号：
10614494
负责人：
AMIT BAR-OR
金额：
$ 7.89万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10614494
关键词：
Address Antigen Targeting Antigens Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocyte Subsets B-Lymphocytes Biological Markers Blood Cellular immunotherapy Chronic Clinical Clinical Research Clinical Trials Clone Cells Communication Communication Programs Development Disease Disease remission Dose Education Engineered Gene Epigenetic Process Fellowship Fostering Functional disorder Funding Future Future Generations Goals Grant Review Human Immune Immune Tolerance Individual Infection Inflammatory Infrastructure Institution Insulin-Dependent Diabetes Mellitus Islet Cell Knowledge Life Maintenance Mediating Mentors MicroRNAs Mucous Membrane Multiple Sclerosis Myelogenous Pancreas Pancreatic Injury Patients Pemphigus Vulgaris Pennsylvania Peripheral Phase Phenotype Physicians Placebos Population Randomized Research Risk Safety Scientist T-Lymphocyte T-Lymphocyte Subsets Time Tissue imaging Tissues Translational Research Travel Treatment Protocols Universities Withdrawal Work anti-CD20 brain magnetic resonance imaging career career development clinical care commensal microbes effective therapy first-in-human innovation insight multiple sclerosis patient next generation novel novel therapeutic intervention open label patient subsets potential biomarker predictive marker programs prospective randomized trial randomized, clinical trials secondary lymphoid organ standard of care synergism transcriptome transcriptome sequencing transcriptomics translational research program translational study treatment effect treatment strategy

项目摘要

The overall goals of the University of Pennsylvania Clinical Autoimmunity Center of Excellence (Penn ACE) are 1) to perform cutting-edge clinical and translational research to advance our understanding of human autoimmunity through Clinical and Collaborative Projects, 2) to encourage the next generation of physician- scientists to pursue clinical and translational research in autoimmunity through Scientific Communications and Mentoring and Enrichment Programs overseen by an Administrative Core, and 3) to provide the financial and regulatory guidance and infrastructure to support collaborative scientific interactions within and between academic institutions nationwide through an ACE Funds Management Core. The clinical and translational research program of the Penn ACE centers around the theme of “B cells as drivers of autoimmunity”, focusing on three debilitating and potentially life-threatening autoimmune diseases (pemphigus vulgaris (PV), multiple sclerosis (MS), and type 1 diabetes (T1D)) for which prospective randomized clinical trials of anti-CD20-mediated B cell depletion have demonstrated significant clinical benefit. Thus, B cells are key drivers of autoimmunity in these conditions, but risk of serious and potentially fatal infections compromises the utility of chronic B cell depletion as a long-term treatment strategy. Each of the proposed Clinical and Collaborative Projects, as well as the Administrative Core, addresses a key question or barrier to progress in the field. The Primary Clinical Project will execute a phase 1b open-label dose escalation study to evaluate the safety, tolerability, and potential efficacy of a novel gene-engineered cellular immunotherapy known as DSG3-CAART to achieve targeted, antigen-specific B cell depletion and lasting disease remission in PV. The Alternate Clinical Project will utilize a prospective randomized trial of ocrelizumab withdrawal in MS to evaluate whether B cell depletion can be safely withdrawn in MS patients without compromising efficacy and will identify potential biomarkers that predict long-term tolerance induction. A Collaborative Project will perform deep phenotyping, immune repertoire analysis, and target antigen discovery for expanded B cell clones in the pancreas, secondary lymphoid organs, and blood of patients with T1D, which may not only identify novel therapeutic strategies for T1D, but also establish a framework for how similar experimental approaches can be used to elucidate the pathophysiology and targets of B cells in a broad range of other autoimmune diseases. Finally, an Administrative Core will implement a scientific communications and mentoring program to foster collaborative research within and beyond the Penn ACE and encourage future generations of physician-scientists to pursue careers in autoimmune disease clinical care and research.

宾夕法尼亚大学临床自身免疫卓越中心（PENN）的总体目标 ACE）是1）进行尖端的临床和翻译研究以促进我们对人类的理解通过临床和协作项目自身免疫，2）鼓励下一代的身体科学家通过科学通信进行自身免疫的临床和转化研究，由行政核心监督的指导和丰富计划，以及3）提供财务和监管指导和基础设施，以支持内部和之间的协作科学互动在全国范围内通过ACE资金管理核心的学术机构。宾夕法尼亚ACE的临床和翻译研究计划以“ B细胞为主题”为中心作为自身免疫性的驱动因素”，专注于三种使人衰弱和潜在威胁生命的自身免疫性疾病（Pemphigus dulgaris（PV），多发性硬化症（MS）和1型糖尿病（T1D））抗CD20介导的B细胞部署的随机临床试验已显示出显着的临床益处。在这些条件下，B细胞是自身免疫的关键驱动因素，但风险严重且可能致命感染损害了慢性B细胞耗竭作为长期治疗策略的效用。每个拟议的临床和协作项目以及行政核心都解决了一个关键问题或野外进步的障碍。主要临床项目将执行1B期开放标签剂量升级研究新型基因工程细胞的安全性，耐受性和潜在有效性免疫疗法称为DSG3-CAART，以实现靶向的，抗原特异性的B细胞部署和持久 PV中的疾病缓解。替代临床项目将利用Ocrelizumab的前瞻性随机试验在MS中提取以评估MS患者是否可以安全撤回B细胞部署损害效率，并将确定预测长期耐受诱导的潜在生物标志物。一个协作项目将进行深度表型，免疫术分析和靶向抗原发现对于胰腺中扩展的B细胞克隆，继发性淋巴器官和T1D患者的血液可能不仅可以识别T1D的新型治疗策略，还可以建立一个框架实验方法可用于阐明B细胞的病理生理学和靶标其他自身免疫性疾病。最后，行政核心将实施科学沟通，并指导计划以促进宾夕法尼亚州内外的协作研究，并鼓励未来几代人的身体科学家致力于自身免疫性疾病临床护理和研究。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Accumulation of meningeal lymphocytes correlates with white matter lesion activity in progressive multiple sclerosis.

DOI：
10.1172/jci.insight.151683
发表时间：
2022-03-08
期刊：
JCI insight
影响因子：
8
作者：
Ahmed SM;Fransen NL;Touil H;Michailidou I;Huitinga I;Gommerman JL;Bar-Or A;Ramaglia V
通讯作者：
Ramaglia V

Adaptive Immune Receptor Repertoire (AIRR) Community Guide to Repertoire Analysis.

DOI：
10.1007/978-1-0716-2115-8_17
发表时间：
2022-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Marquez, Susanna;Babrak, Lmar;Stervbo, Ulrik
通讯作者：
Stervbo, Ulrik

Temporal Outcomes after Rituximab Therapy for Pemphigus Vulgaris.

利妥昔单抗治疗寻常型天疱疮后的时间结果。

DOI：
10.1016/j.jid.2021.09.013
发表时间：
2022-04
期刊：
The Journal of investigative dermatology
影响因子：
0
作者：
Tovanabutra N;Bax CE;Feng R;Kushner CJ;Payne AS
通讯作者：
Payne AS

Multiplexed detection and isolation of viable low-frequency cytokine-secreting human B cells using cytokine secretion assay and flow cytometry (CSA-Flow).

使用细胞因子分泌测定和流式细胞术 (CSA-Flow) 多重检测和分离活的低频细胞因子分泌人 B 细胞。

DOI：
10.1038/s41598-020-71750-z
发表时间：
2020
期刊：
Scientific reports
影响因子：
4.6
作者：
Rezk,Ayman;Li,Rui;Bar-Or,Amit
通讯作者：
Bar-Or,Amit

BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.

DOI：
10.1007/s00401-022-02411-w
发表时间：
2022-04
期刊：
Acta neuropathologica
影响因子：
12.7
作者：
Li R;Tang H;Burns JC;Hopkins BT;Le Coz C;Zhang B;de Barcelos IP;Romberg N;Goldstein AC;Banwell BL;Luning Prak ET;Mingueneau M;Bar-Or A
通讯作者：
Bar-Or A