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（宾夕法尼亚大学） ACE）是1）进行尖端的临床和转化研究，以促进我们对人类的理解 通过临床和合作项目的自身免疫，2）鼓励下一代医生- 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充实计划，以及3）提供财务和 监管指南和基础设施，以支持内部和之间的协作科学互动 通过ACE基金管理核心，在全国范围内的学术机构。 宾夕法尼亚大学ACE的临床和转化研究项目围绕“B细胞”这一主题展开 作为自身免疫的驱动因素”，重点关注三种使人衰弱并可能危及生命的自身免疫性疾病 （寻常天疱疮（PV）、多发性硬化症（MS）和1型糖尿病（T1 D））， 抗-CD 20介导的B细胞耗竭的随机临床试验已经证明了显著的临床益处。 因此，B细胞是这些疾病中自身免疫的关键驱动因素，但存在严重和潜在致命的风险。 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 拟议的临床和合作项目，以及行政核心，解决一个关键问题，或 这是该领域取得进展的障碍。主要临床项目将执行Ib期开放标签剂量递增 一项评估新型基因工程细胞治疗的安全性、耐受性和潜在疗效的研究 称为DSG 3-CAART的免疫疗法，以实现靶向的、抗原特异性的B细胞消耗和持久的免疫治疗。 PV疾病缓解。替代临床项目将利用ocrelizumab的前瞻性随机试验 在MS中退出，以评估B细胞耗竭是否可以在MS患者中安全退出， 并将鉴定预测长期耐受诱导的潜在生物标志物。一 合作项目将进行深入的表型分析，免疫库分析和靶抗原发现 对于T1 D患者胰腺、次级淋巴器官和血液中的扩增B细胞克隆， 不仅可以确定T1 D的新治疗策略，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点， 其他自身免疫性疾病。最后，一个行政核心将实施科学交流和 指导计划，以促进合作研究内外宾夕法尼亚大学ACE，并鼓励未来 几代医生科学家追求自身免疫性疾病临床护理和研究的职业生涯。

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.