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的总体目标(宾夕法尼亚大学 ACE)是1)进行尖端的临床和翻译研究，以增进我们对人类的了解 通过临床和协作项目进行自身免疫，2)鼓励下一代医生- 科学家将通过科学交流和研究开展自身免疫的临床和翻译研究 由行政核心监督的指导和充实计划，以及3)提供财务和 监管指导和基础设施，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的临床和转译研究计划以B细胞为主题 作为自身免疫的驱动力“，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 (寻常型天疱疮(PV)、多发性硬化症(MS)和1型糖尿病(T1D)) 抗CD20介导的B细胞去除的随机临床试验显示了显著的临床益处。 因此，在这些情况下，B细胞是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细胞耗竭作为一种长期治疗策略的效用。每一位 拟议的临床和协作项目以及管理核心解决了一个关键问题，即 这是该领域取得进展的障碍。初级临床项目将执行1b阶段开放标签剂量升级 一种新型基因工程细胞的安全性、耐受性和潜在疗效评价研究 被称为DSG3-CAART的免疫疗法可实现靶向、抗原特异性的B细胞耗竭和持久 PV中的疾病缓解。替代临床项目将利用奥立珠单抗的前瞻性随机试验 撤除多发性硬化症以评估无B细胞耗竭的多发性硬化症患者是否可以安全地撤除B细胞 并将确定预测长期耐受诱导的潜在生物标记物。一个 合作项目将执行深入的表型分析、免疫谱系分析和靶标抗原发现 对于胰腺、次级淋巴器官和T1D患者血液中扩大的B细胞克隆，这是 不仅可以确定T1D的新治疗策略，而且还可以建立一个框架，说明 实验方法可以在很大范围内阐明B细胞的病理生理和靶点 其他自身免疫性疾病。最后，行政核心将实施科学沟通和 指导计划，促进宾夕法尼亚大学ACE内外的合作研究，并鼓励未来 一代代内科科学家致力于自身免疫性疾病的临床护理和研究。

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.