Engineering CAR-T for treatment of alcoholic liver disease

总结 利用工程嵌合抗体重定向T细胞攻击用户指定靶细胞的研究进展 抗原受体（CAR-T）的研究已经导致了强大的基于细胞的治疗剂的开发。 细胞免疫疗法与传统的小分子免疫疗法相比具有几个重要的优势 或基于抗体的疗法，包括通过整合 多个信号，提供定制的治疗有效载荷，并通过 工程控制。 在这里，我们建议调整和利用CAR-T技术作为治疗策略， 酒精性肝病（ALD）这里介绍的正向工程方法利用了 利用合成免疫学原理设计、构建和测试下一代 synNOTCH CAR-T，其仅在存在所展示的双重抗原的情况下被逻辑激活 在枯否细胞（KC）的表面上，肝驻留巨噬细胞。KC代表了一个优秀的 靶细胞群，因为它们在驱动肝脏炎症、纤维化和ALD中起关键作用 进展为不可逆的终末期肝硬化和肝细胞癌。 在目标2中，我们将评估利用在Aim开发的工程化CAR-T细胞的可行性。 1靶向并消除体内活化的KC，使用良好建立的酒精性小鼠模型， 肝脏疾病我们将询问我们的CAR-T是否可以减缓ALD疾病进展， 阻止纤维化和脂肪变性，恢复肝功能。 我们预计，这些研究将建立工程应用的可行性， 靶向KC的CAR-T作为治疗酒精性肝的有效治疗策略 疾病

Summary Advances in redirecting T cells to attack user-specified target cells using engineered chimeric antigen receptors (CAR-T) have led to the development of powerful cell-based therapeutics. Cellular immunotherapies possess several important advantages over traditional small molecule or antibody-based therapeutics, including the capacity to operate logically through integration of multiple signals, deliver customized therapeutic payloads, and activate or deactivate through engineered control. Here, we propose to adapt and exploit CAR-T technology as a therapeutic strategy in the setting of alcoholic liver disease (ALD). The forward engineering approach presented here leverages the principles of synthetic immunology to design, construct and test in vivo next-generation synNOTCH CAR-T, which are logically activated only in the presence of dual antigens displayed on the surface of Kupffer cells (KC), the liver resident macrophages. KC represent an excellent target cell population because of their pivotal role in driving liver inflammation, fibrosis and ALD progression to irreversible, end-stage cirrhosis and hepatocellular carcinoma. In Aim 2, we will evaluate the feasibility of utilizing the engineered CAR-T cells developed in Aim 1 to target and eliminate activated KC in vivo, using well established mouse models of alcoholic liver disease. We will interrogate whether our CAR-T can attenuate ALD disease progression, block fibrosis and steatosis, and restore liver function. We anticipate that these studies will establish the feasibility for the application of engineered CAR-T targeting KC as an effective therapeutic strategy for the treatment of alcoholic liver disease.