Enhancing regeneration of stem cell-derived HIV-specific immune effectors

项目摘要 在之前的U19奖项中，我们开发了一种基于非遗传毒性抗体的方法 造血干/祖细胞(HSPC)移植的条件动物受体。 这种方法现在正在开发用于人类和非人类灵长类动物的测试，方法是 洋红治疗公司是这项提案的商业参与者。我们还开发了一种 一种利用先前工作促进移植后T细胞新生的方法 定义T-能力祖细胞的骨髓利基，创建一个易于管理的 货架上的骨髓冷冻机。皮下注射冷冻胶可改善T 合格的共同淋巴祖细胞(CLP)的产生，胸腺细胞，TREC+细胞， 成熟的T细胞，扩大的TCR谱系和改善小鼠模型的免疫功能。 在这里，我们将把它与Cannon和Kiem实验室的基因改造技术结合起来 而品红的抗体-药物偶联技术来确定我们是否可以增加 功能复杂、HIV保护的适应性免疫系统的再生保护 预防急性艾滋病毒感染，控制受感染宿主的病毒血症，并有可能减少组织 被感染细胞的蓄水池。斯卡登实验室在造血和移植方面的优势 艾伦的艾滋病毒感染和免疫实验室将在测试中相辅相成 在人源化小鼠中的方法。我们将与坎农和基姆实验室就基因进行密切互动 修改方法以设计抗HIV HSPC并将测试扩展到非人类灵长类动物。 总的来说，这些努力将为治愈艾滋病毒的战略提供即时的临床前测试。 通过低毒的方法重建感染者的免疫系统。

Project Summary In the previous U19 award, we developed a non-genotoxic antibody based method of conditioning animal recipients for hematopoietic stem/progenitor cell (HSPC) transplantation. This approach is now being developed for human use and non-human primate testing by Magenta Therapeutics, the commercial participant in this proposal. We also developed a method of enhancing T cell neogenesis post-transplantation that takes advantage of prior work defining the bone marrow niche for T-competent progenitors, creating an easy to administer, off the shelf bone marrow cryogel. Subcutaneous injection of the cryogel leads to improved T competent common lymphoid progenitor (CLP) production, increased thymocytes, TREC+ cells, mature T cells, expanded TCR repertoire and improved immune function in mouse models. Here, we will combine it with the gene modification technology of the Cannon and Kiem labs and the antibody-drug conjugate technology of Magenta to determine whether we can increase the regeneration of a functionally complex, HIV protected adaptive immune system to protect against acute HIV infection, control viremia in infected hosts and potentially, reduce the tissue reservoir of infected cells. The strengths of the Scadden lab in hematopoiesis and transplant and the Allen lab in HIV infection and immunity will complement each other in testing this approach in humanized mice. We will closely interact with the Cannnon and Kiem labs on gene modifying approaches to engineer anti-HIV HSPC and extend testing to the non-human primate. Collectively, these efforts will provide immediate pre-clinical testing a of a strategy to cure HIV through low-toxicity approaches to rebuild an infected individual’s immune system.