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， 使动物受体适应造血干/祖细胞（HSPC）移植。 这种方法现在正在开发用于人类使用和非人类灵长类动物测试， 洋红治疗公司，本提案的商业参与者。我们还开发了一个 利用先前工作增强移植后T细胞新生的方法 为T细胞祖细胞定义骨髓生态位，创造一种易于管理的， 骨髓冷冻凝胶皮下注射冷冻凝胶导致T 有能力的共同淋巴祖细胞（CLP）产生，胸腺细胞，TREC+细胞增加， 在小鼠模型中，成熟T细胞、扩大的TCR库和改善的免疫功能。 在这里，我们将联合收割机与坎农和基姆实验室的基因改造技术相结合 和抗体-药物偶联技术的洋红，以确定我们是否可以增加 再生功能复杂，艾滋病毒保护适应性免疫系统保护 针对急性HIV感染，控制感染宿主的病毒血症，并可能减少组织 受感染细胞的储存库。斯卡登实验室在造血和移植方面的优势 和艾伦艾滋病毒感染和免疫实验室将在测试这方面相互补充 在人源化小鼠中的方法。我们将与坎农和基姆实验室在基因方面密切合作， 修改方法以工程化抗HIV HSPC并将测试扩展到非人灵长类动物。 总的来说，这些努力将为治愈艾滋病毒的策略提供即时的临床前测试 通过低毒性的方法来重建受感染个体的免疫系统。

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.