Immunosuppressive human invariant natural killer T cells for prevention of graft-versus-host disease

项目摘要 异基因造血干细胞移植（HSCT）在治疗高危血液病中起着至关重要的作用， 恶性肿瘤和一些非恶性疾病。然而，许多接受HSCT的患者发生急性 移植物抗宿主病（GVHD）和目前的预防策略，全球免疫抑制或 选择性耗尽T细胞与癌症复发，延迟免疫重建， 增加感染和其他毒性。确定抑制供体T细胞以预防GVHD的最佳方法 而不丧失其有益功能仍然是一个严重未满足的需求。小鼠的过继转移 不变的自然杀伤T（iNKT）细胞显著减少GVHD，许多人类研究支持其作用 iNKT细胞在GVHD抑制中的作用。几种免疫表型和功能不同的iNKT亚群具有 已经在小鼠中定义，并且只有某些子集具有抑制GVHD的能力。尽管取得了这些进展 在理解鼠iNKT细胞时，人iNKT细胞的异质性在很大程度上仍未被探索， 最适合预防GVHD的子集是未知的。该提案的总体目标是定义人iNKT细胞 异质性，并开发用于靶向选择和产生免疫抑制性iNKT的策略 细胞为了实现这一目标，将使用与小鼠中使用的方法类似的方法以及新技术 定义人iNKT亚群的表型、分子和功能特征，以描绘一个 具有预防GVHD潜力的免疫抑制人群。此外，基因工程战略将 用于增强免疫抑制功能。这些实验将大大有助于 为免疫调节iNKT细胞的分离提供科学依据，这将使设计免疫调节iNKT细胞成为可能。 iNKT细胞过继转移用于GVHD预防的未来临床试验。重要的是，这项工作是广泛适用的 GVHD无法控制，因为了解人类iNKT异质性将为未来的研究提供框架 iNKT细胞和基于iNKT的治疗在其他疾病状态，包括自身免疫，癌症和感染。 建议的项目是申请人全面职业发展计划的一部分， 在细胞免疫学和造血干细胞移植方面有丰富的研究经验。在 特别是，她计划获得新的技能，包括高通量蛋白质组和转录组分析 和细胞的基因工程。这项培训将在她的主要导师罗伯特博士的指导下进行 Negrin和她的研究咨询委员会，包括Maria Grazia Roncarolo博士、Matthew Porteus博士、Samuel博士 斯特罗布和霍尔顿·梅克尔。他们的指导和专业知识，加上她的合作者肯博士 温伯格，卡拉戴维斯，尼玛Aghaeepour，和埃弗雷特迈耶，将确保申请人完成 建议学习并获得必要的专业知识，以实现她成为独立的职业目标 他是一名医生科学家，研究项目集中在HSCT中GVHD的免疫调节。

PROJECT SUMMARY Allogeneic hematopoietic stem cell transplantation (HSCT) plays a vital role in treating high-risk hematologic malignancies and some non-malignant conditions. However, many patients undergoing HSCT develop acute graft-versus-host disease (GVHD), and current prevention strategies that globally immunosuppress or selectively deplete T cells are associated with higher risks of cancer relapse, delayed immune reconstitution, increased infections, and other toxicities. Identifying the best way to suppress donor T cells to prevent GVHD while not losing their beneficial functions remains a critically unmet need. The adoptive transfer of murine invariant natural killer T (iNKT) cells significantly reduces GVHD, and a number of human studies support a role for iNKT cells in GVHD suppression. Several immunophenotypically and functionally distinct iNKT subsets have been defined in mice, and only certain subsets have the capacity to suppress GVHD. Despite these advances in understanding murine iNKT cells, the heterogeneity of human iNKT cells remains largely unexplored, and the subset best suited to prevent GVHD is unknown. The overall goal of this proposal is to define human iNKT cell heterogeneity and to develop strategies for the targeted selection and generation of immunosuppressive iNKT cells. To achieve this goal, similar approaches to those used in mice, as well as novel techniques, will be used to define the phenotypic, molecular, and functional characteristics of human iNKT subsets to delineate an immunosuppressive population with the potential to prevent GVHD. In addition, a gene-engineering strategy will be employed to enhance immunosuppressive function. These experiments will contribute substantially by providing the scientific basis for the isolation of immunoregulatory iNKT cells which will enable the design of a future clinical trial of iNKT cell adoptive transfer for GVHD prevention. Importantly, this work is broadly applicable beyond control of GVHD, as understanding human iNKT heterogeneity will provide a framework for future studies of iNKT cells and iNKT-based therapies in other disease states, including autoimmunity, cancer, and infection. The proposed project is part of a comprehensive career development plan for the applicant to build upon her substantial prior research experience in cellular immunology and hematopoietic stem cell transplantation. In particular, she plans to acquire new skillsets including high throughput proteomic and transcriptomic analyses and genetic engineering of cells. This training will occur under the guidance of her primary mentor, Dr. Robert Negrin, and her research advisory committee, including Drs. Maria Grazia Roncarolo, Matthew Porteus, Samuel Strober, and Holden Maecker. Their guidance and expertise, combined with that of her collaborators Drs. Ken Weinberg, Kara Davis, Nima Aghaeepour, and Everett Meyer, will ensure that the applicant completes the proposed studies and acquires the expertise necessary to fulfill her career goal of becoming an independent physician scientist with a research program focusing on immune regulation of GVHD in HSCT.