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

项目总结 异基因造血干细胞移植(HSCT)在治疗高危血液病中发挥着至关重要的作用 恶性肿瘤和一些非恶性疾病。然而，许多接受造血干细胞移植的患者发展为急性 移植物抗宿主病(GVHD)，以及目前全球免疫抑制或 选择性耗尽的T细胞与癌症复发、延迟免疫重建、 感染和其他毒性的增加。寻找抑制供者T细胞以预防GVHD的最佳方法 虽然不会失去它们的有益功能，但仍是一个严重未得到满足的需求。小鼠的领养移植 不变自然杀伤T细胞(INKT)显著降低GVHD，许多人类研究支持这一作用 INKT细胞在GVHD抑制中的作用。几个免疫表型和功能不同的iNKT亚群 在小鼠中被定义，并且只有某些亚群具有抑制GVHD的能力。尽管有这些进步 在理解小鼠iNKT细胞方面，人类iNKT细胞的异质性在很大程度上仍未被探索，而 最适合预防GVHD的子集尚不清楚。这项提案的总体目标是定义人类iNKT细胞 异质性以及针对免疫抑制基因iNKT的靶向选择和产生策略的研究 细胞。为了实现这一目标，将使用类似于在老鼠身上使用的方法，以及新的技术 定义人类iNKT亚群的表型、分子和功能特征，以描绘一个 有可能预防移植物抗宿主病的免疫抑制人群。此外，基因工程战略将 用于增强免疫抑制功能。这些实验将在很大程度上 为分离免疫调节性iNKT细胞提供了科学基础，这将使设计 INKT细胞过继移植预防GVHD的未来临床试验。重要的是，这项工作具有广泛的适用性 超越GVHD的控制，因为了解人类iNKT的异质性将为未来的研究提供一个框架 INKT细胞和基于iNKT的疗法在其他疾病状态下的应用，包括自身免疫、癌症和感染。 拟议的项目是申请者全面职业发展计划的一部分，以此为基础 在细胞免疫学和造血干细胞移植方面有丰富的前期研究经验。在……里面 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 以及细胞的基因工程。这次培训将在她的主要导师罗伯特博士的指导下进行。 Negrin和她的研究顾问委员会，包括Maria Grazia Roncarolo博士，Matthew Porteus博士，Samuel Strober和Holden Maecker。他们的指导和专业知识，以及她的合作者Ken博士的指导和专业知识 Weinberg、Kara Davis、Nima Aghaeepour和Everett Meyer将确保申请人完成 建议学习并获得必要的专业知识，以实现她成为独立人士的职业目标 他是一名内科科学家，主要研究移植后移植物抗宿主病的免疫调节。

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.