Adoptive Transfer of Donor Tregs Specific Against Host Alloantigens for Presentio

描述（由申请人提供）：移植物抗宿主病（GVHD）是异基因造血干细胞移植（HSCT）后干细胞移植相关死亡的主要原因。调节性T细胞在临床前模型和早期试验中预防GVHD。多特异性T细胞的连续转移利用了它们的天然抑制功能，目的是改变T效应子和T细胞的体内平衡。然而，这种方法也可能产生与药物相同的广泛的免疫抑制作用。来自我们实验室和其他实验啮齿动物模型证明，同种抗原特异性TclA在预防GVHD和改善存活率方面比多特异性TclA更有效。我们的长期目标是利用THBE预防人类GVHD，而不抑制针对感染性病原体或恶性细胞的理想免疫反应。鉴于它们在人血液中的低频率，几个研究组已经探索了用于治疗应用的离体Treg扩增，并且这些扩增的Treg保留了抑制活性。与非选择性扩增的多特异性TCLs相反，抗原特异性TCLs产生对同种异体应答的选择性抑制，而对第三方应答没有影响，并促进HSCT和器官移植后的同种异体抗原特异性耐受。在这些结果发现临床应用之前，需要进行早期临床研究来解决科学和机械问题，并推动该领域向前发展。我们的中心假设是，供体特异性抗原的宿主抗原的树突状细胞将更有效地防止GVHD比目前的标准免疫抑制药物，同时保留对病毒病原体和癌症相关抗原的免疫力。本申请的目的是在HLA-相同的同胞HSCT后进行同种异体特异性THBG用于GVHD预防的首次人体I期过继免疫治疗试验。对于Tclad在人HSCT中的潜在应用重要的是开发含有雷帕霉素的免疫抑制平台，其选择性地允许Tclad的存活、扩增和抑制功能，同时抑制其他效应T细胞。通过示踪标记T细胞，我们还将评估过继转移到同种异体移植物受体后Treg的再增殖和存活率。

DESCRIPTION (provided by applicant): Graft-versus-host disease (GVHD) is the main cause of stem cell transplant-related mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Regulatory T cells prevent GVHD in preclinical models and early trials. Adoptive transfer of poly-specific Tregs exploits their natural suppressive functions and aims to alter the in vivo balance of T effectors and Tregs. However, this approach may also produce the same broad immunosuppressive effects that are caused by drugs. Experimental rodent models from our lab and others demonstrate that alloantigen-specific Tregs are more effective at preventing GVHD and improving survival than polyspecific Tregs. Our Long-Term Goal is to exploit Tregs to prevent GVHD in humans without suppressing desirable immune responses against infectious pathogens or malignant cells. Given their low frequency in human blood, several groups have explored ex-vivo Treg expansion for therapeutic application and these expanded Tregs retain suppressive activity. In contrast to polyspecific Tregs expanded non-selectively, antigen-specific Tregs produce selective suppression of allo-responses with no effect on third-party responses and facilitate alloantigen-specific tolerance after HSCT and organ grafting in. Before these results find clinical application, early clinical studies are required to address scientific and mechanistic questions and move the field forward. Our central hypothesis is that donor Tregs specific for host alloantigens presented by dendritic cells will prevent GVHD more effectively than current standard immune suppressive drugs, while preserving immunity to viral pathogens and cancer-associated antigens. The objective of this application is to conduct a first-in-human Phase I adoptive immunotherapy trial of allo-specific Tregs for GVHD prevention after HLA- identical sibling HSCT. Important to the potential application of Tregs to human HSCT, is the development of an immune suppressive platform containing rapamycin that selectively permits survival, expansion and suppressive function of Tregs while inhibiting other effector T cells. By trace-labeling the Tregs, we will also assess Treg repopulation and survival after adoptive transfer to allograft recipients.