Adoptive Transfer of Donor Tregs Specific Against Host Alloantigens for Presentio

描述(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Tregs的过继转移利用了它们的自然抑制功能，目的是改变体内T效应器和Tregs的平衡。然而，这种方法也可能产生与药物相同的广泛免疫抑制效应。我们实验室和其他实验室的实验啮齿动物模型表明，同种异体抗原特异性Tregs在预防GVHD和提高存活率方面比多特异性Tregs更有效。我们的长期目标是利用Tregs来预防人类的GVHD，而不会抑制对感染病原体或恶性细胞的理想免疫反应。鉴于它们在人类血液中的频率很低，几个小组已经探索了体外Treg扩展用于治疗应用，这些扩展的Treg保留了抑制活性。与非选择性扩增的多特异性Tregs不同，抗原特异性Tregs可选择性抑制同种异体反应，而对第三方反应无影响，并促进HSCT和器官移植后的同种异体抗原特异性耐受。在这些结果得到临床应用之前，需要进行早期临床研究，以解决科学和机械问题，并推动该领域的发展。我们的中心假设是，树突状细胞呈递的针对宿主同种异体抗原的供体Tregs将比目前的标准免疫抑制药物更有效地预防GVHD，同时保持对病毒病原体和癌症相关抗原的免疫力。这项应用的目的是进行人类首个同种特异性Tregs的I期过继免疫治疗试验，用于预防HLA相合同胞HSCT后的GVHD。对于Tregs在人类造血干细胞移植中的潜在应用来说，重要的是开发一种含有雷帕霉素的免疫抑制平台，该平台选择性地允许Tregs的生存、扩增和抑制功能，同时抑制其他效应性T细胞。通过跟踪标记Treg，我们还将评估Treg的再繁殖和过继移植到同种异体移植受体后的存活率。

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.