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）是同种异体造血干细胞移植（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的过继转移利用其天然抑制功能，旨在改变T效应物和Tregs在体内的平衡。然而，这种方法也可能产生与药物相同的广泛免疫抑制作用。我们和其他实验室的实验啮齿类动物模型表明，与多特异性treg相比，异体抗原特异性treg在预防GVHD和提高生存率方面更有效。我们的长期目标是利用Tregs在不抑制针对感染性病原体或恶性细胞的理想免疫反应的情况下预防人类GVHD。鉴于Treg在人类血液中的低频率，一些研究小组已经探索了体外扩增Treg用于治疗应用，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treg相比，抗原特异性treg选择性抑制同种异体反应，不影响第三方反应，并促进造血干细胞移植和器官移植后的同种异体抗原特异性耐受。在这些结果找到临床应用之前，需要早期的临床研究来解决科学和机制问题，并推动该领域向前发展。我们的中心假设是，供体Tregs特异性针对树突状细胞呈递的宿主异体抗原，将比目前标准的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。该申请的目的是在HLA-相同的同胞HSCT后进行首次人类I期过继性免疫治疗试验，使用同种异体特异性treg预防GVHD。对于Tregs在人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，该平台可以选择性地允许Tregs的存活、扩增和抑制功能，同时抑制其他效应T细胞。通过对Treg进行标记，我们还将评估Treg移植到同种异体受体后的再生和存活情况。

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.