Alloreactive Regulatory T cells control GVHD and maintain GVL effect

描述（由申请人提供）：造血细胞移植（HCT）可以治愈多种良性和恶性造血系统疾病，但移植物抗宿主病（GVHD）仍然是移植相关发病、残疾和死亡的主要病例，因此限制了HCT的使用。由调节性T细胞（TCR）介导的耐受的主导机制在预防GVHD中具有明显的治疗意义，因为它们可以控制GVHD并且可以根据其TCR特异性而避免GVL效应。在临床HCT中应用TclO的尝试中，目前的方法集中于在HCT之前或之后将多克隆的、离体扩增的、天然衍生的TclO（nTclO）过继转移到移植受体中。然而，预期这些多克隆nT细胞在控制GVHD方面具有低效力，并且产生非选择性免疫抑制而不区分GVHD和GVL反应。目前的提议旨在通过使用同种异体反应性Tcl 3来增加Treg疗法的效力和特异性。我们的长期目标是使用同种异体抗原反应性T细胞来预防GVHD，同时保留人类HCT后的GVL效应。本提案的目的是在小鼠临床前骨髓移植（BMT）模型中实现这一目标。我们的中心假设是，同种异体特异性Tcl 4在GVHD的预防中是高效的，并且对上皮组织而不是恶性细胞表达的mHAg特异性的Tcl 4可以控制GVHD，同时保留GVL活性。我们计划通过追求3个具体目标来检验我们的假设并实现该目标：1）评估同种异体抗原特异性TcR在预防GVHD中的效力; 2）确定受体中的认知抗原分布对Treg介导的GVHD的影响;和3）确定同种异体特异性TcR在GVHD和GVL活性中的影响。从这一提议中获得的信息有望建立一种新的策略，通过赋予Tcl 4某些抗原特异性并将其应用于保护GVHD靶组织而不是肿瘤免受供体T细胞的攻击，来预防GVHD，同时保留GVL效应。

DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) can cure a variety of benign and malignant hematopoietic disorders, but graft-versus-host disease (GVHD) remains the primary case of transplant-related morbidity, disability and mortality, thereby limiting the use of HCT. A dominant mechanism of tolerance mediated by regulatory T cells (Tregs) has obvious therapeutic implications in preventing GVHD, as they can control GVHD and may spare GVL effects depending on their TCR specificity. In an attempt to apply Tregs in clinical HCT, current approaches are focused on adoptive transfer of polyclonal, ex vivo expanded, naturally derived Tregs (nTregs) into transplant recipients before or after HCT. However, these polyclonal nTregs are expected to have a low potency in controlling GVHD and produce non-selective immune suppression without discriminating for GVHD and GVL reactions. The current proposal is aimed at increasing the potency and specificity of Treg therapy by using alloreactive Tregs. Our long-term goal is to using alloantigen-reactive Tregs to prevent GVHD while preserving the GVL effect after HCT in humans. The objective of this proposal is to achieve this goal in pre-clinical bone marrow transplantation (BMT) models in mice. Our central hypothesis is that allo-specific Tregs are highly efficient in the prevention of GVHD, and that Tregs specific for mHAgs expressed by epithelial tissues but not by malignant cells may control GVHD while preserving GVL activity. We plan to test our hypothesis and accomplish the objective by pursuing 3 specific aims: 1) To evaluate the potency of alloantigen-specific Tregs in the prevention of GVHD; 2) To determine the effect of cognized antigen-distribution in the recipient on Treg-mediated GVHD; and 3) To define the effect of allo-specific Tregs in GVHD and GVL activity. The information obtained from this proposal is expected to establish a new strategy to prevent GVHD while sparing GVL effect by conferring Tregs with certain antigen specificities and applying them to protect GVHD target tissues but not tumor from attack by donor T cells.