Alloreactive Regulatory T cells control GVHD and maintain GVL effect

描述(申请人提供)：造血细胞移植(HCT)可以治愈各种良性和恶性的造血疾病，但移植物抗宿主病(GVHD)仍然是移植相关的发病率、残疾和死亡率的主要病例，从而限制了HCT的使用。调节性T细胞(Tregs)介导的一种主要耐受机制在预防GVHD方面具有明显的治疗意义，因为它们可以控制GVHD，并可能因其TCR特异性而避免GVL效应。为了将Tregs应用于临床HCT，目前的方法主要集中在将多克隆的、体外扩增的、自然衍生的Tregs(NTregs)过继转移到HCT前后的移植受者体内。然而，这些多克隆nTregs在控制GVHD方面的效力很低，并且产生非选择性免疫抑制，不区分GVHD和GVL反应。目前的建议旨在通过使用同种异体反应树来提高Treg治疗的效力和特异性。我们的长期目标是使用同种异体抗原反应性Tregs来预防GVHD，同时保留人类HCT后的GVL效应。这项建议的目的是在小鼠的临床前骨髓移植(BMT)模型中实现这一目标。我们的中心假设是，异体特异性Tregs在预防GVHD方面是高效的，并且针对上皮组织而不是恶性细胞表达的mHAgs的Tregs可能在控制GVHD的同时保持GVL活性。我们计划通过三个具体目标来验证我们的假设并实现这一目标：1)评估同种异体抗原特异性Tregs在预防GVHD中的效力；2)确定受体中认知抗原分布对Treg介导的GVHD的影响；以及3)确定同种异体特异性Tregs在GVHD和GVL活性中的作用。从这项建议中获得的信息有望建立一种新的策略来预防GVHD，同时通过赋予Tregs一定的抗原特异性并应用它们来保护GVHD靶组织而不是肿瘤免受供者T细胞的攻击，从而避免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.