Treg Migration in GVHD

描述(申请人提供)：移植物抗宿主病(GVHD)是异基因干细胞移植广泛应用于治疗恶性血液病、实体瘤、骨髓衰竭综合征和先天性疾病患者的主要限制因素。移植物抗宿主病是由同种异体反应性供者T细胞介导的，供者T细胞识别受体抗原提呈细胞呈递的主要或次要组织相容性抗原。这一过程导致一连串的事件，产生促炎细胞因子，并导致受体细胞的破坏。 同种异体反应性T细胞的增殖既受体内平衡增殖的控制，又受调节性T细胞的控制。已证明在多种不同的小鼠模型中，CD4+/CD25+Treg细胞能够抑制GVHD，并且这些细胞的扩增用于临床是可行的。然而，目前对Treg细胞在预防GVHD中的作用机制知之甚少。Treg细胞是否能抑制次级淋巴组织或GVHD靶器官中同种异体反应性T细胞的增殖尚不清楚。目前，Treg细胞向次级淋巴组织迁移的相关蛋白尚不清楚，阻断Treg细胞迁移功能的作用也不清楚。我们的研究小组最近发现，表达L-选择素的Treg细胞能有效地抑制GVHD，而L-选择素Treg细胞对GVHD几乎没有作用。此外，我们最近发现，Treg细胞在激活后表达不同的趋化因子受体模式，趋化因子受体CCR5在激活后显著增加，供体T细胞上CCR5的缺失显著增加了辐射受体动物GVHD的严重程度。在这个方案中，我们将研究GVHD模型中Treg细胞的迁移。将评估以下三个具体目标： 目的1)：探讨L-选择素、CCR5和CCR7在Treg细胞向次级淋巴器官迁移中的作用。 目的：研究Treg细胞在体内是否向发生移植物抗宿主病(GVHD)的实质器官迁移，以及这种迁移是否依赖趋化因子受体CCR4、CCR5或CCR8的表达。 目的：(A)确定GVHD模型中Treg细胞的功能是否依赖于向SLT的迁移。(B)确定Treg细胞的迁移是否依赖于Peyer氏结(PP)或脾的存在。 这项工作的总体目标是在临床试验之前更好地了解Treg细胞的活动机制，评估它们在阻断GVHD方面的效果。

DESCRIPTION (provided by applicant): Graft versus host disease (GVHD) is the major limitation to the widespread utilization of allogeneic stem cell transplantation in the treatment of patients with hematological malignancies, solid tumors, bone marrow failure syndromes and congenital diseases. GVHD is mediated by alloreactive donor T cells that recognize major or minor histocompatibility antigens presented by recipient antigen presenting cells. This process leads to a cascade of events that generate proinflammatory cytokines and causes the destruction of recipient cells. The expansion of alloreactive T cells is controlled both by homeostatic proliferation and regulatory T cells. CD4+/CD25+ Treg cells have been shown to be capable of inhibiting GVHD in multiple different murine models and the expansion of these cells for clinical use is feasible. However, little is known about the mechanism of activity of Treg cells in the prevention of GVHD. Whether Treg cells function to suppress alloreactive T cell proliferation in secondary lymphoid tissue or GVHD target organs is not known. The proteins responsible for the migration of Treg cells into secondary lymphoid tissue have not been demonstrated and the affect of blocking the function of the migration of Treg cells is not clear Our group has recently found that the administration of Treg cells that express L-selectin potently inhibited GVHD while Lselectinlo Treg cells had little effect. Additionally, we have recently shown that Treg cells express a different pattern of chemokine receptors after activation, that the chemokine receptor, CCR5, is markedly increased after activation, and that the absence of CCR5 on donor T cells markedly increased the severity of GVHD in irradiated recipient animals. In this proposal, we will investigate the migration of Treg cells in GVHD models. The following three specific aims will be evaluated: Aim 1): To evaluate the function of L-selectin, CCR5 and CCR7 in the migration of Treg cells into secondary lymphoid organs. Aim 2): To evaluate if Treg cells migrate to parenchymal organs in which GVHD occurs in vivo and if this migration is dependent on the expression of chemokine receptors such as CCR4, CCR5 or CCR8. Aim 3): (a) To determine if Treg cell function in GVHD models is dependent on migration to SLT. (b) To determine if the migration of Treg cells is dependent on the presence of Peyer's patches (PP) or the spleen. The overall goals of this work are to provide a better understanding of the mechanism of activity of Treg cells prior to a clinical trial evaluating their effects in blocking GVHD.