Relationship of post-transplant thymopoiesis with CD4+FoxP3+ regulatory T cell recovery associated with freedom from chronic graft versus host disease.
Relationship of post-transplant thymopoiesis with CD4+FoxP3+ regulatory T cell recovery associated with freedom from chronic graft versus host disease.
复制标题
移植后胸腺生成与 CD4 FoxP3 调节性 T 细胞恢复的关系，与免受慢性移植物抗宿主病相关。
DOI：
10.1038/s41409-018-0394-z
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发表时间：
2019
影响因子：
4.8
通讯作者：
Morris,GeraldP
中科院分区：
文献类型：
--
作者：
Trovillion,ErinM;Gloude,NicholasJ;Anderson,EricJ;Morris,GeraldP
在成人造血干细胞移植（HSCT）中，CD 4 + FoxP 3+调节性T细胞（T细胞）的恢复与防止移植物抗宿主病（GVHD）相关，尽管关于这种影响的程度存在重大争议[1-7]。Treg和GVHD之间缺乏明确定义的关系可能与Treg群体的异质性有关，其在功能反应、增殖能力、组织归巢和抗原反应性方面可能存在显著差异[4，8]。HSCT后调节Treg隔室再生和功能的机制尚未明确，尽管成人HSCT患者中的研究认为移植后Treg主要来源于循环Treg的外周扩增，胸腺生成的贡献最小。胸腺重建功能性自身耐受T细胞区室的能力受到年龄相关性胸腺退化、胸腺GVHD以及放疗和化疗的影响。我们假设，移植后胸腺生成可能是Treg介导的慢性GVHD（cGVHD）保护恢复的重要因素，并且可能是Treg和cGVHD之间关系的不同观察结果的潜在机制解释。由于年龄相关的胸腺退化导致成人胸腺功能降低，因此T淋巴细胞隔室的胸腺依赖性恢复在儿科HSCT中具有更大的作用[9]，我们检查了儿科HSCT受者。我们检查了在移植后14、30、60、90、180、270和360天收集的19名儿科同种异体HSCT患者的纵向外周血样本和临床数据（表S1）。患者在移植后平均16个月（范围3-24个月）进行临床随访，3例患者因疾病复发导致再次移植或HSCT后100天内死亡而被排除在分析之外。将患者分为两组，发生cGVHD的患者（n= 7）（表S2）和在至少12个月的研究持续时间内保持无cGVHD的患者（n= 12）。首次诊断cGVHD的平均时间为移植后133天（范围为移植后101-189天）。HSCT后的T细胞重建最初通过绝对淋巴细胞计数进行评估，并通过流式细胞术测量初始（CD 45 RA+）和记忆（CD 45 RO+）辅助性CD 4+和细胞毒性CD 8 + T细胞。
Recovery of CD4+ FoxP3+ regulatory T cells (Tregs) has been associated with protection from graft versus host disease (GVHD) in adult hematopoietic stem cell transplantation (HSCT), though significant debate exists as to the extent of this influence [1–7]. The lack of a clearly defined relationship between Tregs and GVHD may be related to heterogeneity of Treg populations, which can differ significantly in their functional responses, proliferative capabilities, tissue homing, and antigenic reactivity [4, 8]. Mechanisms regulating Treg compartment regeneration and function after HSCT are not well-defined, though studies in adult HSCT patients posited that post-transplant Tregs were primarily derived from peripheral expansion of circulating Tregs with minimal contribution from thymopoiesis. The ability of the thymus to reconstitute a functionally selftolerant T cell compartment is compromised by age-related thymic involution, thymic GVHD, and radiation and chemotherapy. We hypothesized that post-transplant thymopoiesis may be an important factor in restoration of Tregmediated protection from chronic GVHD (cGVHD), and may be a potential mechanistic explanation for disparate observations of the relationship between Tregs and cGVHD.As thymus-dependent restoration of T lymphocyte compartments has a larger role in pediatric HSCT owing to lower-thymic function in adults due to age-related thymic involution [9], we examined pediatric HSCT recipients. We examined longitudinal peripheral blood samples and clinical data from 19 pediatric allogeneic HSCT patients (Table S1) collected at 14, 30, 60, 90, 180, 270, and 360 days post transplant. Patients were followed clinically for a mean duration of 16 months post transplant (range 3–24 months), with three patients excluded from analysis due to disease relapse leading to re-transplantation or death within 100 days of HSCT. Patients were divided into two groups, patients that developed cGVHD (n= 7)(Table S2) and patients that remained cGVHD-free for the study duration of at least 12 months (n= 12). Mean time to first diagnosis of cGVHD was 133 days post-transplant (range 101–189 days post-transplant). T cell reconstitution after HSCT was initially assessed by absolute lymphocyte count, and measurement of naive (CD45RA+) and memory (CD45RO+) helper CD4+ and cytotoxic CD8+ T cells by flow cyto-