胸腺来源的调节性T细胞在排斥反应前浸润心脏移植器官。

Thymus-Derived Regulatory T Cells Infiltrate the Cardiac Allograft Before Rejection.

作者信息

Boer Karin, Caliskan Kadir, Peeters Annemiek M A, van Groningen Marian C, Samsom Janneke N, Maat Alexander P W M, Betjes Michiel G H, Weimar Willem, Baan Carla C

机构信息

1 Section Nephrology and Transplantation, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. 2 Department of Cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands. 3 Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands. 4 Division of Gastroenterology and Nutrition, Department of Pediatrics, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands. 5 Department of Thoracic Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

出版信息

Transplantation. 2015 Sep;99(9):1839-46. doi: 10.1097/TP.0000000000000730.

DOI:10.1097/TP.0000000000000730

PMID:25886917

Abstract

BACKGROUND

FOXP3+ regulatory T cells (Treg) either originate in the thymus (natural [n]Treg) or are induced in the periphery by antigen exposure and cytokines (induced [i]Treg). It is currently not elucidated which and to what extent these Treg subsets regulate intracardiac allogeneic responses in transplant patients.

METHODS

By using demethylation of the Treg-specific demethylated region in the FOXP3 gene as a marker for nTreg and FOXP3 messenger RNA expression as a marker for the total Treg population, we examined Treg in endomyocardial biopsies (EMBs) of both patients who developed an acute rejection necessitating therapy (rejectors; International Society for Heart and Lung Transplantation rejection grade ≥ 2R) and patients who remained free from rejection (nonrejectors).

RESULTS

In the presence of comparable messenger RNA levels of CD3, IL-10, TGFβ, IL2, IFNγ, and IL17A, the percentage of nTreg was significantly higher in EMB with histological signs of mild rejection (rejection grade 1R) collected before rejection than in 1R EMB of nonrejectors. The total Treg population was comparable in 1R EMB of nonrejectors and 1R EMB collected before rejection, which suggests the presence of iTreg in the EMB of nonrejectors. The relative high percentage of nTreg after rejection was not related to the number of rejections, whereas the total Treg population was inversely related to the number of rejections the first year after transplantation.

CONCLUSIONS

Our data indicate that intragraft nTreg are unable to restrain alloreactivity leading to rejection. Moreover, the indirect evidence of the presence of intragraft iTreg suggests a possible role of iTreg in the regulation of alloreactivity.

摘要

背景

FOXP3+调节性T细胞（Treg）要么起源于胸腺（天然[n]Treg），要么在外周由抗原暴露和细胞因子诱导产生（诱导性[i]Treg）。目前尚不清楚这些Treg亚群在多大程度上以及如何调节移植患者的心脏内同种异体反应。

方法

通过将FOXP3基因中Treg特异性去甲基化区域的去甲基化作为nTreg的标志物，将FOXP3信使核糖核酸表达作为总Treg群体的标志物，我们检测了发生急性排斥反应需要治疗的患者（排斥者；国际心肺移植学会排斥分级≥2R）和未发生排斥反应的患者（非排斥者）的心内膜心肌活检（EMB）中的Treg。

结果

在CD3、IL-10、TGFβ、IL2、IFNγ和IL17A信使核糖核酸水平相当的情况下，排斥前收集的有轻度排斥组织学迹象（排斥分级1R）的EMB中nTreg的百分比显著高于非排斥者的1R EMB。非排斥者的1R EMB和排斥前收集的1R EMB中的总Treg群体相当，这表明非排斥者的EMB中存在iTreg。排斥后nTreg的相对高百分比与排斥次数无关，而总Treg群体与移植后第一年的排斥次数呈负相关。