巨细胞病毒趋化因子受体M33在小鼠移植模型气道移植排斥反应中的作用

Role of CMV chemokine receptor M33 in airway graft rejection in a mouse transplant model.

作者信息

Hanka Isabella, Stamminger Thomas, Ramsperger-Gleixner Martina, Kuckhahn Annika V, Müller Regina, Weyand Michael, Heim Christian

机构信息

Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Krankenhausstaße 12, 91054 Erlangen, Germany.

Institute for Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.

出版信息

Transpl Immunol. 2021 Aug;67:101415. doi: 10.1016/j.trim.2021.101415. Epub 2021 May 24.

DOI:10.1016/j.trim.2021.101415

PMID:34033867

Abstract

BACKGROUND

Cytomegalovirus (CMV) infection is a risk factor for bronchiolitis obliterans (BO), one form of chronic lung allograft dysfunction (CLAD). The viral chemokine receptor M33 is essential for successful spread of murine CMV to host salivary glands. In the present study we investigated the impact of M33 on chronic airway rejection.

METHODS

MHC I-mismatched tracheas of C·B10-H2/LilMcdJ mice were transplanted into BALB/c (H2) recipients and infected at different dates with wild type (WT) or M33-deleted (delM33) MCMV representing clinical settings of viral recipient (R)-donor (D)-serostatus: (D-/R+) or (D+/R-). Grafts were recovered for gene expression and histological / immunofluorescence analysis, respectively.

RESULTS

Evaluations showed significantly increased signs of chronic rejection in WT-infected mice compared to uninfected allografts seen in lower epithelium/lamina propria-ratio (ELR) (ELR 0.46 ± 0.07 [WT post] vs. ELR 0.66 ± 0.10 [non-inf.]; p < 0.05). The rejection in delM33-infected groups was significantly reduced vs. WT-infected groups (0.67 ± 0.04 [delM33 post]; vs. WT post p < 0.05). Furthermore, decreased rejection was observed in WT pre-infected compared to post-infected groups (0.56 ± 0.08 [WT pre]; vs. WT post p < 0.05). CD8 T cell infiltration was significantly higher in WT-post compared to the delM33 infected or non-infected allografts.

CONCLUSIONS

These data support the role of the CMV in accelerating CLAD. The deletion of chemokine receptor M33 leads to attenuated rejection.

摘要

背景

巨细胞病毒（CMV）感染是闭塞性细支气管炎（BO）的一个危险因素，BO是慢性肺移植功能障碍（CLAD）的一种形式。病毒趋化因子受体M33对于鼠巨细胞病毒成功传播至宿主唾液腺至关重要。在本研究中，我们调查了M33对慢性气道排斥反应的影响。

方法

将C·B10-H2/LilMcdJ小鼠的主要组织相容性复合体I类（MHC I）不匹配气管移植到BALB/c（H2）受体中，并在不同日期用野生型（WT）或缺失M33（delM33）的鼠巨细胞病毒感染，分别代表病毒受体（R）-供体（D）血清学状态的临床情况：（D-/R+）或（D+/R-）。分别回收移植物用于基因表达以及组织学/免疫荧光分析。

结果

评估显示，与未感染的同种异体移植物相比，WT感染小鼠的慢性排斥反应迹象显著增加，表现为较低的上皮/固有层比率（ELR）（ELR 0.46 ± 0.07 [WT感染后] 对比ELR 0.66 ± 0.10 [未感染]；p < 0.05）。与WT感染组相比，delM33感染组的排斥反应显著降低（0.67 ± 0.04 [delM33感染后]；对比WT感染后p < 0.05）。此外，与感染后组相比，WT预感染组的排斥反应降低（0.56 ± 0.08 [WT预感染]；对比WT感染后p < 0.05）。与delM33感染或未感染的同种异体移植物相比，WT感染后CD8 T细胞浸润显著更高。