Allogeneic CD4+CD25high T Cells Regulate Obliterative Bronchiolitis of Heterotopic Bronchus Allografts in Both Porcinized and Humanized Mouse Models
Allogeneic CD4+CD25high T Cells Regulate Obliterative Bronchiolitis of Heterotopic Bronchus Allografts in Both Porcinized and Humanized Mouse Models
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同种异体 CD4 CD25high T 细胞调节猪化和人源化小鼠模型中异位支气管同种异体移植物的闭塞性细支气管炎
DOI：
10.1097/tp.0000000000000632
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发表时间：
2015
期刊：
影响因子：
6.2
通讯作者：
Warnecke G
中科院分区：
文献类型：
--
作者：
Sommer W;Knöfel AK;Madrahimov N;Avsar M;Jonigk D;Salman J;Dreckmann K;Jansson K;Salguero;Gustavo;Ulrich A;Tobias;Haverich A;Warnecke G
闭塞性细支气管炎综合征是由同种异体肺移植中纤维增殖过程引起的不可逆性损伤引起的。在这项研究中，我们诱导了闭塞性毛细支气管炎，并研究了调节性T细胞在接受异位猪支气管移植的免疫缺陷小鼠以及主要组织相容性复合体-不相合的猪外周血单核细胞中的作用。此外，我们的目的是在人源化的小鼠模型中证实我们的发现。RAG−/−γc−/−小鼠，以小型猪为组织供体。然后，受体小鼠接受生理盐水(阴性对照)、未分选的MHC不相合的PBMC(阳性对照)、富含CD4+CD25高细胞的PBMC或去除CD4+CD25高细胞的PBMC进行重建。结果在28个节点得到验证。异基因人支气管移植重建RAG−/−γc−/−小鼠。结果同种异体PBMC移植后，小鼠体内出现了与典型的闭塞性毛细支气管炎相似的组织学损害，移植的PBMC去除了CD 4+CD2 5高细胞，这种损害更为严重。相比之下，用富含CD4+CD25高细胞的PBMC重组的组显示出良好的组织学保存。结论猪化和人源化小鼠异位皮下支气管移植模型模拟了闭塞性毛细支气管炎综合征样病变的体内发展过程，并揭示了其对T细胞调节的敏感性。
BackgroundBronchiolitis obliterans syndrome is caused by a fibroproliferative process in lung allografts resulting in irreversible damage. In this study, we induced obliterative bronchiolitis and studied the contribution of regulatory T cells to its development in immune-deficient mice receiving heterotopic porcine bronchus transplants, and major histocompatibility complex-mismatched porcine peripheral blood mononuclear cell. Furthermore, we aimed to corroborate our findings in a humanized mouse model.MethodsHeterotopic bronchus transplantation was performed in 33 NOD. rag−/− γc−/− mice, using miniature pigs as tissue donors. The recipient mice then either received saline (negative control), unsorted MHC-mismatched PBMC (positive control), PBMC enriched with CD4+ CD25 high cells or PBMC depleted of CD4+ CD25 high cells for reconstitution. The results were validated in 28 NOD. rag−/− γc−/− mice undergoing heterotopic human bronchus transplantation and reconstitution with allogeneic human PBMC.ResultsHistological lesions similar to those typical for obliterative bronchiolitis developed in vivo after reconstitution with allogeneic PBMC and were more severe in animals engrafted with PBMC depleted of CD4+ CD25 high cells. In contrast, the group reconstituted with PBMC enriched with CD4+ CD25 high cells showed well-preserved histology. The results of the humanized model confirmed those obtained in the porcinized model.ConclusionsIn conclusion, both porcinized and humanized mouse models of heterotopic subcutaneous bronchus transplantation imitate the in vivo development of bronchiolitis obliterans syndrome–like lesions and reveal its sensitivity to T-cell regulation.
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DOI：
10.1186/2047-1440-1-11
发表时间：
2012-09-28
期刊：
Transplantation research
影响因子：
--
作者：
Geissler EK
通讯作者：
Geissler EK
猪胚胎肌原细胞分化过程中生长因子信使核糖核酸的表达。
影响因子：
3.3
作者：
G. Xi;M. Hathaway;W. Dayton;M. White
通讯作者：
M. White
慢病毒载体编程树突状细胞的预处理治疗可加速 NOD.Rag1-/-.IL-2rγc-/- 小鼠中抗原反应性人类 T 细胞的稳态扩张。
影响因子：
4.2
作者：
G. Salguero;B. Sundarasetty;Sylvia Borchers;D. Wedekind;B. Eiz;S. Velaga;Adan Chari Jirmo;G. Behrens;G. Warnecke;Ann‐Kathrin Knöfel;R. Blasczyk;E. Mischak;A. Ganser;R. Stripecke
通讯作者：
R. Stripecke
影响因子：
8.9
作者：
Yusen, Roger D.;Christie, Jason D.;Stehlik, Josef
通讯作者：
Stehlik, Josef