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Extracellular vesicles derived from injured vascular tissue promote the formation of tertiary lymphoid structures in vascular allografts.
American Journal of Transplantation ( IF 8.8 ) Pub Date : 2019-12-16 , DOI: 10.1111/ajt.15707
Mélanie Dieudé 1, 2, 3 , Julie Turgeon 1, 3 , Annie Karakeussian Rimbaud 1, 3 , Déborah Beillevaire 1, 3 , Shijie Qi 1, 3 , Nathalie Patey 3, 4 , Louis A Gaboury 5 , Éric Boilard 3, 6 , Marie-Josée Hébert 1, 2, 3
Affiliation  

Tertiary lymphoid structures (TLS) accumulate at sites of chronic injury where they function as an ectopic germinal center, fostering local autoimmune responses. Vascular injury leads to the release of endothelial-derived apoptotic exosome-like vesicles (ApoExo) that contribute to rejection in transplanted organs. The purpose of the study was to evaluate the impact of ApoExo on TLS formation in a model of vascular allograft rejection. Mice transplanted with an allogeneic aortic transplant were injected with ApoExo. The formation of TLS was significantly increased by ApoExo injection along with vascular remodeling and increased levels of antinuclear antibodies and anti-perlecan/LG3 autoantibodies. ApoExo also enhanced allograft infiltration by γδT17 cells. Recipients deficient in γδT cells showed reduced TLS formation and lower autoantibodies levels following ApoExo injection. ApoExo are characterized by proteasome activity, which can be blocked by bortezomib. Bortezomib treated ApoExo reduced the recruitment of γδT17 cells to the allograft, lowered TLS formation, and reduced autoantibody production. This study identifies vascular injury-derived extracellular vesicles (ApoExo), as initiators of TLS formation and demonstrates the pivotal role of γδT17 in coordinating TLS formation and autoantibody production. Finally, our results suggest proteasome inhibition with bortezomib as a potential option for controlling TLS formation in rejected allografts.

中文翻译:

来自受损血管组织的细胞外囊泡促进血管同种异体移植物中三级淋巴结构的形成。

三级淋巴结构 (TLS) 在慢性损伤部位积聚,在那里它们充当异位生发中心,促进局部自身免疫反应。血管损伤导致内皮衍生的凋亡外泌体样小泡 (ApoExo) 的释放,这有助于移植器官的排斥反应。该研究的目的是评估 ApoExo 对血管同种异体移植物排斥模型中 TLS 形成的影响。移植了同种异体主动脉移植物的小鼠被注射了 ApoExo。ApoExo 注射显着增加了 TLS 的形成,同时血管重塑和抗核抗体和抗 perlecan/LG3 自身抗体水平增加。ApoExo 还增强了 γδT17 细胞对同种异体移植物的浸润。γδT 细胞缺陷的接受者在 ApoExo 注射后显示 TLS 形成减少和自身抗体水平降低。ApoExo 以蛋白酶体活性为特征,可被硼替佐米阻断。硼替佐米处理的 ApoExo 减少了 γδT17 细胞向同种异体移植物的募集,降低了 TLS 形成,并减少了自身抗体的产生。本研究确定了血管损伤衍生的细胞外囊泡 (ApoExo) 作为 TLS 形成的引发剂,并证明了 γδT17 在协调 TLS 形成和自身抗体产生中的关键作用。最后,我们的结果表明用硼替佐米抑制蛋白酶体是控制排斥同种异体移植物中 TLS 形成的潜在选择。硼替佐米处理的 ApoExo 减少了 γδT17 细胞向同种异体移植物的募集,降低了 TLS 形成,并减少了自身抗体的产生。本研究确定了血管损伤衍生的细胞外囊泡 (ApoExo) 作为 TLS 形成的引发剂,并证明了 γδT17 在协调 TLS 形成和自身抗体产生中的关键作用。最后,我们的结果表明用硼替佐米抑制蛋白酶体是控制排斥同种异体移植物中 TLS 形成的潜在选择。硼替佐米处理的 ApoExo 减少了 γδT17 细胞向同种异体移植物的募集,降低了 TLS 形成,并减少了自身抗体的产生。本研究确定了血管损伤衍生的细胞外囊泡 (ApoExo) 作为 TLS 形成的引发剂,并证明了 γδT17 在协调 TLS 形成和自身抗体产生中的关键作用。最后,我们的结果表明用硼替佐米抑制蛋白酶体是控制排斥同种异体移植物中 TLS 形成的潜在选择。
更新日期:2019-12-17
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