T cell-mediated vascular dysfunction of human allografts results from IFN-gamma dysregulation of NO synthase.
T cell-mediated vascular dysfunction of human allografts results from IFN-gamma dysregulation of NO synthase.
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DOI：
10.1172/jci21767
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发表时间：
2004-09
期刊：
影响因子：
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通讯作者：
Kian Peng Koh;Yinong Wang;T. Yi;S. Shiao;M. Lorber;W. Sessa;G. Tellides;J. Pober
中科院分区：
文献类型：
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作者：
Kian Peng Koh;Yinong Wang;T. Yi;S. Shiao;M. Lorber;W. Sessa;G. Tellides;J. Pober
移植物血管功能障碍易导致动脉硬化和移植物丢失。我们利用免疫缺陷的小鼠宿主研究了移植的人动脉对体内循环的同种异体T细胞的反应是如何发展成功能障碍的。移植动脉在7-9天内出现内皮细胞功能障碍，但对外源性NO仍敏感。到2周时，移植物出现收缩功能受损和对NO脱敏，这两种情况都是VSMC功能障碍的迹象。这些依赖T细胞的变化与eNOS的丢失和iNOS的表达相关-后者主要在浸润性T细胞内。中和干扰素-γ可完全阻止血管功能障碍和一氧化氮合酶表达的改变；中和肿瘤坏死因子可减少干扰素-γ的产生并部分阻止功能障碍。在体内，抑制iNOS在2周时部分保留了对NO的反应，并在4周后减少了移植物的内膜扩张。在体外，记忆CD4+T细胞作用于同种异体培养的内皮细胞，降低eNOS活性及蛋白和mRNA的表达。这些效应需要第II类MHC抗原和共刺激因子(主要是淋巴细胞功能相关抗原-3或LFA-3)在内皮细胞上激活T细胞，并通过产生可溶性介质包括干扰素-γ和肿瘤坏死因子来介导。我们得出结论，干扰素-γ是血管功能障碍的中枢介质，并且通过一氧化氮合酶表达的失调，将早期功能障碍与晚期动脉硬化联系在一起。
Allograft vascular dysfunction predisposes to arteriosclerosis and graft loss. We examined how dysfunction develops in transplanted human arteries in response to circulating allogeneic T cells in vivo using immunodeficient murine hosts. Within 7-9 days, transplanted arteries developed endothelial cell (EC) dysfunction but remained sensitive to exogenous NO. By 2 weeks, the grafts developed impaired contractility and desensitization to NO, both signs of VSMC dysfunction. These T cell-dependent changes correlated with loss of eNOS and expression of iNOS--the latter predominantly within infiltrating T cells. Neutralizing IFN-gamma completely prevented both vascular dysfunction and changes in NOS expression; neutralizing TNF reduced IFN-gamma production and partially prevented dysfunction. Inhibiting iNOS partially preserved responses to NO at 2 weeks and reduced graft intimal expansion after 4 weeks in vivo. In vitro, memory CD4+ T cells acted on allogeneic cultured ECs to reduce eNOS activity and expression of protein and mRNA. These effects required T cell activation by class II MHC antigens and costimulators (principally lymphocyte function-associated antigen-3, or LFA-3) on the ECs and were mediated by production of soluble mediators including IFN-gamma and TNF. We conclude that IFN-gamma is a central mediator of vascular dysfunction and, through dysregulation of NOS expression, links early dysfunction with late arteriosclerosis.