Activation of intragraft endothelial and mononuclear cells during discordant xenograft rejection.
Activation of intragraft endothelial and mononuclear cells during discordant xenograft rejection.
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DOI：
10.1097/00007890-199411000-00001
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发表时间：
1994-11
期刊：
影响因子：
6.2
通讯作者：
M. Blakely;W. J. van der Werf;M. Berndt;A. Dalmasso;F. Bach;W. Hancock
中科院分区：
文献类型：
--
作者：
M. Blakely;W. J. van der Werf;M. Berndt;A. Dalmasso;F. Bach;W. Hancock
大多数异种移植排斥反应的研究都集中在受体异种反应性抗体和补体作为超急性排斥反应介质的作用上，而体内研究基本上没有关于内皮细胞反应在异种移植排斥反应的病理生物学中的作用的数据。我们假设，异种反应性天然抗体和受体补体参与排斥反应的机制涉及供体器官内皮细胞的激活，这种激活的后果对排斥过程有重要作用。我们对接受延迟异种移植排斥反应的未经处理的Lewis大鼠或补体活性耗竭的受体的豚鼠心脏排斥反应进行了动力学分析。我们报道在超急性排斥反应和延迟性异种移植排斥反应中都有广泛的证据表明内皮细胞激活，包括P-选择素和E-选择素的表达，组织因子的上调，以及血栓调节蛋白和抗凝血酶III的表达下调。其中许多变化发生在移植后很早的时间，直到大约3天才完全排斥。在延迟性异种移植排斥反应中，由于激活的巨噬细胞和自然杀伤细胞的逐渐积聚，可以看到强烈的细胞渗透。T细胞受体α/β+T细胞只存在于相对较低的水平。这种细胞浸润物与致炎细胞因子的密集表达有关，包括干扰素-γ、白介素1和肿瘤坏死因子-α。我们认为，活化的巨噬细胞和自然杀伤细胞对血管内皮细胞的激活和渗透可能在异种移植排斥反应中起重要作用。这些新描述的异种排斥反应的特征可能需要通过未来旨在延长异种移植物存活的治疗方案进行靶向治疗。
Most studies of discordant xenograft rejection have focused on the roles of recipient xenoreactive antibody and complement as mediators of hyperacute rejection; there are essentially no data from in vivo studies as to the contribution of endothelial cell responses to the pathobiology of xenograft rejection. We hypothesized that the mechanism by which xenoreactive natural antibodies and complement of the recipient are involved in rejection of a discordant, immediately vascularized xenograft involves donor organ endothelial cell activation, with the consequences of such activation contributing significantly to the rejection process. We performed a kinetic analysis of rejection of guinea pig hearts by untreated Lewis rats or recipients depleted of complement activity that underwent delayed xenograft rejection. We report that in both hyperacute rejection and delayed xenograft rejection there is widespread evidence of endothelial cell activation, including expression of P-selectin and E-selectin, upregulation of tissue factor, and downregulation of thrombomodulin and antithrombin III expression. Many of these changes occur very early posttransplantation in grafts that are not completely rejected until approximately 3 days. In delayed xenograft rejection, an intense cellular infiltrate is seen that results from progressive accumulation of activated macrophages and natural killer cells. T cell receptor alpha/beta+T cells are present only at relatively low levels. This cellular infiltrate is associated with dense expression of pro-inflammatory cytokines, including interferon gamma, interleukin 1, and tumor necrosis factor-alpha. We conclude that both endothelial cell activation and infiltration by activated macrophages and natural killer cells may play an important role in xenograft rejection. These newly described features of the xenogeneic rejection response may require targeting by future therapeutic regimens aimed at prolonging xenograft survival.