T-cell costimulatory blockade in experimental chronic cardiac allograft rejection: effects of cyclosporine and donor antigen.
T-cell costimulatory blockade in experimental chronic cardiac allograft rejection: effects of cyclosporine and donor antigen.
复制标题
实验性慢性心脏同种异体移植排斥中的 T 细胞共刺激阻断：环孢菌素和供体抗原的作用。
DOI：
10.1097/00007890-199704270-00002
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发表时间：
1997
期刊：
影响因子：
6.2
通讯作者：
Sayegh,MH
中科院分区：
文献类型：
--
作者：
Chandraker,A;Russell,ME;Glysing-Jensen,T;Willett,TA;Sayegh,MH
慢性排斥反应是一个T细胞依赖性过程，融合蛋白CTLA 4 Ig阻断CD 28-B7 T细胞共刺激活化途径已被证明可预防慢性心脏同种异体移植排斥大鼠模型中加速移植物动脉硬化的发展。在临床相关模型中，T细胞共刺激阻断剂联合环孢素治疗预防慢性同种异体移植排斥反应的有效性尚未研究。使用成熟的LEW进入F334异位心脏同种异体移植模型，我们表明，当环孢素与CTLA 4 Ig联合给药时，它消除了先前证明的CTLA 4 Ig在预防慢性同种异体移植排斥反应中的保护作用。来自用环孢霉素和CTLA 4 Ig的组合治疗的动物的长期存活的同种异体移植物具有42.2%的平均血管腔闭塞，由于加速的动脉硬化影响超过90%的移植血管。这与移植物内CD 4、共刺激分子B7、T细胞细胞因子干扰素-γ、单核细胞趋化蛋白-1和纤维化生长因子转化生长因子-β的mRNA表达上调有关;所有这些先前已被证明与该模型中慢性排斥反应的发生有关。相比之下，将供体脾细胞添加到CTLA 4 Ig和环孢霉素治疗方案的组合中显著降低了动脉硬化的量;平均血管管腔闭塞为11.3%，影响约50%的血管。这与移植物内CD 4、B7、干扰素-γ、单核细胞趋化蛋白-1和转化生长因子-β的表达降低有关。这些数据表明，CTLA 4 Ig在减弱慢性排斥反应中的作用机制是环孢霉素敏感的，并且暗示CTLA 4 Ig和环孢霉素的组合的策略在临床上可能不可取。如果CTLA 4 Ig和环孢霉素联合使用，则可能需要供体抗原的给药，以防止慢性排斥反应的过程。
Chronic rejection is a T cell-dependent process and blockade of the CD28-B7 T-cell costimulatory activation pathway by the fusion protein CTLA4Ig has been shown to prevent the development of accelerated graft arteriosclerosis in a rat model of chronic cardiac allograft rejection. The effectiveness of T-cell costimulatory blockade at preventing chronic allograft rejection in a clinically relevant model in combination with cyclosporine therapy has not been investigated. Using the well-established LEW into F334 heterotopic cardiac allograft model, we show that when cyclosporine is administered in combination with CTLA4Ig, it abrogates the previously demonstrated protective effect of CTLA4Ig in preventing chronic allograft rejection. Long-term surviving allografts from animals treated with a combination of cyclosporine and CTLA4Ig had a mean vascular luminal occlusion of 42.2%, affecting more than 90% of graft vessels due to accelerated arteriosclerosis. This was associated with up-regulation of intragraft expression of mRNA for CD4, the costimulatory molecule B7, the T-cell cytokine interferon-γ, monocyte chemoattractant protein-1, and the fibrogenic growth factor transforming growth factor-β; all have been previously shown to be associated with development of chronic rejection in this model. In comparison, the addition of donor splenocytes to the combination of CTLA4Ig and cyclosporine therapy protocol significantly reduced the amount of arteriosclerosis; mean vascular luminal occlusion was 11.3%, affecting approximately 50% of vessels. This was associated with decreased intragraft expression of CD4, B7, interferon-γ, monocyte chemoattractant protein-1, and transforming growth factor-β. These data indicate that the mechanism of action of CTLA4Ig in attenuating chronic rejection is cyclosporine sensitive, and that strategies implying combination of CTLA4Ig and cyclosporine may not be clinically desirable. Administration of donor antigen may be necessary if CTLA4Ig and cyclosporine are to be combined, to prevent the process of chronic rejection.