Batten P, McCormack A M, Page C S, Yacoub M H, Rose M L
Division of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of School of Medicine at Harefield Hospital, Middlesex, UK.
Transplantation. 1999 Nov 27;68(10):1552-60. doi: 10.1097/00007890-199911270-00020.
Human T cells proliferate in response to both human umbilical vein endothelial cells (HUVEC) and porcine aortic endothelial cells (PAEC) via the second signals LFA-3/CD2 and B7-2 (CD86), respectively. Previous studies have shown that stimulation of T cells via CD28 or phorbol myristate acetate (PMA) activation is highly resistant to inhibition by cyclosporine A (CsA) and tacrolimus (FK506), as is the response of T cells to phytohemmaglutinin in the presence of endothelial cells. We have investigated the inhibitory effects of CsA and FK506 on the direct response of human CD4+ T cells to HUVEC and PAEC and the effect of adding B7-1 transfectants.
T cell proliferation, interleukin-2 release bioassays and a multiple cytokine bioassay employing the TF-1 cell line were used as indicators of T cell responses to HUVEC and PAEC either in the presence or absence of CsA and FK506. In some experiments, B7-1 transfectants were also added.
Proliferative responses and interleukin-2 release were highly sensitive to CsA, the ID50 being significantly less for HUVEC (6.5 ng/ml) than PAEC (15 ng/ml). The ID50 of CsA for the mixed lymphocyte response (MLR) was similar to PAEC (18.6 ng/ml), all these values being significantly less than the T cell activation by phytohemmaglutinin (PHA) (227 ng/ml). Addition of B7-1 transfectants significantly increased interleukin-2 production by T cells/HUVEC and resistance to CsA was greatly increased to an ID50 of > 1000 ng/ml. In contrast, addition of B7-1 transfectants to T cells/PAEC had no effect either on T cell proliferation, IL-2 production, or CsA resistance. Similar results were obtained with FK506. Using the TF-1 cell line, it was determined that cytokines other than IL-2 are released during CD4+ T cell/EC interactions, with similar sensitivity to CsA and FK506.
It is concluded that both allogeneic and xenogeneic T cell/endothelial responses should be inhibited by therapeutic levels of CsA in vivo, assuming the absence of trans-stimulation by B7 molecules.
人类T细胞分别通过第二信号LFA - 3/CD2和B7 - 2（CD86）对人脐静脉内皮细胞（HUVEC）和猪主动脉内皮细胞（PAEC）产生增殖反应。先前的研究表明，通过CD28或佛波醇肉豆蔻酸酯乙酸酯（PMA）激活刺激T细胞对环孢素A（CsA）和他克莫司（FK506）的抑制具有高度抗性，内皮细胞存在时T细胞对植物血凝素的反应也是如此。我们研究了CsA和FK506对人CD4 + T细胞对HUVEC和PAEC直接反应的抑制作用以及添加B7 - 1转染子的影响。
T细胞增殖、白细胞介素 - 2释放生物测定以及使用TF - 1细胞系的多种细胞因子生物测定被用作T细胞对HUVEC和PAEC反应的指标，无论是否存在CsA和FK506。在一些实验中，还添加了B7 - 1转染子。
增殖反应和白细胞介素 - 2释放对CsA高度敏感，HUVEC的半数抑制浓度（ID₅₀）（6.5 ng/ml）明显低于PAEC（15 ng/ml）。CsA对混合淋巴细胞反应（MLR）的ID₅₀与PAEC相似（18.6 ng/ml），所有这些值均明显低于植物血凝素（PHA）激活T细胞的值（227 ng/ml）。添加B7 - 1转染子显著增加了T细胞/HUVEC产生的白细胞介素 - 2，并且对CsA的抗性大大增加至ID₅₀>1000 ng/ml。相反，向T细胞/PAEC添加B7 - 1转染子对T细胞增殖、IL - 2产生或CsA抗性均无影响。使用FK506获得了类似结果。使用TF - 1细胞系确定，在CD4 + T细胞/内皮细胞相互作用期间会释放除IL - 2之外的细胞因子，对CsA和FK506具有相似的敏感性。
得出结论，假设不存在B7分子的反式刺激，体内治疗水平的CsA应能抑制同种异体和异种T细胞/内皮细胞反应。
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