Bergese S D, Pelletier R P, Ohye R G, Vallera D A, Orosz C G
Department of Surgery, Ohio State University College of Medicine, Columbus 43210.
Transplantation. 1994 Mar 15;57(5):711-7. doi: 10.1097/00007890-199403150-00013.
In vivo treatment of mice with anti-CD3 mAb causes polyclonal T cell activation and cytokine release. Since several cytokines are known to alter expression of MHC molecules and adhesion molecules on endothelia, we hypothesized that anti-CD3 mAb treatment should result in activation of vascular endothelia. In previous studies, we established that vascular endothelial cells in murine heterotopic cardiac grafts can develop at least 2 stable inflammatory phenotypes: cardiac allograft endothelia characteristically develop reactivity with MECA-32 mAb (undefined endothelial epitope) and M/K-2 mAb (murine vascular cell adhesion molecule-1 [VCAM-1]), whereas cardiac isografts develop reactivity with MECA-32, but not M/K-2 mAb. We now report that a single treatment of cardiac isograft recipients with the anti-CD3 mAb 145-2C11 caused expression of VCAM-1 on all cardiac isograft endothelia, including the microvascular endothelia. In contrast, expression of endothelial VCAM-1 in the native heart of the isograft recipient was limited to patchy areas of larger arteries. This patchy, arterial pattern of VCAM-1 expression was observed in lung, liver, kidney, and thymus of all mice treated with 145-2C11, whether or not they were implanted with a cardiac isograft, and was dissociated from expression of MECA-32 mAb reactivity. Hence, treatment of mice with anti-CD3 mAb causes systemic endothelial activation (VCAM-1 expression), and endothelial cells of recently implanted cardiac isografts appear to be hypersensitive to induction of VCAM-1 by anti-CD3 mAb treatment. Further studies showed that (1) treatment with 145-2C11 F(ab)'2 fragments did not induce endothelial activation, (2) intravenous pretreatment with pentoxifylline eliminated all endothelial effects of 145-2C11 treatment, (3) induction of endothelial activation by 145-2C11 mAb always paralleled the expression of adverse physiologic symptoms, and (4) mice exhibit strain-specific differences in endothelial responses to 145-2C11 treatment. We propose that anti-CD3 mAb treatment causes simultaneous activation of circulating T cells and systemic vascular endothelial cells which may facilitate systemic lymphocyte-endothelial interactions, and may explain the rapid disappearance of T cells from the circulation that is associated with anti-CD3 treatment in mouse and man.
用抗CD3单克隆抗体对小鼠进行体内治疗会导致多克隆T细胞活化和细胞因子释放。由于已知几种细胞因子会改变内皮细胞上MHC分子和黏附分子的表达，我们推测抗CD3单克隆抗体治疗应会导致血管内皮细胞活化。在先前的研究中，我们确定小鼠异位心脏移植中的血管内皮细胞可形成至少两种稳定的炎症表型：心脏同种异体移植内皮细胞通常会产生与MECA - 32单克隆抗体（未定义的内皮表位）和M/K - 2单克隆抗体（小鼠血管细胞黏附分子 - 1 [VCAM - 1]）的反应性，而心脏同基因移植则会产生与MECA - 32的反应性，但不产生与M/K - 2单克隆抗体的反应性。我们现在报告，用抗CD3单克隆抗体145 - 2C11对心脏同基因移植受体进行单次治疗会导致所有心脏同基因移植内皮细胞，包括微血管内皮细胞上VCAM - 1的表达。相比之下，同基因移植受体的天然心脏中内皮VCAM - 1的表达仅限于较大动脉的散在区域。在用145 - 2C11治疗的所有小鼠的肺、肝、肾和胸腺中均观察到这种散在的、动脉型的VCAM - 1表达模式，无论它们是否植入了心脏同基因移植，且这种表达模式与MECA - 32单克隆抗体反应性的表达无关。因此，用抗CD3单克隆抗体治疗小鼠会导致全身内皮细胞活化（VCAM - 1表达），并且最近植入的心脏同基因移植的内皮细胞似乎对抗CD3单克隆抗体治疗诱导VCAM - 1的作用高度敏感。进一步的研究表明：（1）用145 - 2C11 F(ab)'2片段治疗不会诱导内皮细胞活化；（2）用己酮可可碱进行静脉预处理消除了145 - 2C11治疗的所有内皮细胞效应；（3）145 - 2C11单克隆抗体诱导的内皮细胞活化总是与不良生理症状的表达平行；（4）小鼠在对145 - 2C11治疗的内皮细胞反应中表现出品系特异性差异。我们提出，抗CD3单克隆抗体治疗会导致循环T细胞和全身血管内皮细胞同时活化，这可能促进全身淋巴细胞 - 内皮细胞相互作用，并可能解释与小鼠和人类抗CD3治疗相关的循环中T细胞的快速消失。
