Pankonin G, Reipert B, Ager A
Central Institute for Cancer Research, Berlin-Buch, Germany.
Immunology. 1992 Sep;77(1):51-60.
A prerequisite for the successful immunotherapy of solid tumours with interleukin-2 (IL-2)-activated lymphocytes is their ability to home to the tumour tissue. Lymphocyte homing is a complex process which is known to involve at least two independently regulated events: adhesion to the luminal surface of vascular endothelium and the subsequent transendothelial migration of lymphocytes. In this study we have used an in vitro model of lymphocyte homing which employs specialized high endothelium to ask whether IL-2-activated lymphocytes are able to migrate across vascular endothelium in order to leave the blood vessel. Both the adhesion of IL-2-activated cells and their migration across monolayers of cultured high endothelial cells (HEC) were increased in comparison with non-activated lymphocytes. The adhesion of IL-2-activated lymphocytes was mediated by lymphocyte function-associated antigen-1 (LFA-1) and a very late activation antigen-4 (VLA-4)-related pathway. LFA-1-dependent adhesion was mediated by ligands on HEC other than the intercellular adhesion molecule-1 (ICAM-1) and the VLA-4-related pathway was mediated by ligands other than the CS1 domain of fibronectin. HEC-adherent lymphocytes were enriched in natural killer (NK) cells and CD8+ T cells which are known to be the tumour-cytotoxic cells in IL-2-activated lymphocytes. However, there was no evidence of cytotoxicity towards the endothelial layer using a syngeneic model. The interaction of IL-2-activated lymphocytes and endothelial cells was not specific for high endothelium since equal numbers of activated lymphocytes bound to and migrated across aortic endothelium. The inability of IL-2-activated lymphocytes to discriminate between high endothelium and non-specialized 'flat' endothelium could be responsible for the widespread dissemination of the cells throughout the body following their adoptive transfer and the unwanted side-effects at non-involved sites.
用白细胞介素-2（IL-2）激活的淋巴细胞对实体瘤进行成功免疫治疗的一个先决条件是它们归巢至肿瘤组织的能力。淋巴细胞归巢是一个复杂的过程，已知至少涉及两个独立调节的事件：与血管内皮腔表面的黏附以及随后淋巴细胞的跨内皮迁移。在本研究中，我们使用了一种淋巴细胞归巢的体外模型，该模型采用特殊的高内皮来研究IL-2激活的淋巴细胞是否能够穿过血管内皮以离开血管。与未激活的淋巴细胞相比，IL-2激活的细胞的黏附及其穿过培养的高内皮细胞（HEC）单层的迁移均增加。IL-2激活的淋巴细胞的黏附由淋巴细胞功能相关抗原-1（LFA-1）和一条与极晚期激活抗原-4（VLA-4）相关的途径介导。LFA-1依赖性黏附由HEC上除细胞间黏附分子-1（ICAM-1）以外的配体介导，VLA-4相关途径由除纤连蛋白CS1结构域以外的配体介导。黏附于HEC的淋巴细胞富含自然杀伤（NK）细胞和CD8 + T细胞，已知它们是IL-2激活的淋巴细胞中的肿瘤细胞毒性细胞。然而，在同基因模型中没有证据表明对内皮细胞层具有细胞毒性。IL-2激活的淋巴细胞与内皮细胞的相互作用并非高内皮所特有的，因为等量的激活淋巴细胞与主动脉内皮结合并穿过主动脉内皮迁移。IL-2激活的淋巴细胞无法区分高内皮和非特化的“扁平”内皮，这可能是细胞在过继转移后在全身广泛扩散以及在非受累部位产生不良副作用的原因。
