Rafi-Janajreh A Q, Chen D, Schmits R, Mak T W, Grayson R L, Sponenberg D P, Nagarkatti M, Nagarkatti P S
Department of Biology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg 24061, USA.
J Immunol. 1999 Aug 1;163(3):1619-27.
At sites of chronic inflammation seen during infections, autoimmunity, graft-vs-host response, and cytokine therapy, endothelial cell injury is known to occur, the exact mechanism of which is unknown. In the current study we used IL-2-induced vascular leak syndrome (VLS) as a model to investigate whether cytotoxic lymphocytes use CD44 in mediating endothelial cell injury. Administration of IL-2 to wild-type mice triggered significant VLS in the lungs and liver. In contrast, in CD44 knockout (KO) mice, IL-2-induced VLS was markedly reduced in the lungs and liver. IL-2-treated wild-type and CD44 KO mice had similar levels of perivascular infiltration with lymphocytes in the lungs and liver. This suggested that the decrease in VLS seen in CD44 KO mice was not due to the inability of lymphocytes to migrate to these organs. Ultrastructural studies demonstrated extensive endothelial cell damage in the lungs and liver of IL-2-treated wild-type, but not CD44 KO, mice. Moreover, CD44-KO mice exhibited a marked decrease in IL-2-induced lymphokine-activated killer cell activity. The induction of VLS was dependent on the expression of CD44 on immune cells rather than endothelial cells because adoptive transfer of CD44+, but not CD44- spleen cells along with IL-2 into CD44 KO mice triggered VLS. The IL-2-induced VLS was blocked by administration of F(ab')2 of Abs against CD44. The current study demonstrates that CD44 plays a key role in endothelial cell injury. Blocking CD44 in vivo may offer a novel therapeutic approach to prevent endothelial cell injury by cytotoxic lymphocytes in a variety of clinical disease models.
在感染、自身免疫、移植物抗宿主反应和细胞因子治疗期间出现的慢性炎症部位，已知会发生内皮细胞损伤，但其确切机制尚不清楚。在本研究中，我们使用白细胞介素-2（IL-2）诱导的血管渗漏综合征（VLS）作为模型，以研究细胞毒性淋巴细胞是否利用CD44介导内皮细胞损伤。给野生型小鼠注射IL-2会引发肺部和肝脏明显的VLS。相比之下，在CD44基因敲除（KO）小鼠中，IL-2诱导的VLS在肺部和肝脏中明显减少。经IL-2处理的野生型和CD44 KO小鼠在肺部和肝脏中血管周围淋巴细胞浸润水平相似。这表明CD44 KO小鼠中VLS的减少不是由于淋巴细胞无法迁移到这些器官。超微结构研究表明，经IL-2处理的野生型小鼠而非CD44 KO小鼠的肺部和肝脏存在广泛的内皮细胞损伤。此外，CD44-KO小鼠在IL-2诱导的淋巴因子激活的杀伤细胞活性方面表现出明显下降。VLS的诱导依赖于免疫细胞而非内皮细胞上CD44的表达，因为将CD44+而非CD44-脾细胞与IL-2一起过继转移到CD44 KO小鼠中会引发VLS。IL-2诱导的VLS可通过给予抗CD44抗体的F(ab')2来阻断。本研究表明，CD44在内皮细胞损伤中起关键作用。在体内阻断CD44可能为预防各种临床疾病模型中细胞毒性淋巴细胞引起的内皮细胞损伤提供一种新的治疗方法。
