An Antibody to the Sixth Ig-like Domain of VCAM-1 Inhibits Leukocyte Transendothelial Migration without Affecting Adhesion
An Antibody to the Sixth Ig-like Domain of VCAM-1 Inhibits Leukocyte Transendothelial Migration without Affecting Adhesion
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DOI：
10.4049/jimmunol.1103803
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发表时间：
2012-11-01
影响因子：
4.4
通讯作者：
Chung, Junho
中科院分区：
文献类型：
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作者：
Lee, Sukmook;Yoon, Il-Hee;Chung, Junho
VCAM-1 在炎症反应期间的白细胞运输中发挥着关键作用。然而，该功能的分子机制尚未明确阐明。在本研究中，我们利用噬菌体展示技术开发了一种兔/人嵌合 VCAM-1 Ab，称为 VCAM-1 结构域 6 (VCAM-1-D6)，它特异性识别第六个 Ig 样结构域内的氨基酸 511-599。我们报告说，VCAM-1-D6 Ab 阻断了 U937 细胞跨激活的 HUVEC 的迁移，但没有改变 U937 细胞与 HUVEC 的粘附。我们还证明 VCAM-1-D6 不会改变 TNF-α 刺激的内皮细胞趋化因子或细胞因子的产生。此外，通过使用小鼠胰岛同种异体移植模型进行体内功效测试，我们证明 VCAM-1-D6 通过阻止白细胞浸润到移植胰岛来显着减轻同种异体移植排斥。综上所述，我们的结果表明 VCAM-1-D6 Ab 可以阻断 VCAM-1 介导的炎症，并可能成为治疗炎症性疾病的有用工具。免疫学杂志，2012，189：4592-4601。
VCAM-1 plays a key role in leukocyte trafficking during inflammatory responses. However, molecular mechanisms underlying this function have not been clearly elucidated. In this study, using phage display technology, we developed a rabbit/human chimeric VCAM-1 Ab, termed VCAM-1 domain 6 (VCAM-1-D6), which specifically recognizes aa 511-599 within the sixth Ig-like domain. We report that the VCAM-1-D6 Ab blocked U937 cell transmigration across activated HUVECs but did not alter adhesion of U937 cells to the HUVECs. We also demonstrate that VCAM-1-D6 does not alter TNF-alpha-stimulated endothelial cell chemokine or cytokine production. Furthermore, through in vivo efficacy testing using a mouse islet allograft model, we demonstrate that VCAM-1-D6 significantly alleviates allograft rejection by blocking leukocyte infiltration to the grafted islets. Taken together, our results suggest that the VCAM-1-D6 Ab may block VCAM-1-mediated inflammation and could be a useful tool in treating inflammatory diseases. The Journal of Immunology, 2012, 189: 4592-4601.