Cancer Research Institute, Xenotransplantation Research Center, College of Medicine, Seoul National University, Seoul 110-799, Korea.
J Immunol. 2012 Nov 1;189(9):4592-601. doi: 10.4049/jimmunol.1103803. Epub 2012 Oct 1.
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-α-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.
VCAM-1 在炎症反应期间的白细胞迁移中发挥关键作用。然而，其功能的分子机制尚未明确阐明。在这项研究中，我们使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 aa511-599。我们报告称，VCAM-1-D6 Ab 阻断了 U937 细胞穿过活化的 HUVEC 的迁移，但不改变 U937 细胞与 HUVEC 的黏附。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疗效测试，我们证明 VCAM-1-D6 通过阻断白细胞浸润移植物胰岛来显著减轻移植物排斥反应。总之，我们的结果表明，VCAM-1-D6 Ab 可能阻断 VCAM-1 介导的炎症，并且可能是治疗炎症性疾病的有用工具。
