Wang Shixuan, Boonman Zita F H M, Li Hao-Chuan, He YuGuang, Jager Martine J, Toes Rene E M, Niederkorn Jerry Y
Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
J Immunol. 2003 Sep 15;171(6):2789-96. doi: 10.4049/jimmunol.171.6.2789.
Although the anterior chamber of the eye expresses immune privilege, some ocular tumors succumb to immune rejection. Previous studies demonstrated that adenovirus-induced tumors, adenovirus type 5 early region 1 (Ad5E1), underwent immune rejection following transplantation into the anterior chamber of syngeneic mice. Intraocular tumor rejection required CD4(+) T cells, but did not require the following: 1) CD8(+) T cells, 2) B cells, 3) TNF, 4) perforin, 5) Fas ligand, or 6) NK cells. This study demonstrates that CD4(+) T cell-dependent tumor rejection does not occur in IFN-gamma-deficient mice. Ad5E1 tumor cells expressed DR5 receptor for TRAIL and were susceptible to TRAIL-induced apoptosis. Although IFN-gamma did not directly induce apoptosis of the tumor cells, it rendered them 3-fold more susceptible to TRAIL-induced apoptosis. Both CD4(+) T cells and corneal endothelial cells expressed TRAIL and induced apoptosis of Ad5E1 tumor cells. The results suggest that Ad5E1 tumor rejection occurs via TRAIL-induced apoptosis as follows: 1) tumor cells express TRAIL-R2 and are susceptible to TRAIL-induced apoptosis, 2) IFN-gamma enhances TRAIL expression on CD4(+) T cells and ocular cells, 3) IFN-gamma enhances tumor cell susceptibility to TRAIL-induced apoptosis, 4) apoptotic tumor cells are found in the eyes of rejector mice, but not in the eyes of IFN-gamma knockout mice that fail to reject intraocular tumors, 5) CD4(+) T cells and corneal endothelial cells express TRAIL and induce apoptosis of tumor cells, and 6) apoptosis induced by either CD4(+) T cells or corneal cells can be blocked with anti-TRAIL Ab.
尽管眼球前房表现出免疫赦免，但一些眼部肿瘤仍会被免疫排斥。先前的研究表明，腺病毒诱导的肿瘤，即5型腺病毒早期区域1（Ad5E1），在移植到同基因小鼠的前房后会发生免疫排斥。眼内肿瘤排斥需要CD4(+) T细胞，但不需要以下细胞或分子：1）CD8(+) T细胞，2）B细胞，3）肿瘤坏死因子（TNF），4）穿孔素，5）Fas配体，或6）自然杀伤细胞（NK细胞）。本研究表明，在干扰素-γ（IFN-γ）缺陷的小鼠中不会发生CD4(+) T细胞依赖性肿瘤排斥。Ad5E1肿瘤细胞表达肿瘤坏死因子相关凋亡诱导配体（TRAIL）的DR5受体，并且对TRAIL诱导的凋亡敏感。尽管IFN-γ不会直接诱导肿瘤细胞凋亡，但它使肿瘤细胞对TRAIL诱导的凋亡敏感性增加了3倍。CD4(+) T细胞和角膜内皮细胞均表达TRAIL，并诱导Ad5E1肿瘤细胞凋亡。结果表明，Ad5E1肿瘤排斥通过TRAIL诱导的凋亡发生如下：1）肿瘤细胞表达TRAIL-R2并对TRAIL诱导的凋亡敏感，2）IFN-γ增强CD4(+) T细胞和眼部细胞上TRAIL的表达，3）IFN-γ增强肿瘤细胞对TRAIL诱导凋亡的敏感性，4）在排斥肿瘤的小鼠眼中发现凋亡的肿瘤细胞，但在未能排斥眼内肿瘤的IFN-γ基因敲除小鼠眼中未发现，5）CD4(+) T细胞和角膜内皮细胞表达TRAIL并诱导肿瘤细胞凋亡，6）CD4(+) T细胞或角膜细胞诱导的凋亡可被抗TRAIL抗体阻断。
