Gan Runliang, Yin Zhihua, Liu Tengfei, Wang Lijiang, Tang Yunlian, Song Ying
Cancer Research Institute, Medical School, Nanhua University, Hengyang 421001, China.
Cancer Sci. 2003 Sep;94(9):796-801. doi: 10.1111/j.1349-7006.2003.tb01521.x.
We previously constructed human peripheral blood lymphocyte (hu-PBL)/severe combined immunodeficiency mouse (SCID) chimeras and induced human B-cell lymphomas associated with Epstein-Barr virus (EBV) in SCID mice. However, a number of SCID mice died of graft-versus-host disease (GVHD) during the early experimental course. The aim of this study was to test the efficacy of cyclosporine A (CSA) for prevention of GVHD and to define how CSA inhibits the occurrence of GVHD and the production of soluble interleukin (IL) 2 receptor (sIL-2R) in hu-PBL/SCID mice. No mouse died in the active EBV infection group with CSA administration, while 17 mice in three groups without CSA administration died of GVHD. Mortalities in these three groups were 55.56% (5/9), 30.43% (7/23), and 27.78% (5/18), and the medium life span was 17 days. Over the first 33 days after hu-PBL transplantation, serum level of human sIL-2R in hu-PBL/SCID chimeras was stable in the active EBV infection plus CSA group, while sIL-2R concentration gradually increased in the sera of mice with active EBV infection without CSA administration and peaked at 22 days. Thirty-two mice developed tumors among the 43 surviving SCID mice. There was no significant difference of tumor incidence between the active EBV infection groups with CSA and without CSA administration (P > 0.05). From their morphological and immunohistochemical features, as well as detection of human Alu-sequence and EBV in tumor cells, these EBV-induced tumors were identified as human B-cell lymphomas. Thus, CSA can strikingly inhibit GVHD in hu-PBL/SCID chimeras, and should therefore be effective to establish a stable SCID mouse model of human lymphoma associated with EBV. Treatment with CSA had no effect on the tumor incidence in hu-PBL/SCID chimeras after active EBV infection. Accordingly, serum level of sIL-2R is a valuable indicator of GVHD occurrence in hu-PBL/SCID chimeras.
我们之前构建了人外周血淋巴细胞（hu - PBL）/重症联合免疫缺陷小鼠（SCID）嵌合体，并在SCID小鼠中诱导出与爱泼斯坦 - 巴尔病毒（EBV）相关的人B细胞淋巴瘤。然而，在早期实验过程中，许多SCID小鼠死于移植物抗宿主病（GVHD）。本研究的目的是测试环孢素A（CSA）预防GVHD的疗效，并确定CSA如何抑制hu - PBL/SCID小鼠中GVHD的发生以及可溶性白细胞介素（IL）2受体（sIL - 2R）的产生。在给予CSA的活动性EBV感染组中没有小鼠死亡，而在未给予CSA的三组中有17只小鼠死于GVHD。这三组的死亡率分别为55.56%（5/9）、30.43%（7/23）和27.78%（5/18），平均寿命为17天。在hu - PBL移植后的前33天，活动性EBV感染加CSA组中hu - PBL/SCID嵌合体的人sIL - 2R血清水平稳定，而在未给予CSA的活动性EBV感染小鼠血清中，sIL - 2R浓度逐渐升高，并在22天达到峰值。在43只存活的SCID小鼠中，有32只发生了肿瘤。给予CSA和未给予CSA的活动性EBV感染组之间的肿瘤发生率没有显著差异（P>0.05）。从肿瘤细胞的形态学和免疫组化特征以及人Alu序列和EBV的检测结果来看，这些EBV诱导的肿瘤被鉴定为人B细胞淋巴瘤。因此，CSA可以显著抑制hu - PBL/SCID嵌合体中的GVHD，因此对于建立稳定的与EBV相关的人淋巴瘤SCID小鼠模型应该是有效的。在活动性EBV感染后，用CSA治疗对hu - PBL/SCID嵌合体中的肿瘤发生率没有影响。因此，sIL - 2R血清水平是hu - PBL/SCID嵌合体中GVHD发生的一个有价值的指标。
