Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Chin Med J (Engl). 2009 Aug 20;122(16):1917-21.
Chemokines and their receptors have been a research focus in transplantation immunology. Chemokines and their receptors play a role in lymphocyte recruitment and differentiation process. This study aimed to observe whether IL-4 and IL-10 may regulate the expression of chemokine receptors CCR3, CCR5 and CXCR3 on CD4(+) T cells in CBA/JxDBA/2 mouse model and to explore the role of CCR3, CCR5, CXCR3 in immune tolerance in pregnancy.
The mouse model of spontaneous abortion (CBA/JxDBA/2) and the normal pregnant mouse model (CBA/JxBALB/c) were used. CBA/JxDBA/2 mice were injected with IL-4 (CBA/JxDBA/2-IL-4), IL-4 and IL-10 (CBA/JxDBA/2-IL-4+IL-10), or normal saline (CBA/JxDBA/2-NS) as a control. The expression of CCR3, CCR5 and CXCR3 on CD4(+) T cells from mouse peripheral blood was measured by the double-labelled FCM method, and the embryo resorption rate was also examined.
The embryo resorption rate in the CBA/JxDBA/2 group without any treatment was significantly higher than that in the CBA/JxBALB/c group (17.9% vs 3.7%, P < 0.01). The embryo resorption rate in the CBA/JxDBA/2 group immunized with IL-4 or IL-4 together with IL-10 was significantly decreased, compared with that in the control and NS groups respectively. CCR3 expression on CD4(+) T cells in the CBA/JxDBA/2 group without any treatment was significantly lower than that in the CBA/JxBALB/c group (0.3738 +/- 0.3575 vs 1.2190 +/- 0.2772, P < 0.01); both CCR5 (3.0900 +/- 1.5603 vs 1.2390 +/- 0.6361, P < 0.01) and CXCR3 (2.4715 +/- 0.9074 vs 0.9200 +/- 0.5585, P < 0.01) expressions on CD4(+) T cells of the CBA/JxDBA/2 group without any treatment were significantly higher than those of the CBA/JxBALB/c group. Significant up-regulation of CCR3 and down-regulation of CXCR3 were found in the CBA/JxDBA/2 group treated with IL-4 (CCR3: 2.0360 +/- 0.6944, CXCR3: 1.3510 +/- 0.5263, P < 0.01) or IL-4 and IL-10 (CCR3: 1.8160 +/- 1.0947, CXCR3:1.0940 +/- 0.7168, P < 0.01). Because of the CCR5, IL-4 and IL-10 (1.9400 +/- 0.8504 vs 3.0900 +/- 1.5603, P < 0.05), but IL-4 alone (2.5310 +/- 1.3595 vs 3.0900 +/- 1.5603, P > 0.05) treatment significantly decreased the expression of CCR5 in CBA/JxDBA/2.
The abnormal expression of CCR3, CCR5 and CXCR3 on CD4(+) T cells may play an important role in the pathogenesis of spontaneous abortion. The pregnancy immune tolerance may be induced through selective induction of CCR3, CCR5 and CXCR3 expressions by IL-4 together with IL-10.
趋化因子及其受体一直是移植免疫研究的重点。趋化因子及其受体在淋巴细胞募集和分化过程中发挥作用。本研究旨在观察白细胞介素 4（IL-4）和白细胞介素 10（IL-10）是否可调节 CBA/JxDBA/2 小鼠模型中 CD4+T 细胞上的趋化因子受体 CCR3、CCR5 和 CXCR3 的表达，并探讨 CCR3、CCR5 和 CXCR3 在妊娠免疫耐受中的作用。
采用自发流产（CBA/JxDBA/2）和正常妊娠（CBA/JxBALB/c）小鼠模型。CBA/JxDBA/2 小鼠分别注射 IL-4（CBA/JxDBA/2-IL-4）、IL-4 和 IL-10（CBA/JxDBA/2-IL-4+IL-10）或生理盐水（CBA/JxDBA/2-NS）作为对照。用双标 FCM 法检测外周血 CD4+T 细胞上 CCR3、CCR5 和 CXCR3 的表达，并检测胚胎吸收率。
未处理的 CBA/JxDBA/2 组胚胎吸收率明显高于 CBA/JxBALB/c 组（17.9%比 3.7%，P<0.01）。用 IL-4 或 IL-4 联合 IL-10 免疫的 CBA/JxDBA/2 组胚胎吸收率明显低于对照组和 NS 组。未处理的 CBA/JxDBA/2 组 CD4+T 细胞上 CCR3 的表达明显低于 CBA/JxBALB/c 组（0.3738±0.3575 比 1.2190±0.2772，P<0.01）；CCR5（3.0900±1.5603 比 1.2390±0.6361，P<0.01）和 CXCR3（2.4715±0.9074 比 0.9200±0.5585，P<0.01）的表达也明显高于 CBA/JxBALB/c 组。用 IL-4（CCR3：2.0360±0.6944，CXCR3：1.3510±0.5263，P<0.01）或 IL-4 和 IL-10（CCR3：1.8160±1.0947，CXCR3：1.0940±0.7168，P<0.01）处理后，CCR3 表达上调，CXCR3 表达下调。由于 CCR5、IL-4 和 IL-10（1.9400±0.8504 比 3.0900±1.5603，P<0.05），但单独用 IL-4（2.5310±1.3595 比 3.0900±1.5603，P>0.05）处理后，CCR5 的表达明显降低。
CD4+T 细胞上 CCR3、CCR5 和 CXCR3 的异常表达可能在自发性流产的发病机制中起重要作用。通过 IL-4 联合 IL-10 选择性诱导 CCR3、CCR5 和 CXCR3 的表达，可能诱导妊娠免疫耐受。
