Wang Jiang, Zhao Rong, Zhang Fuqin, Li Jianping, Huo Binliang, Cao Yunxin, Dou Kefeng
Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Adv Ther. 2008 Dec;25(12):1331-41. doi: 10.1007/s12325-008-0121-z.
The action of cortistatin (CST), a novel cyclic neuropeptide, as an anti-inflammatory factor has been studied, but few investigations have explored the immunomodulatory role of CST in transplantation. In the present study, we examined whether CST affects the alloimmune response in a mouse model of skin transplantation and the effects of CST on T lymphocytes.
BALB/c (H-2K(d)) recipient mice (n=70) were divided into seven groups (n=10 per group) and given an intraperitoneal injection of CST or a somatostatin analog, SMS 201-995 (octreotide), on the day of skin transplantation from C57BL/6 (B6) (H-2K(b)) donors. Injections were continued for 7 consecutive days. Groups 1-3 received CST at doses of 0.02, 0.2, or 2 mg/kg, respectively. Groups 4-6 received SMS 201-995 at the same doses. Group 7 was a control group and received injections of phosphate buffered saline. Survival of the allografts was recorded. A semiquantitative reverse transcriptase polymerase chain reaction study of Foxp3 expression and a flow cytometry study of CD4 and CD25 markers of T lymphocytes were conducted to determine whether CD4(+)CD25(+) Foxp3(high) regulatory T cells (T(reg)) were generated in vivo.
BALB/c mice given CST (0.2 or 2 mg/kg) had prolonged graft survival (median survival time [MST], 13 and 14 days, respectively; P<0.05 compared with controls). SMS 201-995 at the same concentrations did not have a significant effect on allograft survival (MST, 8 days for both groups). We found more than a twofold increase of CD4(+)CD25(+) T(reg) cells in the CD4(+) T-cell population and the expression of Foxp3 was up-regulated in the CST treatment groups, compared with control and SMS 201-995 treatment groups.
In our study, CST induced a significant prolongation in survival time of allogeneic skin grafts and increased the generation of CD4(+)CD25(+) Foxp 3(high) T(reg) cells. These results suggest that CST may become a new modality in controlling allograft rejection.
可体松（CST）是一种新型环肽神经肽，其作为抗炎因子的作用已得到研究，但很少有研究探讨CST在移植中的免疫调节作用。在本研究中，我们检测了CST是否影响皮肤移植小鼠模型中的同种异体免疫反应以及CST对T淋巴细胞的影响。
将BALB/c（H-2K(d)）受体小鼠（n = 70）分为七组（每组n = 10），并在从C57BL/6（B6）（H-2K(b)）供体进行皮肤移植的当天腹腔注射CST或生长抑素类似物SMS 201-995（奥曲肽）。连续注射7天。第1-3组分别接受0.02、0.2或2 mg/kg剂量的CST。第4-6组接受相同剂量的SMS 201-995。第7组为对照组，接受磷酸盐缓冲盐水注射。记录同种异体移植物的存活情况。进行Foxp3表达的半定量逆转录聚合酶链反应研究以及T淋巴细胞CD4和CD25标志物的流式细胞术研究，以确定体内是否产生CD4(+)CD25(+) Foxp3(高)调节性T细胞（T(reg)）。
给予CST（0.2或2 mg/kg）的BALB/c小鼠移植物存活时间延长（中位存活时间[MST]分别为13天和14天；与对照组相比，P<0.05）。相同浓度的SMS 201-995对同种异体移植物存活没有显著影响（两组MST均为8天）。与对照组和SMS 201-995治疗组相比，我们发现CST治疗组CD4(+) T细胞群体中CD4(+)CD25(+) T(reg)细胞增加了两倍多，且Foxp3表达上调。
在我们的研究中，CST显著延长了同种异体皮肤移植物的存活时间，并增加了CD4(+)CD25(+) Foxp3(高) T(reg)细胞的产生。这些结果表明，CST可能成为控制移植物排斥反应的一种新方法。
