Control of allograft rejection in mice by applying a novel neuropeptide, cortistatin.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Wang
Jiang
J
Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Zhao
Rong
R
Zhang
Fuqin
F
Li
Jianping
J
Huo
Binliang
B
Cao
Yunxin
Y
Dou
Kefeng
K
D000818:Animals; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007155:Immunologic Factors / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009479:Neuropeptides / Q000627:therapeutic use*; D015282:Octreotide / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007155:Immunologic Factors; D053645:Interleukin-2 Receptor alpha Subunit; D009479:Neuropeptides; C099323:cortistatin; D015282:Octreotide