Investigation of the involvement of immunity in the spontaneously occurring chronic pancreatitis in male Wisar Bonn/Kobori rats and human.
| Project/Area Number |
12670507
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Nagoya City University |
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Principal Investigator |
YAMADA Tamaki Nagoya City University Medical School, Associate Professor, 医学部, 助教授 (20295588)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAZAWA Takahiro Nagoya City University Medical School, Research Associate, 医学部, 助手 (70305522)
OHARA Hirotaka Nagoya City University Medical School, Assistant Professor, 医学部, 講師 (80285212)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | chronic pancreatitis / apoptosis / T cell / sex hormones / androgen receptor antagonist / Tacrolimus / T cell / 自己免疫疾患 / 自然発症 / 膵腺房細胞 / FK506 |
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| Research Abstract |
In the first part of the present study, we purposed to assess the immunologic mechanism and investigated T-cell association with acinar cell apoptosis and a preventive effect of tacrolimus, a T-cell suppressant, on the development o chronic pancreatitis in male WBN/Kob rats. At 15 week, cellular infiltrates composed of F4/80 positive cells (=monocytes/macrophages), CD4 positive cells, and CD8 positive cells were extensive in the interlobular connective tissue and parenchyma. In particular, CD8 positive cells invaded pancreatic lobules and formed close associations with acinar cells, some of which demonstrated features of apoptosis. Repeated subcutaneous injection of tacrolimus for 10 weeks completely prevented the occurrence of acinar cell apoptosis, infiltration of CD4 and CD8 positive cells, and development of pancreatitis at the age of 20 weeks.
The second study was conducted with the aim of : 1) quantitatively determining the influence of estradiol on acinar cell apoptosis and chron
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ic pancreatitis ; and 2) assessing the mechanism of its protection. Treatment with estradiol for 10 weeks significantly decreased the number of apoptotic acinar cells stained with an anti-single strand DNA antibody, histological scores, and pancreatic MPO activity at 20 week old WBN/Kob rats as compared with the control values. It also significantly attenuated the increase in pancreatic hydroxyproline content, an indicator of collagen deposition, at 20 weeks. Estradiol caused significant decrease in the numbers of CD4 and CD8 T cells in the pancreas. Estradiol significantly reduced 1 % phytohemagglutinin-induced incorporation of BrdU into the splenocytes in vitro. Androgen receptors could not be immunohistochemically identified in the pancreas at 20 weeks and dietary treatment with flutamide did not influence the chronic pancreatitis.
We also tried to induce chronic pancreatitis in male Wistar rats by intravenously injecting splenocytes derived from 20 week old male WBN/Kob rats and to assess the gene expression by RT-PCR in the biopsy samples obtained from the human pancreas using endoscopic ultrasound technique. However, these trials has resulted in failure.
In conclusion, we demonstrated that T cells, possibly CD8 positive cells, are involved in inducing apoptosis of acinar cells and raises the possibility that tacrolimus might find clinical application in the treatment of autoimmune chronic pancreatitis and that estradiol dose-dependently attenuates acinar cell apoptosis and development of chronic pancreatitis by suppressing infiltration and function of T cells. We are still conducting the investigations regarding the pathogenesis of chronic pancreatitis by assessing the effect of new drug on the chronic pancreatitis and pancreatic fibrosis in the present model. Less
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Report
(3 results)
Research Products
(3 results)
