FTY720, an immunosuppressant, attenuates chronic pancreatitis in rats by suppressing T-cell infiltration
FTY720, an immunosuppressant, attenuates chronic pancreatitis in rats by suppressing T-cell infiltration
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DOI：
10.1097/01.mpa.0000157386.15898.3a
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发表时间：
2005-04-01
期刊：
影响因子：
2.9
通讯作者：
Itoh, M
中科院分区：
文献类型：
--
作者：
Okamoto, T;Yamada, T;Itoh, M
目的：FTY 720是一种新型的合成免疫抑制剂，通过加速外周血淋巴细胞归巢至外周淋巴结、肠系膜淋巴结和派尔集合淋巴结来减少外周血淋巴细胞。我们以前报道，他克莫司，另一种免疫抑制剂，减轻慢性胰腺炎，抑制T细胞浸润雄性Wistar波恩/Kobori大鼠，但也可能导致毒性。为了评估FTY 720对相同模型中胰腺炎症和纤维化发展的影响，将溶解在生理盐水中的药剂皮下注射到10周龄的雄性WBN/Kob大鼠10周。方法：评估炎症和纤维化的参数，并通过RT-PCR测定胰腺中的干扰素-γ和转化生长因子-β 1 mRNA。FTY 720治疗减弱了胰腺的总体变化，包括色素沉着和萎缩。胰腺重量显著增加，胰腺髓过氧化物酶活性（粒细胞浸润指数）、胰腺羟脯氨酸含量（胶原沉积指数）、纤维组织比率和组织学评分降低，定量证实了这种保护作用。FTY 720几乎完全阻止了盐水组中CD 4和CD 8阳性T细胞向胰腺中的明显浸润，FTY 720还抑制了胰腺中干扰素和转化生长因子β 1 mRNA的过表达。我们的结论是FTY 720通过抑制CD 4-和CD 8-的浸润来预防胰腺炎症和纤维化。阳性T细胞和通过下调胰腺中干扰素和转化生长因子-β 1 mRNA的诱导。
Objectives: FTY720, a novel synthetic immunosuppressant, decreases peripheral blood lymphocytes by accelerating their homing to the peripheral and mesenteric lymph nodes and Peyer's patches. We previously reported that tacrolimus, another immunosuppressant, attenuates chronic pancreatitis by suppressing T-cell infiltration in male Wistar Bonn/Kobori rats but also may cause toxicity. To assess the effects of FTY720 on the development of pancreatic inflammation and fibrosis in the same model, the agent dissolved in physiologic saline was subcutaneously injected to 10-week-old male WBN/Kob rats for 10 weeks.Methods: Parameters for inflammation and fibrosis were assessed and interferon-gamma and transforming growth factor-beta 1 mRNA in the pancreas were determined by RT-PCR.Results: Treatment with FTY720 attenuated gross alterations in the pancreas, including pigmentation and atrophy. This protective effect was quantitatively confirmed by significant increase in pancreatic weights and decreases in pancreatic myeloperoxidase activity ( an index of granulocyte infiltration), pancreatic hydroxyproline content (an index of collagen deposition), ratio of fibrous tissue, and histologic scores. The obvious infiltration of CD4- and CD8-positive T cells into the pancreas in the saline group was almost completely prevented by administration of FTY720, which also suppressed overexpression of interferon and transforming growth factor-beta 1 mRNA in the pancreas.Conclusion: We conclude that FTY720 prevents pancreatic inflammation and fibrosis by suppressing infiltration of CD4- and CD8-positive T cells and by downregulating induction of interferon and transforming growth factor-beta 1 mRNA in the pancreas.