Immunological study of pathogenesis and fibrosis in autoimmune pancreatitis

自身免疫性胰腺炎发病机制及纤维化的免疫学研究

• 批准号: 18590755
• 负责人: OKAZAKI Kazuichi
• 金额: $ 2.46万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590755/
• 关键词: autoimmune pancreatitis; regulatory T cell; IgG4; animal model; WBN; Kob rat; 自己抗体; PSTI

Autoimmune pancreatitis (AIP) is a new clinical entity of pancreatic disorder. There are several immunologic and histologic abnormalities specific for the disease, including increased levels of serum IgG4, and infiltration of lymphocytes and IgG4-positive plasmacytes. The role of IgG4 is unclean Recently regulatory T cells (Tregs) have been reported to be involved in the development of various autoimmune diseases and B-cell shifting to IgG4. To clarify the role of Treg in pathophysiology of AIP, we analyzed circulating Tregs in AIP.We recruited 28 patients with MP for this study. For comparison, we also recruited 23 patients with various other pancreatic diseases and 32 healthy subjects as controls. We analyzed Tregs as CD4+CD25high and CD4+CD25+CD45RA+ (naive) from peripheral blood by flow cytometry. In peripheral blood, CD4+CD25high Tregs were significantly increased in AIP patients (2.99±1.75%, p<0.05) compared with alcoholic chronic pancreatitis (CP) (1.65±0.58%, p<0.05), idiopathi … More c CP (1.53±0.56%, p<0.05), and healthy control (1.72±0.81%, p<0.05). Naive Tregs significantly decreased in MP (0.32±0.22%, p<0.005) compared with healthy control (0.83±0.65%). Naive Tregs in AIP tended to be decreased compared with alcoholic CP (0.60±0.45%) and idiopathic CP (0.41±0.31%) (p=0.08). In untreated MP patients, the number of naive Tregs and IgG4 are correlated (R=0.286). Increased number of CD4+CD25high Tregs may influence IgG4 production in AIR while decreased number of naive Tregs may be involved in pathogenesis in AIP.We also established an animal model of autoimmune pancreatitis using Male Wistar Bonn/Kobori rat (WBN/Kob rat), which is a model of spontaneous chronic pancreatitis with widely distributed fibrosis and degeneration of parenchyma with the infiltration of lymphocytes. In addition to pancreatitis, we demonstrated dacryoadenitis in 3 months of age, and sialadenitis, thyroditis, sclerotic cholangitis and even tubulointerstitial nephritis in over 18 months of age of WBN/Kob rats. Infiltration of CD8^+ cells and deposition of tissue-specific IgG2b were observed in the injured pancreas and lacrymal glands. Furthermore, regulatory T cells (Tregs) defined as CD4^+Foxp3^+ cells decreased in the periphery of WBN/Kob rats, which suggests that the onset of these diseases is at least, attributable to the failure in the maintenance of peripheral immune tolerance. These features clearly show that WBN/Kob rats can be a useful animal model for autoimmune pancreatitis with Sjogren-like syndrome or multifocal fibrosclerosis in the human patients. We also show that these autoimmune diseases can be prevented with a newly devised strategy of bone marrow transplantation (BMT) where bone marrow cells (BMCs) are directly injected into the bone marrow cavity; intra BM BMT (IBM-BMT). These results identify the WBN/Kob rat as the first spontaneous animal model of human AIP and multifocal fibrosclerosis.In conclusion, we identified the role of regulatory T cells in the development of autoimmune pancreatitis in human and animal model. Less

自身免疫性胰腺炎（AIP）是胰腺疾病的一种新的临床实体。该疾病存在多种特异性免疫学和组织学异常，包括血清 IgG4 水平升高、淋巴细胞和 IgG4 阳性浆细胞浸润。 IgG4 的作用不明确 最近有报道称调节性 T 细胞 (Treg) 参与了各种自身免疫性疾病的发生以及 B 细胞向 IgG4 的转变。为了阐明 Treg 在 AIP 病理生理学中的作用，我们分析了 AIP 中的循环 Treg。我们招募了 28 名 MP 患者进行这项研究。为了进行比较，我们还招募了 23 名患有各种其他胰腺疾病的患者和 32 名健康受试者作为对照。我们通过流式细胞术分析了外周血中 CD4+CD25high 和 CD4+CD25+CD45RA+（原始）的 Tregs。在外周血中，与酒精性慢性胰腺炎（CP）（1.65±0.58%，p<0.05）、特发性CP（1.53±0.56%，p<0.05）和健康对照（1.72±0.81%，p<0.05）相比，AIP患者的CD4+CD25high Tregs显着增加（2.99±1.75%，p<0.05）。 p<0.05）。与健康对照 (0.83±0.65%) 相比，初始 Tregs 的 MP 显着下降 (0.32±0.22%，p<0.005)。与酒精性 CP (0.60±0.45%) 和特发性 CP (0.41±0.31%) 相比，AIP 中的 Naive Tregs 趋于减少 (p=0.08)。在未经治疗的 MP 患者中，初始 Tregs 和 IgG4 的数量是相关的 (R=0.286)。 CD4+CD25high Tregs数量增加可能影响AIR中IgG4的产生，而幼稚Treg数量减少可能参与AIP的发病机制。我们还使用雄性Wistar Bonn/Kobori大鼠（WBN/Kob大鼠）建立了自身免疫性胰腺炎动物模型，这是一种伴有广泛分布的纤维化和实质变性的自发性慢性胰腺炎模型 随着淋巴细胞的浸润。除胰腺炎外，我们还发现WBN/Kob大鼠在3月龄时出现泪腺炎，在18月龄以上时出现唾液腺炎、甲状腺炎、硬化性胆管炎甚至肾小管间质性肾炎。在受损的胰腺和泪腺中观察到CD8^+细胞的浸润和组织特异性IgG2b的沉积。此外，WBN/Kob 大鼠外周的调节性 T 细胞（Treg）（定义为 CD4^+Foxp3^+ 细胞）减少，这表明这些疾病的发生至少可归因于维持外周免疫耐受的失败。这些特征清楚地表明，WBN/Kob 大鼠可以成为治疗人类患者伴有干燥综合征或多灶性纤维硬化症的自身免疫性胰腺炎的有用动物模型。我们还表明，可以通过新设计的骨髓移植（BMT）策略来预防这些自身免疫性疾病，其中将骨髓细胞（BMC）直接注射到骨髓腔中； BM 内 BMT（IBM-BMT）。这些结果将 WBN/Kob 大鼠确定为人类 AIP 和多灶性纤维硬化症的第一个自发动物模型。 总之，我们确定了调节性 T 细胞在人和动物模型中自身免疫性胰腺炎发展中的作用。较少的

项目成果

Is IgG4-associated multifocal systemic fibrosis the same disease entity as autoimmune pancreatitis

IgG4相关的多灶性系统性纤维化与自身免疫性胰腺炎是同一疾病实体吗

• 发表时间: 2007
• 期刊: Intern Med. 46
• 作者: Sakaguchi Y;Inaba M;Tsuda M;Quan GK;Omae M;Ando Y;UchidaK;Okazaki IKehara S;Okazaki K.
• 通讯作者: Okazaki K.

Effects of sensory denervation by neonatal capsaicin administration on experimental pancreatitis induced by dibutyltin dichloride

新生儿辣椒素去感觉神经对二氯化二丁基锡诱发实验性胰腺炎的影响

• 发表时间: 2007
• 期刊: Med Mol Morphol 40
• 作者: Ikeura T;Kataoka Y;Takamido S;Okazaki K;Yamada H.
• 通讯作者: Yamada H.

Pancreatic cancer associated with autoimmune pancreatitis in remission

• DOI: 10.2169/internalmedicine.47.0334
• 发表时间: 2008-01-01
• 期刊: INTERNAL MEDICINE
• 影响因子: 1.2
• 作者: Fukui, Toshiro;Mitsuyama, Toshiyuki;Okazaki, Kazuichi
• 通讯作者: Okazaki, Kazuichi

PSCとAIPの免疫異常

PSC 和 AIP 的免疫异常

• 发表时间: 2007
• 期刊: 肝胆膵 54
• 作者: 岡崎 和一;内田 一茂;三好 秀明;鉢嶺 大作;松下 光伸;高岡 亮
• 通讯作者: 高岡 亮

Consensus of primary care in acute pancreatitis in Japan

日本急性胰腺炎初级保健共识

• 发表时间: 2006
• 期刊: World J Gastroenterol 12(21)
• 作者: Otsuki M;Okazaki K;et al.
• 通讯作者: et al.