Establishment of a spontaneous single gene model for Sjogren's syndrome

干燥综合征自发单基因模型的建立

• 批准号: 07557032
• 负责人: TSUBATA Takeshi
• 金额: $ 1.28万
• 依托单位: Tokyo Medical and Dental University (1996)Kyoto University (1995)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557032/
• 关键词: aly mouse; autoimmune disease; exocrine organs; Sjogren's syndrome; CD4^+ T cells; IL-10; animal model; chronic pancreatitis; 自己免疫

Mice homozygous for an autosomal recessive mutation aly (alymphoplasia) lack both lymph nodes and Peyer's patches, and show defects in both humoral and cellular immunity. Histopathological analysis revealed chronic inflammatory changes in exocrine organs such as the salivery gland, lacrimal gland and pancreas of the homozygotes (aly/aly) but not the heterozygotes (aly/+). In these exocrine organs, mononuclear cells consisting mainly of CD4^+ T cells infiltrate periductal areas, and, in some cases, the cell infiltration extended to lobules. Inflammatory changes were also observed in the lung of the homozygotes. Because we maintained the aly mice by mating the homozygotes with heterozygotes. Because we maintained the aly mice by mating the homozygotes with heterozygotes, the association of the inflammatory changes to homozygotes strongly suggest that the lesions are caused by aly mutation itself or the gene close to the aly gene. Since Sjogren's syndrome is characterized by diffuse lymph … More ocyte infiltration in the periductal areas of the lacrimal and salivary glands and is occasionally associated with pulmonary disease, aly/aly mice may serve as a unique single gene model of Sjogren's syndrome.The inflammatory changes in exocrine organs were transferred by a CD4^+ T cell-enriched fraction of spleen cells from homozygous animals. These results suggest that autoimmune mechanisms mediated by self-reactive T cells may be involved in the inflammatory lesions of various exocrine organs in the homozygous mice although these mice show immunodeficiency. We further assessed the role of cytokines controling Th1 differentiation such as IL-10. When we treated aly/aly mice with anti-IL-10, the severity of the inflammatory changes in the exocrine organes were significantly reduced. This result indicates that IL-10 play some roles in the pathogenesis of the inlammation of the exocrine organs in aly mice and suggests that Sjogren syndrome may be treated by blocking the activity of IL-10. Less

患有常染色体隐性突变（发育不全）的纯合小鼠缺乏淋巴结和派尔氏集结，并且表现出体液和细胞免疫缺陷，组织病理学分析显示外分泌器官（例如唾液腺、泪腺和胰腺）存在慢性炎症变化。在这些外分泌器官中，主要由单核细胞组成。的CD4^+T细胞浸润导管周围区域，并且在某些情况下，在纯合子的肺部也观察到了炎症变化，因为我们通过将纯合子与杂合子交配来维持aly小鼠。通过将纯合子与杂合子交配来维持 aly 小鼠，炎症变化与纯合子的关联强烈表明病变是由 aly 突变引起的由于干燥综合征的特征是泪腺和唾液腺导管周围区域的弥漫性淋巴细胞浸润，并且偶尔与肺部疾病相关，因此 aly/aly 小鼠可能作为一种独特的单一基因。干燥综合征的基因模型。外分泌器官的炎症变化是由来自纯合动物的脾细胞的富含CD4^+T细胞的部分转移的。结果表明，尽管这些小鼠表现出免疫缺陷，但由自身反应性 T 细胞介导的自身免疫机制可能参与了各种外分泌器官的炎症病变。我们用抗IL-10治疗aly/aly小鼠，外分泌器官炎症变化的严重程度显着减轻，这一结果表明IL-10在发病机制中发挥了一定作用。小鼠外分泌器官的炎症表明干燥综合征可以通过阻断 IL-10 的活性来治疗。

项目成果

Masahiko Nishimura: "The SMXA: A new set of recombinant strains of mice consisting of 26 substrains and their genetic profile." Mammal. Genome. 6. 850-857 (1995)

Masahiko Nishimura：“SMXA：一组新的重组小鼠品系，由 26 个亚品系及其遗传图谱组成。”

Sazuku Nisitani: "Administration of interleukins 5 or 10 activates peritoneal B-1 cells and induces autoimmune hemolytic anemia in anti-erythrocyte autoantibody transgenic mice." Europian Journal of Immunology. 25. 3047-3052 (1995)

Sazuku Nisitani：“在抗红细胞自身抗体转基因小鼠中，给予白细胞介素 5 或 10 会激活腹膜 B-1 细胞并诱导自身免疫性溶血性贫血。”

Masao Murakami: "Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells." International Immunology. 7. 877-882 (1995)

Masao Murakami：“通过消除 B-1 细胞来预防有自身免疫倾向的小鼠的自身免疫症状。”

Tsubata, R.: "Autoimmune Disease of Exocrine Organs in Immunodeficient alymphoplasia mice : a spontaneous model for Sjogren's syndrome." Eur.J.Immunol.26. 2742-2748 (1996)

Tsubata, R.：“免疫缺陷性淋巴发育不全小鼠外分泌器官的自身免疫性疾病：干燥综合征的自发模型。”

Furukawa, M.: "T cell receptor repertoire of infiltrating T cells in lachrymal glands, salivary glands, and kidneys from alymphoplasia (aly) mutant mice : a new model for Sjogren's syndrome." Br.J.Rheumatol.35. 1223-1230 (1996)

Furukawa, M.：“来自发育不全（aly）突变小鼠的泪腺、唾液腺和肾脏中浸润性 T 细胞的 T 细胞受体库：干燥综合征的新模型。”