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

常染色体隐性突变aly（淋巴发育不全）纯合子小鼠缺乏淋巴结和派尔集合淋巴结，并表现出体液和细胞免疫缺陷。组织病理学分析显示，纯合子（aly/aly）的唾液腺、泪腺和胰腺等外分泌器官出现慢性炎症改变，而杂合子（aly/+）则无此改变。在这些外分泌器官中，主要由CD 4 ^+ T细胞组成的单核细胞浸润导管周围区域，在某些情况下，细胞浸润延伸至小叶。在纯合子的肺中也观察到炎症变化。因为我们通过纯合子与杂合子交配来维持aly小鼠。因为我们通过将纯合子与杂合子交配来维持aly小鼠，所以炎症变化与纯合子的关联强烈地表明病变是由aly突变本身或与aly基因接近的基因引起的。由于干燥综合征的特点是弥漫性淋巴 ...更多信息 aly/aly小鼠的泪腺和唾液腺导管周围区域存在CD 4 + T细胞浸润，偶尔与肺部疾病相关，因此aly/aly小鼠可作为干燥综合征的独特单基因模型。这些结果表明，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纯合子小鼠的炎症病变，虽然这些小鼠表现出免疫缺陷。我们进一步评估了控制Th 1分化的细胞因子如IL-10的作用。当我们用抗IL-10治疗aly/aly小鼠时，外分泌器官中炎症变化的严重程度显著降低。这一结果表明IL-10在小鼠外分泌器官炎症的发病机制中发挥了一定作用，并提示可以通过阻断IL-10的活性来治疗干燥综合征。少

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。”

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。”

Tsubata,R.: "Autoimmune Disease of Exocrine Organs in Immunodeficient alymphoplasia mice : a spontaneous model 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：自发模型干燥综合征。”

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。”