In vivo function of Fas antigen in the immune system

Fas抗原在免疫系统中的体内功能

• 批准号: 07457086
• 负责人: YONEHARA Shin
• 金额: $ 4.61万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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-07457086/
• 关键词: Fas Antigen (Fas); Apoptosis; Transgenic mouse; gld mouse; Autoimmune disease; Rheumatold arthritis; glomerulonephritis; 胸腺; lprマウス; 劇症肝炎

Fas antigen (Fas/CD95) is a cell surface receptor protein that mediates apoptosis-inducing signals. To assess the role of apoptosis mediated by Fas in the development and function of T lymphocytes, we generated transgenic mice overexpreesing murine Fas (mFas) specifically on T cells in the thymus and periphery. These transgenic mice possessed less CD4^+ CD8^+ and CD4^+ CD8^- T cells in the thymus than normal mice, although the numbers of the other thymocytes did not decease. In the periphery, the overexperssed mFas does not enhance the clonal deletion of activated T cells. Thus, overexpressed murine Fas on T cells was shown to play an important role in T cell development in thymus, especially in the differentiation from immature CD4^+ CD8^+ to mature CD4^+ single-positive T cells.To analyze the function of Fas in vivo, we examined the effects of agonistic anti-Fas antibodies in mice. The intraperitoneal administration of the hamster anti-mouse Fas mAb, RK-8 which induced apoptosis both … More in vivo and in vitro, did not kill adult mice, whereas those given the another hamster anti-mouse Fas mAb, Jo2, rapidly die of fulminant hepatitis with hemorrhage. Histological analyzes of mice given RK-8 indicated severe damage of the thymus and moderate damage of the spleen and liver. Most of the thymocytes and some hepatocytes underwent apoptosis within one day of administration. At day 7 after administration, the thymus was atrophied. These in vivo effects of RK-8 were transient ; the thymus was regenerated, and the liver and spleen were apparently normaal one month after injection. These results indiated that functional Fas, which introduces the death signal in vivo, is expresses on thymocytes, CD4-positive splenocytes, and some mouse hepatocytes. Then, anti-Fas mAb RK-8 was administrated into MRL-gld/gld mice, and the autoimmune mice were thoroughly recovered from glomerulonephritis, arthritis, sialadenitis, vasculitis, and lymphoadenoathy. The serum level of autoantibodies were decreased and the all therapeutic effects of RK-8 persisted for over 6 months. These findings suggest that the systemic administration of agonistic anti-Fas antibody is a useful therapeutic strategy for treating systemic autoimmune disease. Less

Fas 抗原 (Fas/CD95) 是一种介导细胞凋亡诱导信号的细胞表面受体蛋白。为了评估 Fas 介导的细胞凋亡在 T 淋巴细胞发育和功能中的作用，我们培育了转基因小鼠，它们在胸腺和外周的 T 细胞上过度表达鼠 Fas (mFas)。这些转基因小鼠的胸腺中CD4^+CD8^+和CD4^+CD8^-T细胞比正常小鼠少，但其他胸腺细胞的数量没有减少。在外周，过度表达的 mFas 不会增强活化 T 细胞的克隆删除。因此，T细胞上过表达的鼠Fas被证明在胸腺T细胞发育中发挥重要作用，特别是在未成熟CD4^+CD8^+向成熟CD4^+单阳性T细胞的分化中。为了分析Fas在体内的功能，我们检查了激动性抗Fas抗体在小鼠中的作用。腹腔注射仓鼠抗小鼠 Fas mAb RK-8 在体内和体外均可诱导细胞凋亡，但不会杀死成年小鼠，而给予另一种仓鼠抗小鼠 Fas mAb Jo2 的小鼠则迅速死于暴发性肝炎并出血。对给予 RK-8 的小鼠进行组织学分析表明胸腺严重受损，脾脏和肝脏中度受损。大多数胸腺细胞和一些肝细胞在给药一天内发生凋亡。给药后第7天，胸腺萎缩。 RK-8 的这些体内作用是短暂的；注射1个月后，胸腺再生，肝、脾明显正常。这些结果表明，在体内引入死亡信号的功能性Fas在胸腺细胞、CD4阳性脾细胞和一些小鼠肝细胞上表达。然后，将抗Fas mAb RK-8给予MRL-gld/gld小鼠，自身免疫小鼠的肾小球肾炎、关节炎、唾液腺炎、血管炎和淋巴结病彻底康复。血清自身抗体水平降低，RK-8的所有治疗效果持续6个月以上。这些发现表明，激动性抗 Fas 抗体的全身给药是治疗全身性自身免疫性疾病的有用治疗策略。较少的

项目成果

Kazuhiro Sakamaki, Hisahiro Yoshida, Yoshiko Nishimura, Shin-ichi Nisikawa, Noboru Manabe, and Shin Yonehara.: "Involvement of Fas antigen in ovarian follicular atresia and luteolysis." Molecular Reproduction and Development. (in press). (1997)

Kazuhiro Sakamaki、Hisahiro Yoshida、Yoshiko Nishimura、Shin-ichi Nisikawa、Noboru Manabe 和 Shin Yonehara：“Fas 抗原参与卵巢卵泡闭锁和黄体溶解”。

Yoshiko Nishimura: "Expression and Function of Mouse Fas Antigen on Immature and Mature T Cells" The Journal of Immunology. 154. 4395-4403 (1995)

Yoshiko Nishimura：“小鼠 Fas 抗原在未成熟和成熟 T 细胞上的表达和功能”免疫学杂志。

Kazuhiro Sakamaki: "Involvement of Fas antigen in ovarian follicular atresia and luteolysis" Molecular Reproduction and Development. (in press).

Kazuhiro Sakamaki：“Fas 抗原参与卵巢卵泡闭锁和黄体溶解”分子生殖和发育。

Yosshiko Nishimura, Yoko Hirabayashi, Yumi Matsuzaki, Philippe Musette, Ai Ishii, Hiromitsu Nakauchi, Tohru Inoue, and Shin Yonehara.: "In vivo analysis of Fas antigen-mediated apoptosis : effects of agonistic anti-mouse Fas mAb on thymus, spleen and live

Yosshiko Nishimura、Yoko Hirabayashi、Yumi Matsuzaki、Philippe Musette、Ai Ishii、Hiromitsu Nakauchi、Tohru Inoue 和 Shin Yonehara。：“Fas 抗原介导的细胞凋亡的体内分析：激动性抗小鼠 Fas mAb 对胸腺、脾脏和

Yoshiko Nishimura: "In vivo analysis of Fas antigen-mediated apoptosis : effects of agonistic anti-mouse Fas mAb on thymus,spleen and liver" International Immunology. 9(2). 307-316 (1997)

Yoshiko Nishimura：“Fas 抗原介导的细胞凋亡的体内分析：激动性抗小鼠 Fas 单克隆抗体对胸腺、脾脏和肝脏的影响”国际免疫学。