Takahashi K, Satoh J, Sagara M, Zhu X P, Muto G, Muto Y, Fukuzawa M, Nishimura S, Miyaguchi S, Toyata T
Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
J Autoimmun. 1995 Jun;8(3):335-46. doi: 10.1006/jaut.1995.0026.
Recently we reported that lymphotoxin (LT) administration protected non-obese diabetic (NOD) mice and BB rats from insulin-dependent diabetes mellitus. In this study we analysed the protection mechanism of LT by using cyclophosphamide (CY)-induced autoimmune diabetes in NOD mice. Pre-administration of 500 or 1000 U of LT three times a week between the age of 4 and 11-13 weeks before CY-treatment strongly inhibited CY-induced diabetes. This inhibition was reproduced by LT pre-administration at an earlier age (4 to 7 weeks) but not at a later age (8 to 11 or 10 to 12 wks). LT post-administration (100 U daily or 500 U twice a week) after CY-treatment at 14 weeks of age also strongly inhibited CY-induced diabetes. Spleen cell transfer was carried out using various combinations of donors and recipients. Spleen cell transfer from the non-diabetic mice, which were LT pre-administered between the age of 4 and 13 wks, to CY-treated mice did not significantly inhibit CY-induced diabetes, while transfer of the cells from the similarly treated mice to irradiated recipients did induce diabetes although the onset of diabetes was significantly delayed. Diabetes was not transferred by spleen cells from diabetic mice to LT pre-administered and CY-treated mice. LT administration did not change subpopulations and adhesion molecule expressions of the spleen lymphocyte. Taken together, these results suggest that LT protects NOD mice from CY-induced diabetes by making the mice resistant to autoimmune diabetes and possibly by suppressing anti-islet effector cells, but not by inducing adoptively transferable suppressor cells, although the precise mechanisms still remain to be elucidated.
最近我们报道，给予淋巴毒素（LT）可保护非肥胖糖尿病（NOD）小鼠和BB大鼠免受胰岛素依赖型糖尿病的侵害。在本研究中，我们利用环磷酰胺（CY）诱导NOD小鼠发生自身免疫性糖尿病，分析了LT的保护机制。在CY治疗前，于4至11 - 13周龄之间每周三次预先给予500或1000 U的LT，可强烈抑制CY诱导的糖尿病。在更早的年龄（4至7周）预先给予LT可重现这种抑制作用，但在较晚的年龄（8至11周或10至12周）则不能。在14周龄进行CY治疗后，给予LT（每日100 U或每周两次500 U）也可强烈抑制CY诱导的糖尿病。使用供体和受体的各种组合进行脾细胞转移。将在4至13周龄之间预先给予LT的非糖尿病小鼠的脾细胞转移至经CY治疗的小鼠，并未显著抑制CY诱导的糖尿病，而将来自同样处理小鼠的细胞转移至受照射的受体则确实诱发了糖尿病，尽管糖尿病的发病明显延迟。糖尿病小鼠的脾细胞不会将糖尿病转移至预先给予LT并经CY治疗的小鼠。给予LT并未改变脾淋巴细胞的亚群和黏附分子表达。综上所述，这些结果表明，LT通过使小鼠对自身免疫性糖尿病产生抗性并可能通过抑制抗胰岛效应细胞，而非通过诱导可转移性抑制细胞，来保护NOD小鼠免受CY诱导的糖尿病侵害，尽管确切机制仍有待阐明。
