Satoh J, Seino H, Shintani S, Tanaka S, Ohteki T, Masuda T, Nobunaga T, Toyota T
Third Department of Internal Medicine, Tohoku University School of Medicine, Miyagi, Japan.
J Immunol. 1990 Sep 1;145(5):1395-9.
We previously reported that streptococcal preparation (OK-432), which is a TNF inducer, inhibits insulitis and development of autoimmune diabetes in nonobese diabetic (NOD) mice and Bio-Breeding (BB) rats, as animal models of insulin-dependent diabetes mellitus. We have recently shown that recombinant human (h)TNF-alpha also suppresses development of diabetes in NOD mice. In this study we have extended our observation on TNF to BB rats in order to see whether TNF generally inhibits autoimmune diabetes. A total of 5 x 10(4) U of rhTNF-alpha was administered i.p., twice a week to male and female BB rats from 4 to 27 wk of age. The cumulative incidence of diabetes by 27 wk of age in nontreated rats was 36.4% (8/22), whereas that in hTNF-alpha-treated rats was 0% (0/21) (p less than 0.001). The hTNF-alpha-treated rats did not lose body weight and maintained normal blood glucose concentrations. Immunologic and histologic examinations were performed at the end of the experiment. Spleen cell cytotoxicities for NK-sensitive YAC-1 and rat insulinoma (RINm5F) cells in hTNF-alpha-treated rats significantly decreased in comparison with nontreated and nondiabetic BB rats. Intensity of insulitis was also inhibited in hTNF-alpha-treated rats. Interestingly, a huge hepatomegaly and splenomegaly was found in two of the 21 hTNF-alpha-treated rats. The latter consisted of W3/13dull+ and W3/25dull+ cells, which did not exhibit cytotoxicity for either YAC-1 or RINm5F cells. These results indicate that the chronic and systemic administration of TNF has a regulatory role in autoimmune diabetes in BB rats as well as in NOD mice, and that these animals may have a defect in TNF-mediated immunoregulation.
我们之前报道过，作为胰岛素依赖型糖尿病动物模型，链球菌制剂（OK-432）是一种肿瘤坏死因子（TNF）诱导剂，可抑制非肥胖糖尿病（NOD）小鼠和生物繁殖（BB）大鼠的胰岛炎及自身免疫性糖尿病的发展。我们最近发现，重组人（h）TNF-α也能抑制NOD小鼠糖尿病的发展。在本研究中，我们将对TNF的观察扩展至BB大鼠，以探究TNF是否普遍抑制自身免疫性糖尿病。从4至27周龄，每周两次腹腔注射总计5×10⁴U的rhTNF-α给雄性和雌性BB大鼠。27周龄时，未治疗大鼠的糖尿病累积发病率为36.4%（8/22），而hTNF-α治疗大鼠的发病率为0%（0/21）（p<0.001）。hTNF-α治疗的大鼠体重未减轻，血糖浓度维持正常。实验结束时进行了免疫学和组织学检查。与未治疗及非糖尿病BB大鼠相比，hTNF-α治疗大鼠的脾细胞对NK敏感的YAC-1和大鼠胰岛素瘤（RINm5F）细胞的细胞毒性显著降低。hTNF-α治疗大鼠的胰岛炎强度也受到抑制。有趣的是，在21只hTNF-α治疗的大鼠中有两只出现了巨大的肝肿大和脾肿大。后者由W3/13迟钝⁺和W3/25迟钝⁺细胞组成，对YAC-1或RINm5F细胞均无细胞毒性。这些结果表明，TNF的慢性全身给药对BB大鼠以及NOD小鼠的自身免疫性糖尿病具有调节作用，并且这些动物可能在TNF介导的免疫调节方面存在缺陷。
