Basic study on prevention and treatment of type 1 diabetes mellitus with biological respomse modifiers.

我们之前报道了一种链球菌制剂（OK-432），一种BRMs，在NOD小鼠中抑制胰岛素炎并预防胰岛素依赖性（1型）糖尿病（IDDM）。在这个项目中，我们将之前的观察扩展到两个研究；1)作为另一种IDDM模型的OK-432对BB大鼠IDDM的影响；2)通过nod小鼠分析OK-432的作用机制。研究结果和结论如下：1) BB大鼠30周龄时糖尿病的累计发病率为27.7%(13/47)，而每周并腹腔注射0.2 mg OK-432的大鼠糖尿病的累计发病率为7.4% （4/54,p<0.01）。组织学检查显示，与未处理的大鼠相比，ok -432处理的BB大鼠保留了更多未见淋巴细胞浸润的完整胰岛。与未处理的大鼠相比，OK-432处理的BB大鼠脾脏细胞对大鼠胰岛素瘤细胞系RIN的细胞毒活性被显著抑制，因此，OK-432处理不仅在NOD小鼠中，而且在BB大鼠中也抑制了胰岛素炎和糖尿病的发展。2)约85%未接受治疗的NOD小鼠在25周龄时患上糖尿病。另一方面，从4或5周龄到15或20周龄，每周注射（ip或iv） 0.1mg OK-432完全抑制了糖尿病的发展，即使停止OK-432治疗，这些NOD小鼠也没有发生糖尿病。环磷酰胺在未治疗的NOD小鼠中促进了糖尿病的发展，而在ok -432治疗的小鼠中没有。未处理NOD小鼠的脾细胞可转移糖尿病，而ok -432处理小鼠的脾细胞不能转移糖尿病。此外，ok -432处理小鼠的脾脏细胞抑制环磷酰胺处理小鼠糖尿病的发展，这种抑制作用被抗thy -1抗体和补体处理的细胞消除。这表明，ok -432处理抑制了诱导针对胰腺B细胞的细胞毒效应细胞，这种作用是由抑制性T细胞介导的。少

We previously reported that a streptococcal preparation (OK-432), one of BRMs, inhibited insulitis and prevented insulin-dependent (type 1) diabetes mellitus (IDDM) in NOD mice. In this project, we extended our previous observation to two studies; 1) effect of OK-432 on IDDM in BB rats as an another model of IDDM and 2) analysis of mechanisms of OK-432-action by usingNOD mice. The results and conslusions are as follows.1)The cumulative incidence of diabetes was 27.7% (13/47) by 30 weeks of age in BB rats, whereas that was significantly suppressed in the rats (7.4%, 4/54, p<0.01) who were weekly and intraperitoneally treated with 0.2 mg of OK-432. Histological examinations revealed that the OK-432-treated BB rats retained a greater number of intact islets without lymphocytic infiltrations than did thenon-treated rats. The cytotoxic activities of spleen cells directed against a rat insulinoma cell line, RIN, were significantly suppressed in the OK-432-treated BB rats as compared with tho … More se in the non-treated rats, Thus, the OK-432 treatment suppressed insulitis and inhibited development of diabetes not only in NOD mice but also in BB rats.2) Approximately 85% of the non-treated NOD mice developed diabetes by 25 weeks of age. On the other hand, the weekly injection (ip or iv) of 0.1mg of OK-432 from 4 or 5 to 15 ro 20 weeks of age completely inhibited development of diabetes and these NOD mice did not develop diabetes even after ceasing the OK-432-treatment. Cyclophosphamide enhanced the development of diabetes in thenon-treated NOD mice but not in the OK-432-treated mice. The diabetes wastransfered by the spleen cells from the non-treated NOD mice but not by the cells from the OK-432-treated mice. In addition, the spleen cells from the OK-432-treated mice inhibited the development of diabetes in the cyclophosphamide-treated mice and this inhibitory effect was eliminated by the treatment of cells with anti-Thy-1 antibody and complement. These indicate that the OK-432-treatment inhibited the induction of cytotoxic effector cells directed against pancreatic B cells and this effect was mediated by suppressor T cells. Less