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Study on mechanism of action of biological response modifier (BRM) in prevention of type 1 diabetes mellitus.

生物反应调节剂（BRM）预防1型糖尿病的作用机制研究。

基本信息

批准号：
63570520
负责人：
SATOH Jo
金额：
$ 1.28万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-63570520/
关键词：
Type 1 diabetes IDDM NOD mice BB rats Immunotherapy biological response modifier OK-432 Tumor necrosis factor シクロホスファミド OK-432 TNF IDDM

项目摘要

We previously reported that a streptococcal preparation (OK-432), a non-immunosuppressive biological response modifier (BRM), inhibited insulitis and development of insulin-dependent diabetes mellitus (IDDM) in NOD mice and BB rats as animal models of IDDM. In this study we analyzed the mechanism of action of BRM in the inhibition of IDDM by using OK-432 and the animal models. The following results were obtained.1. Administration of OK-432 to NOD mice inhibited the generation of effector cells for the pancreatic B cell destruction. However, the same treatment did not suppress the induction of cytotoxic T lymphocytes directed against allogenous tumor cells and the production of anti-SRBC antibody.2. NOD mice sera after intravenous injection of OK-432 also suppressed development of IDDM in NOD mice. These sera contained approximately 25 U/ml of TNF, but not detectable IL-1, IL-2 and IFN gamma with a bioassay. The 0K-432 sera lost the suppressive effect on diabetes after the treatment with anti-TNF antibody.3. Recombinant human and mouse TNFalpha significantly inhibited diabetes in both NOD mice and BB rats.4. NOD mice had not only the effector cells, but also L3T4-positive suppressor T lymphocytes for the pancreatic B cell destruction.These results showed a rationale for the possible therapeutic use of BRMs to human IDDM and indicate that the various BRMs in the natural environment may have inhibitory effect on the development of genetically-determined IDDM.

我们先前报道了一种非免疫抑制生物反应调节剂(BRM)-链球菌制剂(OK-432)，可以抑制作为IDDM动物模型的NOD小鼠和BB大鼠的胰岛素依赖型糖尿病(IDDM)的发生和发展。本研究利用OK-432细胞模型和动物模型分析了BRM抑制IDDM的作用机制。取得了以下研究成果：1.给NOD小鼠注射OK-432可抑制破坏胰腺B细胞的效应细胞的产生。然而，相同的处理并不能抑制针对同种异体肿瘤细胞的细胞毒性T淋巴细胞的诱导和抗SRBC抗体的产生。NOD小鼠静脉注射OK-432后的血清也能抑制NOD小鼠IDDM的发生。这些血清含有约25U/ml的肿瘤坏死因子，但用生物检测不能检测到IL-1、IL-2和干扰素-γ。经抗肿瘤坏死因子抗体治疗后，0K-432血清失去对糖尿病的抑制作用。重组人和小鼠肿瘤坏死因子α对NOD小鼠和BB大鼠的糖尿病均有明显的抑制作用。NOD小鼠不仅具有破坏胰腺B细胞的效应细胞，而且存在L3T4阳性的抑制T细胞，这些结果为BRM治疗人类IDDM提供了可能的理论基础，并表明自然环境中的各种BRM可能对遗传决定的IDDM的发生具有抑制作用。