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

我们以前曾报道过一种非免疫抑制性生物反应调节剂（BRM）链球菌制剂（OK-432），在作为胰岛素依赖性糖尿病（IDDM）动物模型的NOD小鼠和BB大鼠中抑制胰岛炎和IDDM的发展。本研究采用OK-432和动物模型分析BRM抑制胰岛素依赖型糖尿病的作用机制。得到以下结果.向NOD小鼠施用OK-432抑制了胰腺B细胞破坏的效应细胞的产生。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.静脉注射OK-432后的NOD小鼠血清也抑制NOD小鼠中IDDM的发展。这些血清含有约25 U/ml的TNF，但用生物测定法检测不到IL-1、IL-2和IFN γ。经抗TNF抗体治疗后，MK-432血清对糖尿病的抑制作用消失.重组人和小鼠TNF α显著抑制NOD小鼠和BB大鼠的糖尿病。NOD小鼠不仅有效应细胞，而且有L3 T4阳性的抑制性T淋巴细胞，对胰腺B细胞有破坏作用，这些结果为BRM治疗人胰岛素依赖型糖尿病提供了理论依据，并提示自然环境中的各种BRM对遗传决定型胰岛素依赖型糖尿病的发生发展可能具有抑制作用。

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.