Screening of biological response modifiers (BRMs) for preventive effects on type 1 diabetes mellitus in animal models.

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。本研究筛选了临床上使用或可能使用的其他BRM对动物模型的预防作用，共筛选出15种BRM。3个来自细菌来源; OK-432、N-CWS和LPS：4个来自植物来源;香菇多糖、PSK、甘草甜素和乌苯美司; 1个合成产物; Lobebzarit二钠（CCA）; 7个重组细胞因子;人IL-1 α、人IL-2、人TNF α、小鼠TNF α、人TNF β、小鼠IFN γ、小鼠GM-CSF。在非细胞因子BRMS中，OK-432，LPS和香菇多糖可明显抑制NOD小鼠IDDM的发生。N-CWS的抑制作用较弱。PSK、甘草甜素、乌苯美司和CCA对NOD小鼠的糖尿病无抑制作用，但其最佳剂量尚未确定。在各种细胞因子中，只有人和小鼠TNF α显著抑制NOD小鼠中的IDDM。然而，其他细胞因子的剂量效应没有得到彻底的评价。TNF β的作用正在进行中。OK-432和TNF-α对NOD小鼠和BB大鼠的糖尿病均有抑制作用，这些结果表明，不同的BRM对人的胰岛素依赖型糖尿病可能有治疗作用，细菌和植物来源的环境因素可能对遗传决定的胰岛素依赖型糖尿病有抑制作用。

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 screened other BRMS, which were clinically used or possibly to be used, for the possible preventive effects on IDDM of the animal models.Fifteen kinds of BRMs were screened. Three from the bacteria origin; OK-432, N-CWS and LPS: four from the plant origin; Lentinan, PSK, Glycyrrhizin and Ubenimex; one synthetic product; Lobebzarit disodium (CCA); seven recombinant cytokines; human IL-1alpha , human IL-2, human TNFalpha, mouse TNFalpha , human TNFbeta , mouse IFNgamma, mouse GM-CSF.Of non-eytokine BRMS, OK-432, LPS and Lentinan strongly inhibited development of IDDM in NOD mice. N-CWS had the weak inhibitory effects. PSK, Glycyrrhizin, Ubenimex and CCA had no suppressive effects on the NOD mice diabetes, although the optimal dose was not examined enough. Only human and mouse TNFalpha out of the various cytokines significantly suppressed IDDM in NOD mice. However, the dose-effect of the other cytokines was not thoroughly evaluated. The effect of TNFbeta is in progress. OK-432 and TNFalpha had the inhibitory effect on diabetes in both NOD mice and BB rats.These results indicate that the various BRMs have possible therapeutic effects on human IDDM and that the environmental factors of bacteria and plant origins may have the inhibitory effects on the genetically-determined IDDM.