Schorlemmer H U, Bosslet K, Dickneite G, Lüben G, Sedlacek H H
Behring Inst Mitt. 1984 May(74):157-73.
The effects of Bestatin, a low molecular weight metabolite of Streptomyces olivoreticuli on the human and mouse/rat immune system, have been studied in detail. To describe the activity of the immunomodulating dipeptide, it has been tested in vitro, ex vivo and in vivo in various experimental models. Bestatin simultaneously applied with selected antigens to mice was able to enhance the DTH response against a challenge injection of the respective antigen given into the footpad. Serum antibody levels against those antigens were uneffected. However, an increase of PFC could be found in those mice given high doses of Bestatin. On natural killer cell activity against Yac-1 tumor cells the dipeptide had no effect in low responder (DBA2/J) mice. In high responder mice (CBA/JCr), however, a significant increase of NK cell activity of spleen cells could be found, when the drug was given on day 0 or on days 0 to 3 and the test was performed on day 4. Bestatin had no effect on the generation of allogeneic cytotoxic T-lymphocytes in vivo or in vitro and even a suppressive effect on the induction of syngeneic antitumor CTL. Contrary to this suppressive effect, Bestatin increases in the popliteal lymph node assay the weights in a dose-dependent way. When mouse macrophages or human monocytes were either incubated in vitro with Bestatin or mice were treated with the dipeptide parenterally or orally and the macrophages from those mice were investigated, Bestatin induced in vitro and in vivo a dose-dependent increase in pinocytic uptake of radioactive colloidal gold. Also the oxidative metabolism was dose-dependently augmented as measured by chemiluminescence. Bestatin modulates the macrophage mediated cytotoxicity. In vitro or in vivo activated mononuclear phagocytes exhibited a dose-dependent increase in cytotoxic activity for several tumor target cells. A minimum ratio of 50:1 effector to target cells was necessary for this cytotoxic effect. A similar degree of activation was observed in macrophages from athymic nu/nu-mice or from endotoxin resistant C3H/HeJ-mice. Other parameters of macrophage activation were determined by measuring secretion of lysosomal enzymes and liberation of prostaglandins. Bestatin interacts with macrophages in vivo and in vitro by increasing their secretory activity of acid hydrolases (beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-D-glucosaminidase). This release was dose- and time-dependent and not associated with any sign of cell death. Another class of mediators produced by macrophages after stimulation with Bestatin were the prostaglandins E2 and F2a.(ABSTRACT TRUNCATED AT 400 WORDS)
对橄榄网状链霉菌的一种低分子量代谢产物Bestatin对人和小鼠/大鼠免疫系统的影响进行了详细研究。为描述这种免疫调节性二肽的活性，已在各种实验模型中进行了体外、离体和体内测试。将Bestatin与选定抗原同时应用于小鼠，能够增强针对足垫注射相应抗原激发注射的迟发型超敏反应（DTH）。针对这些抗原的血清抗体水平未受影响。然而，在给予高剂量Bestatin的小鼠中可发现空斑形成细胞（PFC）增加。对于针对Yac-1肿瘤细胞的自然杀伤细胞活性，该二肽在低反应性（DBA2/J）小鼠中无作用。然而，在高反应性小鼠（CBA/JCr）中，当在第0天或第0至3天给予该药物并在第4天进行测试时，可发现脾细胞的自然杀伤细胞活性显著增加。Bestatin在体内或体外对同种异体细胞毒性T淋巴细胞的产生无作用，甚至对同基因抗肿瘤细胞毒性T淋巴细胞（CTL）的诱导有抑制作用。与这种抑制作用相反，Bestatin在腘窝淋巴结试验中以剂量依赖性方式增加重量。当小鼠巨噬细胞或人单核细胞在体外与Bestatin孵育，或小鼠经该二肽经肠胃外或口服处理并研究这些小鼠的巨噬细胞时，Bestatin在体外和体内均诱导放射性胶体金的吞噬摄取呈剂量依赖性增加。通过化学发光测量，氧化代谢也呈剂量依赖性增强。Bestatin调节巨噬细胞介导的细胞毒性。体外或体内活化的单核吞噬细胞对几种肿瘤靶细胞的细胞毒性活性呈剂量依赖性增加。这种细胞毒性作用需要效应细胞与靶细胞的最小比例为50:1。在无胸腺裸鼠或对内毒素有抗性的C3H/HeJ小鼠的巨噬细胞中观察到类似程度的活化。通过测量溶酶体酶的分泌和前列腺素的释放来确定巨噬细胞活化的其他参数。Bestatin在体内和体外与巨噬细胞相互作用，通过增加其酸性水解酶（β-葡萄糖醛酸酶、β-半乳糖苷酶和N-乙酰-β-D-氨基葡萄糖苷酶）的分泌活性。这种释放是剂量和时间依赖性的，且与任何细胞死亡迹象无关。在用Bestatin刺激后巨噬细胞产生的另一类介质是前列腺素E2和F2a。（摘要截于400字）
