生物谷援引华文生技网报道:美国伊利诺斯大学生化教授David M. Kranz最近在Nature Medicine上发表文章声称获得一种治疗肠毒素B感染的新方法。肠毒素B是一种由金黄色葡萄球菌产生的毒素,是导致食物中毒的常见原因之一。金黄色葡萄球菌肠毒素B(SEB)是超级抗原,在人体和其它动物体内引起剧烈的免疫反应,与T细胞受体的可变区结合,导致一系列级联反应事件,包括释放各类细胞因子,如IL-1,IL-6等,甚至因过度免疫反应导致中毒或死亡的发生。
研究小组利用细胞工程学手段得到一种新的蛋白,这种蛋白的结构与SEB靶向的T细胞受体结合位点相似。研究人员通过将蛋白表达在酵母细胞表达(“酵母展示”),并制造突变使蛋白与SEB的结合更牢固。通过多轮突变和筛选之后获得一种新的可溶蛋白,它与SEB的亲和力达到最开始的一百万倍。 这一发现意味着这种蛋白在体内可以阻止中毒症状的发作。
Kranz教授 说:“毒素和T细胞结合是关键。如果阻断毒素与T细胞受体结合,就能预防免疫级联反应的开始。”
动物实验表明,这种蛋白能明显抑制接触过SEB的兔子的中毒症状。与目前临床常用的SEB抗体相比,这种蛋白既有优势也有劣势。优势在于这利蛋白分子非常小,不到抗体的1/10,这种体积能够深入到组织深处,激发免疫反应的几率降低,还能被大肠杆菌表达,因此可以非常廉价地生产这种蛋白。另一方面,抗体能够在体内保持数天至数周,这种新蛋白在体内作用的周期不到1h。但无论如何,这种蛋白将来有可能会成为SEB治疗中的一种新的选择。
原始出处:
Nature Medicine (21 May 2007) Letters
Published online: 21 May 2007; | doi:10.1038/nm1584
Neutralization of staphylococcal enterotoxin B by soluble, high-affinity receptor antagonists
Rebecca A Buonpane1, 5, Hywyn R O Churchill1, Beenu Moza2, Eric J Sundberg2, Marnie L Peterson3, Patrick M Schlievert4 & David M Kranz1
1 Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.
2 Boston Biomedical Research Institute, Watertown, Massachusetts 02472, USA.
3 Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
4 Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
5 Present address: MedImmune Inc., 1 MedImmune Way, Gaithersburg, Maryland 20878, USA.
Abstract
Correspondence should be addressed to David M Kranz d-kranz@uiuc.eduExotoxins of Staphylococcus aureus belong to a family of bacterial proteins that act as superantigens by activating a large subset of the T-cell population, causing massive release of inflammatory cytokines. This cascade can ultimately result in toxic shock syndrome and death. Therapeutics targeting the early stage of the pathogenic process, when the superantigen binds to its receptor, could limit the severity of disease. We engineered picomolar binding affinity agents to neutralize the potent toxin staphylococcal enterotoxin B (SEB). A single immunoglobulin-like domain of the T-cell receptor (variable region, V) was subjected to multiple rounds of directed evolution using yeast display. Soluble forms of the engineered V proteins produced in Escherichia coli were effective inhibitors of SEB-mediated T-cell activation and completely neutralized the lethal activity of SEB in animal models. These V proteins represent an easily produced potential treatment for diseases mediated by bacterial superantigens.