生物谷援引華文生技網(wǎng)報(bào)道：美國(guó)伊利諾斯大學(xué)生化教授David M. Kranz最近在Nature Medicine上發(fā)表文章聲稱獲得一種治療腸毒素B感染的新方法,。腸毒素B是一種由金黃色葡萄球菌產(chǎn)生的毒素,，是導(dǎo)致食物中毒的常見(jiàn)原因之一。金黃色葡萄球菌腸毒素B（SEB）是超級(jí)抗原,，在人體和其它動(dòng)物體內(nèi)引起劇烈的免疫反應(yīng),，與T細(xì)胞受體的可變區(qū)結(jié)合,，導(dǎo)致一系列級(jí)聯(lián)反應(yīng)事件，包括釋放各類細(xì)胞因子,，如IL-1,，IL-6等，甚至因過(guò)度免疫反應(yīng)導(dǎo)致中毒或死亡的發(fā)生,。
研究小組利用細(xì)胞工程學(xué)手段得到一種新的蛋白,，這種蛋白的結(jié)構(gòu)與SEB靶向的T細(xì)胞受體結(jié)合位點(diǎn)相似。研究人員通過(guò)將蛋白表達(dá)在酵母細(xì)胞表達(dá)（“酵母展示”），并制造突變使蛋白與SEB的結(jié)合更牢固,。通過(guò)多輪突變和篩選之后獲得一種新的可溶蛋白,，它與SEB的親和力達(dá)到最開始的一百萬(wàn)倍。 這一發(fā)現(xiàn)意味著這種蛋白在體內(nèi)可以阻止中毒癥狀的發(fā)作,。
Kranz教授 說(shuō)：“毒素和T細(xì)胞結(jié)合是關(guān)鍵,。如果阻斷毒素與T細(xì)胞受體結(jié)合，就能預(yù)防免疫級(jí)聯(lián)反應(yīng)的開始,。”
動(dòng)物實(shí)驗(yàn)表明,，這種蛋白能明顯抑制接觸過(guò)SEB的兔子的中毒癥狀。與目前臨床常用的SEB抗體相比,，這種蛋白既有優(yōu)勢(shì)也有劣勢(shì),。優(yōu)勢(shì)在于這利蛋白分子非常小，不到抗體的1/10,，這種體積能夠深入到組織深處,，激發(fā)免疫反應(yīng)的幾率降低，還能被大腸桿菌表達(dá),，因此可以非常廉價(jià)地生產(chǎn)這種蛋白,。另一方面，抗體能夠在體內(nèi)保持?jǐn)?shù)天至數(shù)周,，這種新蛋白在體內(nèi)作用的周期不到1h,。但無(wú)論如何，這種蛋白將來(lái)有可能會(huì)成為SEB治療中的一種新的選擇,。
原始出處：
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 [email protected] 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.
