A humanized transgenic mouse model for studying staphylococcal enterotoxin B

葡萄球菌肠毒素B(SEB)是由金黄色葡萄球菌产生的一种多肽外毒素。 属于一种被称为“超级抗原”的微生物蛋白质家族。SEB，直接与MHC II类结合 分子并有效激活表达某些T细胞受体(TCR)β的CD4+和CD8+T细胞 链可变区，与其抗原特异性无关。因此，SEB可引起多种临床症状 疾病范围从自限性食物中毒到更严重的中毒性休克综合征，后者可能是 致命的。由于其强大的免疫刺激特性，SEB还可用作生物恐怖主义或 生物战。然而，在我们对这一问题的理解上存在着重大的知识差距。 SEB的免疫发病机制，很大程度上归因于缺乏合适的动物模型。SEB与以下各项的结合较差 非人MHC II类分子共同导致免疫系统无效激活 并限制其在SEB研究中的使用。尽管如此，人类白细胞抗原类基因的转基因表达 小鼠体内的分子修复了这些缺陷，并显著增强了对SEB的免疫反应 通过几条不同的路线运送。忠实地复制人类疾病并适应各种 免疫学和遗传学实验使人类白细胞抗原II类转基因小鼠成为研究的理想工具 金黄色葡萄球菌肠毒素B的体内生物学效应 深入了解SEB临床综合征，明确有效的治疗方法和预防措施 对SEB所致临床综合征的干预。 具体目标1：描述由呼吸道暴露引起的临床综合征的免疫发病机制 对SEB；特定目标2：寻找有效的免疫调节剂治疗SEB诱导的临床 具体目标3：设计和评估针对SEB的新型疫苗。 这种细菌毒素，葡萄球菌肠毒素B(SEB)，会导致许多人类疾病，也可以是 用作生物武器。SEB致病的机制还知之甚少 因为没有好的实验动物模型。我们建议使用开发的独一无二的小鼠品系 通过我们(表达人类分子)来了解SEB如何导致疾病和随后的发展 治疗和预防由SEB引起的疾病的有效药物/疫苗。

Staphylococcal enterotoxin B (SEB) is a polypeptide exotoxin produced by Staphylococcus aureus and belongs to a family of microbial proteins called "superantigens". SEB, directly binds to MHC class II molecules and potently activates both CD4+ and CD8+ T cells expressing certain T cell receptor (TCR) beta chain variable region irrespective of their antigen specificities. As a result, SEB can cause a variety of clinical illnesses ranging from self-limiting food poisoning to the more severe toxic shock syndrome, which can be lethal. By virtue of its robust immunostimulatory property, SEB can also be used as agents of bioterrorism or biological warfare. There is, however, a significant knowledge gap in our understanding of the immunopathogenesis of SEB, largely attributed to a dearth of suitable animal models. Poor binding of SEB to non-human MHC class II molecules results in ineffective activation of the immune system in common laboratory animals and restricts their use in SEB research. Nonetheless, transgenic expression of HLA class molecules in mice restores these defects and dramatically augments the immune response to SEB delivered by several different routes. Faithful reproduction of human diseases and amenability to a variety of immunological and genetic experimentations render HLA class II transgenic mice an ideal tool for studying the in vivo biological effects of Staphylococcal enterotoxin B. Using this robust model, we propose to thoroughly understand SEB-induced clinical syndrome and idetify effective theraeutic as well as preventive interventions for SEB-induced clinical syndrome. Specific Aim 1: Delineate the immunopathogenesis of the clinical syndrome resulting from airway exposure to SEB;Specific Aim 2: Identify effective immunomodulatory agents for the treatment of SEB-induced clinical syndrome; and Specific Aim 3: Design and evaluate novel vaccines specific for SEB. The bacterial toxin, Staphylococcal enterotoxin B (SEB), causes many human diseases and can also be used as a biological weapon. The mechanisms by which SEB causes diseases are poorly understood because there are no good laboratory animal models. We propose to use the unique line of mice developed by us (that express human molecules) to understand how SEB causes diseases and subsequently develop effective drugs/vaccines for treating and preventing diseases caused by SEB.