A humanized transgenic mouse model for studying staphylococcal enterotoxin B

用于研究葡萄球菌肠毒素 B 的人源化转基因小鼠模型

• 批准号: 7497343
• 负责人: CHELLA S DAVID
• 金额: $ 22.67万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2008-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497343
• 关键词: Aerosols; Affinity; Animal Model; Antigens; Bacterial Toxins; Binding; Biological; Biological Warfare; Bioterrorism; CD8-Positive T-Lymphocytes; CD8B1 gene; Categories; Class; Clinical; Country; Defect; Development; Disease; Epitope Mapping; Event; Exotoxins; Exposure to; Family; Food Poisoning; Genetic; Goals; Histocompatibility Antigens Class II; Human; Human Development; Immune; Immune response; Immune system; Immunoglobulin Variable Region; Inflammatory; Knowledge; Laboratory Animal Models; Laboratory Animals; Mediating; Modeling; Mus; Pharmaceutical Preparations; Preventive Intervention; Process; Property; Proteins; Range; Reproduction; Research; Role; Route; Serum; Specificity; Staphylococcal Enterotoxin B; Staphylococcus aureus; Superantigens; Syndrome; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Therapeutic Uses; Toxic Shock Syndrome; Transgenic Mice; Transgenic Organisms; United States; United States National Institutes of Health; Vaccines; base; beta Chain Antigen T Cell Receptor; biodefense; cancer therapy; cytokine; design; human disease; immunopathology; in vivo; microbial; mouse model; neutralizing antibody; novel vaccines; pathogen; polypeptide; prevent; tool

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.

葡萄球菌肠毒素B（SE B）是由金黄色葡萄球菌产生的多肽外毒素， 属于一个被称为“超级抗原”的微生物蛋白家族。SEB，直接结合MHC II类 分子并有效激活表达某些T细胞受体（TCR）β的CD 4+和CD 8 + T细胞 链可变区，而与其抗原特异性无关。因此，SEB可引起多种临床症状， 从自限性食物中毒到更严重的中毒性休克综合征， 致命的由于其强大的免疫刺激特性，SEB也可用作生物恐怖主义或生物免疫学的试剂。 生物战然而，在我们对这一问题的理解方面， 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 非人MHC II类分子通常导致免疫系统的无效激活， 实验室动物，并限制其在SEB研究中的使用。尽管如此，HLA类的转基因表达 小鼠体内的SEB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再现人类疾病和顺从各种 免疫学和遗传学实验使HLA II类转基因小鼠成为研究 葡萄球菌肠毒素B的体内生物学效应。使用这个强大的模型，我们建议 深入了解SEB引起的临床症状，确定有效的治疗和预防措施 SEB引起的临床综合征的干预措施。 具体目标1：阐明气道暴露导致临床综合征的免疫发病机制 具体目标2：确定有效的免疫调节剂，用于治疗SEB诱导的临床 具体目标3：设计和评估SEB特异性的新型疫苗。 细菌毒素，葡萄球菌肠毒素B（SE B），引起许多人类疾病，并且也可以是 用作生物武器。SEB引起疾病的机制知之甚少 因为没有好的实验动物模型。我们建议使用独特的小鼠品系 通过我们（表达人类分子）来了解SEB如何引起疾病并随后发展 用于治疗和预防SEB引起的疾病的有效药物/疫苗。