HLA class II transgenic mice as models for bacterial superantigen induced disease

描述（由申请人提供）：细菌超级抗原是多肽外毒素的一个家族。与传统抗原不同，细菌超级抗原根据其T细胞受体可变基因β的使用，而不是抗原特异性，引起很大比例的CD4+和CD8+ T细胞的强大激活。细菌超级抗原与一系列疾病有关，如食物中毒、中毒性休克综合征、川崎病、哮喘、特应性皮炎以及血管和自身免疫性疾病。细菌超级抗原，特别是葡萄球菌肠毒素B，也可以用作生物武器。超级抗原主要由金黄色葡萄球菌和化脓性链球菌产生。前者甚至可以存在于被称为携带者的健康个体中（尤其是鼻腔通道）。尽管它们具有巨大的临床重要性，但在我们对细菌超级抗原的免疫生物学的理解方面存在显著的知识差距。这在很大程度上归因于缺乏能够概括人类疾病的合适动物模型，因为细菌超级抗原不能与非人MHC II类分子有效地相互作用。人类MHC II类分子（细菌超抗原的高亲和力配体）在小鼠体内的转基因表达显著增强了小鼠对细菌超抗原的免疫反应，并使HLA II类转基因小鼠对超抗原介导的病理（包括中毒性休克）敏感。这些方便的小鼠模型的可用性使我们能够更好地了解细菌超抗原的病理生物学。我们已经开发了许多HLA II类转基因小鼠，并在这些小鼠中引入了许多具有免疫学意义的遗传操作。利用这些强大的人源化小鼠模型，我们计划：(1)描述细菌超级抗原诱导的急性临床综合征的发病机制；(2)剖析免疫系统各组成部分在细菌超抗原诱导的急性临床综合征发病机制中的作用；(3)评价葡萄球菌超抗原在某些呼吸系统炎性疾病发病机制中的作用。超级抗原是细菌毒素，对人体危害极大；微量就足以引起严重的疾病。由于超级抗原不能在常用的实验小鼠中诱导疾病，我们开发了表达人类分子的新小鼠品系。这些小鼠和人类一样患有超级抗原诱导的疾病，可以有效地用于了解与细菌超级抗原相关的疾病过程，并开发新的药物和疫苗。

DESCRIPTION (provided by applicant): Bacterial superantigens are a family of polypeptide exotoxins. Unlike conventional antigens, bacterial superantigens cause robust activation of a large proportion of CD4+ and CD8+ T cells based on their T cell receptor variable gene beta usage and not on their antigen specificities. Bacterial superantigens are implicated in a spectrum of diseases such as food poisoning, toxic shock syndromes, Kawasaki disease, asthma, atopic dermatitis and vasculitic and autoimmune disorders. Bacterial superantigens, especially staphylococcal enterotoxin B, may also be used as biological weapons. Superantigens are produced primarily by Staphylococcus aureus and Streptococcus pyogenes. The former can be present even in healthy individuals (particularly the nasal passage) called carriers. In spite of their immense clinical importance, there is a significant knowledge gap in our understanding of the immunobiology of bacterial superantigens. This is largely attributed to the dearth of suitable animal models that can recapitulate human diseases because bacterial superantigens fail to interact efficiently with non-human MHC class II molecules. Transgenic expression of human MHC class II molecules (which are the high affinity ligands for bacterial superantigens) in mice dramatically augments their immune response to bacterial superantigens and renders HLA class II transgenic mice susceptible to superantigen-mediated pathology including toxic shock. Availability of these convenient mouse models enables us to better understand the pathobiology of bacterial superantigens. We have developed numerous lines of HLA class II transgenic mice and introduced a number of genetic manipulations of immunological significance in these mice. Using these robust humanized mouse models, we plan to: (1) Delineate the pathogenesis of bacterial superantigen-induced acute clinical syndrome; (2) Dissect the role of components of the immune system in the pathogenesis of bacterial superantigen-induced acute clinical syndrome; and (3) Evaluate the role of staphylococcal superantigens in the etiopathogenesis of certain inflammatory disorders of respiratory system. Superantigens are bacterial toxins, which are extremely harmful to human beings; miniscule quantities are sufficient to cause severe disease. As superantigens fail to induce disease in commonly used experimental mice, we have developed new strains of mice expressing human molecules. These mice suffer from superantigen-induced disease like humans and can be effectively used to understand disease process associated with bacterial superantigens and to develop novel drugs and vaccines.