Engineering Soluble T Cell Receptors to Treat Exotoxin Induced Pulmonary Disease

工程可溶性 T 细胞受体治疗外毒素引起的肺部疾病

• 批准号: 8127695
• 负责人: Daiva Maria Mattis
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2015-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127695
• 关键词: Affinity; Animal Model; Antigens; Autoimmune Diseases; Bacteria; Binding; Cardiovascular Diseases; Communities; Community Hospitals; Disease; Engineering; Enterotoxins; Exotoxins; Family member; Functional disorder; Goals; Gram-Positive Bacteria; Health; Heart Diseases; Human; Immune system; In Vitro; Infection; Inflammatory; Interleukin-2; Laboratories; Ligands; Link; Lung; Lung diseases; Major Histocompatibility Complex; Methods; Organ; Peptides; Play; Pneumonia; Prevalence; Primary idiopathic dilated cardiomyopathy; Proteins; Reaction; Role; Staphylococcal Enterotoxin B; Staphylococcus aureus; Superantigens; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; Targeted Toxins; Testing; Tissues; Toxic Shock Syndrome; Toxic Shock Syndrome Toxin-1; Toxic effect; Toxin; airway inflammation; antigen binding; cytokine; directed evolution; engineering design; methicillin resistant Staphylococcus aureus; mortality; novel; receptor binding; response; staphylococcal enterotoxin

DESCRIPTION (provided by applicant): T cell receptors recognize peptide antigens bound to and presented by the major histocompatibility complex (MHC) in a highly specific manner. A unique class of ligands called superantigens (SAgs), which are a type of toxin secreted by bacteria, bind to the T cell receptor in a different manner than normal antigens. When a foreign antigen enters the immune system, T cell receptors are activated and the normal response activates a small percentage of the immune system, less than 0.01 percent. In comparison, these toxins can activate up to 30 percent of the immune system. This overstimulation of the immune system leads to a massive release of cytokines such as TNF-a and IL-2, thereby causing severe inflammatory reactions. Though these toxins have been identified as the cause of Toxic Shock Syndrome and linked to other diseases, in recent years these toxins have increasingly been implicated in several pulmonary and cardiovascular diseases. Necrotizing pneumonia is among these diseases, which can involve airway inflammation, permanent airway destruction, and mortality. Most importantly for the present application, studies have shown that these exotoxins contribute directly to severe lung infection caused by Community- Associated Methicillin-Resistant S. Aureus (CA-MRSA). The increase in prevalence of MRSA, both in hospitals and the community, emphasizes the immediate need to target the toxins secreted by this bacterium. Therefore, in this application, T-cells will be engineered against these exotoxins. The exotoxins that will be focused on include Staphylococcal enterotoxin B (SEB), Staphylococcal enterotoxin C3 (SEC3), and toxic shock syndrome toxin 1 (TSST-1). The approach is to use a novel method of directed evolution to engineer T cell receptors that bind with high affinity to these clinically important toxins. Soluble forms of high affinity T cell receptors can neutralize the systemic toxicity of the SAgs, as has been recently shown in animal models with the toxin SEB. PUBLIC HEALTH RELEVANCE: The long-term goal of this application is to engineer soluble T cell receptors to treat exotoxin-induced pulmonary disease. To accomplish this goal, the first specific aim is to design, engineer, and express T cell receptors that bind with high-affinity to the SAg exotoxins SEC3 and TSST-1. The second aim of this application is to characterize and evaluate the anti-toxin efficacy of the soluble T cell antagonist proteins in vitro and in pulmonary disease animal models.

描述（由申请人提供）：T细胞受体以高度特异性的方式识别与主要组织相容性复合物（MHC）结合并呈现的肽抗原。一种称为超抗原（SAGS）的独特的配体，是细菌分泌的一种毒素的类型，其与正常抗原不同的方式与T细胞受体结合。当外国抗原进入免疫系统时，T细胞受体被激活，正常反应激活了一小部分免疫系统，小于0.01％。相比之下，这些毒素可以激活多达30％的免疫系统。免疫系统的过度刺激导致细胞因子（例如TNF-A和IL-2）的大量释放，从而引起严重的炎症反应。尽管这些毒素已被确定为毒性休克综合征的原因并与其他疾病有关，但近年来，这些毒素越来越涉及几种肺部和心血管疾病。坏死性肺炎是这些疾病之一，可能涉及气道炎症，永久气道破坏和死亡率。对于本应用，最重要的是，研究表明，这些外毒素直接导致由耐甲氧西林的金黄色葡萄球菌（CA-MRSA）引起的严重肺部感染。在医院和社区中，MRSA患病率的提高强调了针对该细菌分泌的毒素的迫切需要。因此，在此应用中，T细胞将针对这些外毒素进行设计。将重点关注的外毒素包括葡萄球菌肠毒素B（SEB），葡萄球菌肠毒素C3（SEC3）和毒性休克综合征毒素1（TSST-1）。该方法是使用一种新型的定向进化方法来设计与这些临床上重要的毒素高亲和力结合的T细胞受体。高亲和力T细胞受体的可溶性形式可以中和SAG的全身毒性，如毒素SEB的动物模型最近所示。公共卫生相关性：该应用的长期目标是设计可溶性T细胞受体来治疗外毒素诱导的肺部疾病。为了实现这一目标，第一个具体的目的是设计，工程和表达T细胞受体，它们与SAG Exotoxins Sec3和TSST-1结合起来。该应用的第二个目的是表征和评估可溶性T细胞拮抗剂蛋白在体外和肺部疾病动物模型中的抗毒素疗效。