Novel peptide antagonist theraphy for superantigen- induced lethal shock

用于超抗原诱导致死性休克的新型肽拮抗剂疗法

• 批准号: 8233382
• 负责人: Alan S. Cross
• 金额: $ 23.62万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233382
• 关键词: Agonist; Animals; Antigens; Bacillus anthracis; Binding; Binding Sites; Biological; Bypass; CD28 gene; Categories; Cells; Clinical; Dendritic Cells; Endotoxins; Enzyme-Linked Immunosorbent Assay; Epitopes; Exotoxins; Exposure to; Face; Family suidae; Galactosamine; Germ Lines; Histocompatibility; Host Defense; Human; IL2 gene; Immune; Immune response; Immune system; Immunoglobulin G; Infection; Interferons; Intoxication; Knock-out; Lead; Life; Ligands; Lipopolysaccharides; MHC Class II Genes; Mediating; Modeling; Mus; Pathology; Peptides; Phase; Process; Production; Protein Family; Receptor Signaling; Safety; Sepsis; Serum; Shock; Signal Transduction; Staphylococcal Enterotoxin B; Staphylococcal enterotoxin A; Staphylococcus aureus; Stimulus; Streptococcus pyogenes; Streptococcus pyogenes SpeA protein; Superantigens; Surface; T cell anergy; T-Cell Receptor; T-Lymphocyte; TLR4 gene; TNF gene; Testing; Therapeutic; Time; Toll-like receptors; Toxic Shock Syndrome Toxin-1; Toxic effect; base; beta Chain Antigen T Cell Receptor; biodefense; clinically relevant; cytokine; dimer; mimetics; monocyte; mouse model; novel; novel therapeutic intervention; prevent; receptor; receptor binding; receptor expression; response; staphylococcal enterotoxin; toll-like receptor 4; weapons

Bacterial superantigens (SAg) are exotoxins that trigger an excessive immune response that may lead to lethal shock. Because of their ability to induce incapacitation at exceedingly low concentrations and to elicit shock, their ease of production and their exceptional stability, SAgs are classified as Category B biological weapons. Attempts to reverse the deleterious effects of SAg intoxication by blocking downstream effectors such as TNF-a have failed owing to the massive levels induced. We prepared peptide mimetics of the contact domains in the SAg and a novel SAg receptor essential for the induction of Th1 cytokines which prevent lethal shock in a D-galactosamine (D-GalN)-sensitized mouse model of SEB as well as incapacitation in pigs. Since co-exposure of SAg with Gram-negative bacterial endotoxin (LPS) may be more clinically relevant, this proposal will test the hypothesis that antagonist peptides can prevent SAg/LPS svnergistic lethality and rescue exposed animals, while preserving adaptive immune responses. In Specific Aim I we will determine whether antagonist peptides protect and rescue mice from LPS/SAg lethal synergy. Exposure to SAg and gut-derived LPS likely mimics the clinical situation, and the mechanism of SAg-induced pathology differs from that which occurs with D-GaIN sensitization. In Specific Aim II, we will define the mechanism of antagonist peptide-mediated protection, show that it is broad-spectrum against SAgs, and assess whether peptide antagonists impair responses to immune stimulation with antigens or host defenses against live infection. IgG purified from the serum of mice challenged with SAg in the presence of peptide antagonist will be.tested by ELISA against peptides from different domains of SAg. These studies will be followed by cross-inhibition ELISA studies to identify IgG levels specific for SAg conserved epitopes. Since recent studies suggest that SAgs may alter APC function, in Specific Aim III we will analyze whether peptide antagonists (1) inhibit SAg effects on human monocytes, particularly Toll-like receptor expression and cytokine induction or (2) impair the ability of human dendritic cells to present B. anthracis antigens to T lymphocytes. These studies will further define a new mechanism of SAg signaling and the efficacy and safety of a novel therapeutic intervention against multiple SAgs. If we are successful, these peptide mimetics could soon be ready for phase I testing.

细菌超抗原（SAG）是外毒素，触发过度免疫反应，可能导致 致命的冲击。因为它们能够在极低的浓度下诱导丧失能力并引起 震惊，易于生产和出色的稳定性，SAG被归类为B类生物学 武器。试图通过阻止下游效应器来扭转SAG中毒的有害影响 例如，由于巨大的水平，TNF-A失败了。我们准备了肽的肽 SAG中的接触域和一种新型的SAG受体，对于诱导Th1细胞因子必不可少 防止D-半乳酰胺（D-甘酸）敏感的小鼠模型以及SEB的致命冲击 猪丧失能力。由于革兰氏阴性细菌内毒素（LPS）的SAG共同暴露可能更多 临床上相关的是，该提案将检验以下假设：拮抗剂肽可以防止SAG/LPS Svnergistic的致死性和救援动物，同时保留适应性免疫反应。具体 目的，我将确定拮抗剂肽是否保护和营救小鼠免受LPS/SAG致命协同作用。 暴露于SAG和肠道衍生的LP可能模仿临床状况，而SAG诱导的机制 病理与D Goin敏化发生的病理不同。在特定的目标II中，我们将定义 拮抗剂肽介导的保护机理，表明它是针对下垂的广谱，并且 评估肽拮抗剂是否会损害对抗原或宿主防御的免疫刺激的反应 反对现场感染。在存在肽存在下，从SAG挑战的小鼠血清中纯化的IgG ELISA对拮抗剂的拮抗剂将对来自SAG不同域的肽进行测试。这些研究将是 然后进行交叉抑制ELISA研究，以鉴定针对SAG保守表位的IgG水平。自从 最近的研究表明，下垂可能会改变APC功能，在特定的目标III中，我们将分析是否是否 肽拮抗剂（1）抑制对人单核细胞的SAG影响，尤其是Toll样受体表达 和细胞因子诱导或（2）损害人树突状细胞呈现鼻芽孢杆菌抗原的能力 淋巴细胞。这些研究将进一步定义一种新的SAG信号传导和功效和功效和 针对多个下垂的新型治疗干预的安全性。如果我们成功，这些肽 Mimetics很快就可以准备进行I期测试。