Novel peptide antagonist theraphy for superantigen- induced lethal shock

细菌超抗原（SAg）是一种外毒素，可引发过度的免疫反应， 致命电击因为它们能够在极低浓度下诱导失能， 由于抗冲击性、易于生产性和特殊的稳定性，SAg被归类为B类生物制品 武器通过阻断下游效应物来逆转SAg中毒的有害作用的尝试 例如TNF-α由于诱导的大量水平而失败。我们制备了肽模拟物， SAg中的接触结构域和对诱导Th 1细胞因子所必需的新型SAg受体， 在D-半乳糖胺（D-GalN）致敏的SEB小鼠模型中预防致死性休克， 猪的无能力由于SAg与革兰氏阴性细菌内毒素（LPS）的共同暴露可能会导致更多的 与临床相关，该建议将测试拮抗肽可以预防SAg/LPS的假设 在保持适应性免疫反应的同时，在特定 目的：我们将确定拮抗肽是否保护和拯救小鼠免受LPS/SAg致死协同作用。 暴露于SAg和肠源性LPS可能模拟临床情况，并且SAg诱导的LPS的机制可能与临床情况相似。 病理学不同于D-GaIN致敏所发生的病理学。在具体目标II中，我们将定义 拮抗剂肽介导的保护机制，表明它是广谱抗SAgs的， 评估肽拮抗剂是否损害对抗原或宿主防御的免疫刺激的应答 对抗活体感染在肽存在下从用SAg攻击的小鼠的血清纯化的IgG 将通过ELISA针对来自SAg的不同结构域的肽测试拮抗剂。这些研究报告将 随后进行交叉抑制ELISA研究以鉴定对SAg保守表位特异的IgG水平。以来 最近的研究表明，SAgs可能改变APC功能，在具体目标III中，我们将分析是否 肽拮抗剂（1）抑制SAg对人单核细胞的作用，特别是Toll样受体表达 和细胞因子诱导或（2）损害人树突细胞呈递B的能力。炭疽T抗原 淋巴细胞这些研究将进一步确定SAg信号传导的新机制和SAg的功效， 针对多种SAg的新型治疗干预的安全性。如果我们成功了，这些肽 模拟物可能很快就可以进行第一阶段的测试。

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.