Design and evaluation of HLA-A, -B, and -C binding peptides that disrupt inhibitory KIR/MHC interaction and activate NK cells

设计和评估 HLA-A、-B 和 -C 结合肽，破坏抑制性 KIR/MHC 相互作用并激活 NK 细胞

• 批准号: 9227710
• 负责人: Dirk M Zajonc
• 金额: $ 27万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227710
• 关键词: Alleles; Alpha Cell; Amino Acids; Antibodies; B-Lymphocytes; Binding; Binding Sites; Biological Assay; Blocking Antibodies; C-terminal; Cell physiology; Cell surface; Cells; Cellular Stress; Charge; Chimeric Proteins; Complex; Crystallization; Cytotoxic T-Lymphocytes; Detection; Epitopes; Equilibrium; Evaluation; Family; Flow Cytometry; Government; HLA-A gene; HLA-A2 Antigen; HLA-B Antigens; HLA-C Antigens; Hematopoietic Neoplasms; Histocompatibility; Immune; Impairment; Incubated; Infection; Infection Control; Insecta; Institutes; K562 Cells; Ligands; Limb structure; MART-1 Tumor Antigen; Measures; Mediating; NK Cell Activation; NK cell receptor NKB1; Natural Killer Cells; Peptides; Persons; Phase II Clinical Trials; Physiologic pulse; Proteins; Receptor Activation; Relapse; Scanning; Signal Transduction; Structure; Sum; Surface; Surface Plasmon Resonance; T-Lymphocyte; Technology; Testing; Therapeutic; Up-Regulation; Variant; Virus; YARS gene; base; cell killing; chemotherapy; design; flexibility; immunoglobulin receptor; in vitro Assay; killings; neoplastic cell; novel; prevent; receptor; receptor binding; tumor; tumor progression

Project Summary Natural Killer (NK) cells are immune cells that very rapidly detect and eradicate infected or aberrant target cells. They constantly scan the surface of these cells for changes that would indicate infection or alteration by the tumor. NK cell receptor activation is achieved by binding to target cell expressed ligands that either activate or inhibit the NK cell. Engagement of inhibitory ligands prevents NK cell activation, thus allowing the healthy cell to leave unharmed. However, upon infection, activating ligands are now expressed by the target cell, leading to the activation of the NK cell and direct killing of the infected cell. Since viruses or tumors can actively prevent the expression of activating ligands in an effort to evade NK cell detection and killing we propose to disrupt the binding to inhibitory receptors by altering the structure of the inhibitory ligands. This in turn removes the brakes of NK cell inhibition, leading to NK cell activation and killing. Our strategy is built on our recent discovery that certain peptides bind and alter the structure of one class of ligands, termed Major Histocompatibility (MHC) class I molecules that engage inhibitory Killer Immunoglobulin receptors (KIRs). By preventing the interaction between these two cell-surface expressed proteins, we propose to re-activate otherwise inhibited NK cells. In this proposal we will study the universality of this structural change across the entire family of MHC I molecules, and test the activation of NK cells using designed peptides in a cell-based in vitro assay.

项目概要 自然杀伤 (NK) 细胞是一种免疫细胞，可以非常快速地检测并根除受感染的细胞 或异常的靶细胞。他们不断扫描这些细胞的表面以寻找变化 表明肿瘤的感染或改变。实现NK细胞受体激活 通过与靶细胞表达的配体结合，激活或抑制 NK 细胞。 抑制性配体的参与可防止 NK 细胞激活，从而使健康的细胞 细胞不受伤害。然而，感染后，激活配体现在表达 通过靶细胞，导致 NK 细胞激活并直接杀死感染者 细胞。由于病毒或肿瘤可以主动阻止激活配体的表达 为了逃避 NK 细胞的检测和杀伤，我们建议破坏与 通过改变抑制性配体的结构来抑制受体。这反过来 消除 NK 细胞抑制的阻碍，导致 NK 细胞激活和杀伤。我们的 该策略建立在我们最近发现某些肽结合并改变结构的基础上 一类配体，称为主要组织相容性 (MHC) I 类分子， 参与抑制性杀伤免疫球蛋白受体 (KIR)。通过阻止交互 在这两种细胞表面表达的蛋白质之间，我们建议重新激活，否则 抑制 NK 细胞。在本提案中，我们将研究这种结构变化的普遍性 涵盖整个 MHC I 分子家族，并使用以下方法测试 NK 细胞的激活 在基于细胞的体外测定中设计了肽。