Protection of vaccine immunity by inhibiting Fas/FasL signaling

通过抑制 Fas/FasL 信号传导保护疫苗免疫力

• 批准号: 7853033
• 负责人: Maria S. Salvato
• 金额: $ 49.28万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853033
• 关键词: AIDS related cancer; Acquired Immunodeficiency Syndrome; Address; Anti-Retroviral Agents; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Blood Cells; CD8B1 gene; CD95 Antigens; Cell Death; Cell Death Signaling Process; Cells; Cellular Immunity; Cytolysis; DNA; DNA Vaccines; Development; Elements; Equilibrium; Event; Hand; Homeostasis; Immune; Immune response; Immunity; Immunization; Immunologic Surveillance; Infection; Leukocytes; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; Molecular; Mus; Opportunistic Infections; Pathway interactions; Physical Chemistry; Proteins; Relative (related person); Research Personnel; Resistance; Runaway; SIV Vaccines; Signal Pathway; Signal Transduction; Simian immunodeficiency virus Gag protein p27; Solutions; Specificity; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; TNF gene; Testing; Tumor Necrosis Factor Receptor; Tumor Suppression; Vaccination; Vaccine Antigen; Vaccines; Viral Vaccines; base; fighting; inhibitor/antagonist; killings; neoplastic; nonhuman primate; novel; prevent; public health relevance; response; small molecule; structural biology; tumor

DESCRIPTION (provided by applicant): Lymphocytes bearing high levels of FasL are known to suppress cell-mediated immunity and destroy the efficacy of DNA vaccines. Their ability to kill the antigen-presenting cells can be eliminated by several different mechanisms and we are exploring a number of these mechanisms to find one optimal for promoting cell- mediated responses to SIVGag vaccination. It is our hypothesis that treatment with small molecules that block Fas/FasL signaling could prevent the destruction of antigen-presenting-cells (APC), and allow the development of vigorous anti-retroviral immunity. High levels of CD4+FasL+ cells during AIDS also reduce immunity against opportunistic infections and neoplastic events. Therefore, treatments to block signals delivered by these cells could boost resistance to opportunistic infections and to AIDS-associated cancers. The experimental plan is to develop novel small-molecule inhibitors of Fas/FasL signaling to prevent APC lysis after vaccination. We identified three different strategies for Fas/FasL inhibition which will be compared in mouse immunization studies to identify the strategy, or combination of strategies, most suitable for promoting cell-mediated immunity to a common SIV vaccine antigen, p27Gag. Among our approaches we are investigating the use of pre-ligand assembly domains (PLAD) that are critical for function in TNF receptor superfamily proteins. PLAD represent a novel class of TNF and Fas receptor inhibitors with important advantages for use during DNA vaccination and prime-boost strategies. We propose structural biology studies to address key questions about PLAD structural/functional elements critical for inhibiting Fas/FasL. Our studies will compare inhibitors of FasL signaling that should have short-term effects and highly-specific targets, yet should not interfere with the development of strong functional responses to vaccine antigens PUBLIC HEALTH RELEVANCE: People with AIDS carry a subset of white blood cells that destroy their ability to fight opportunistic infections and to prevent cancer. Attempts to fix this problem with long-lasting solutions would endanger the normal balance of blood cells. Our studies propose to test inhibitors of cell-death signals that would have short-term effects and highly-specific targets, yet would not interfere with the development of strong responses against cancers or infections.

描述（由申请人提供）：已知具有高水平FASL的淋巴细胞抑制细胞介导的免疫力并破坏DNA疫苗的功效。它们可以通过几种不同的机制消除它们杀死抗原呈递细胞的能力，我们正在探索许多此类机制，以找到一种最佳的，以促进对SIVGAG疫苗接种的细胞介导的反应。我们的假设是，用小分子进行阻断FAS/FASL信号传导的治疗可以防止抗原呈现细胞（APC）的破坏，并允许发展剧烈的抗逆转录病毒免疫。辅助过程中高水平的CD4+ FASL+细胞还可以降低针对机会性感染和肿瘤事件的免疫力。因此，阻止这些细胞传递的信号的处理可以增强对机会性感染和与艾滋病相关的癌症的抗性。实验计划是开发FAS/FASL信号传导的新型小分子抑制剂，以防止疫苗接种后APC裂解。我们确定了FAS/FASL抑制作用的三种不同策略，这些策略将在小鼠免疫研究中进行比较，以识别策略或策略的组合，最适合于促进细胞介导的对常见的SIV疫苗抗原的免疫，P27GAG。在我们的方法中，我们正在研究使用凸面体组装域（PLAD）的使用，这些结构域（PLAD）对于TNF受体超家族蛋白的功能至关重要。 PLAD代表了一种新型的TNF和FAS受体抑制剂，具有在DNA疫苗接种和促进策略中使用的重要优势。我们提出了结构生物学研究，以解决有关抑制FAS/FASL至关重要的plad结构/功能元件的关键问题。我们的研究将比较应具有短期效应和高度特异性靶标的FASL信号的抑制剂，但不应干扰对疫苗抗原的强大功能反应的发展 公共卫生相关性：艾滋病患者携带着一部分白细胞，破坏了他们对机会主义感染和预防癌症的能力。试图通过持久的解决方案解决此问题会危害血细胞的正常平衡。我们的研究建议测试具有短期影响和高度特异性靶标的细胞死亡信号抑制剂，但不会干扰针对癌症或感染的强烈反应的发展。