Protection of vaccine immunity by inhibiting Fas/FasL signaling

描述(由申请人提供)：已知携带高水平FasL的淋巴细胞会抑制细胞免疫并破坏DNA疫苗的效力。它们杀死抗原提呈细胞的能力可以通过几种不同的机制来消除，我们正在探索这些机制中的一些，以找到一种最佳的机制来促进细胞对SIVGag疫苗的反应。我们的假设是，用阻断Fas/FasL信号转导的小分子治疗可以防止抗原提呈细胞(APC)的破坏，并允许发展强有力的抗逆转录病毒免疫。艾滋病期间高水平的CD4FasL细胞也降低了对机会性感染和肿瘤事件的免疫力。因此，阻断这些细胞传递的信号的治疗可以提高对机会性感染和艾滋病相关癌症的抵抗力。实验计划是开发新型的Fas/FasL信号小分子抑制剂，以防止疫苗接种后APC的裂解。我们确定了三种不同的抑制Fas/FasL的策略，将在小鼠免疫研究中进行比较，以确定最适合促进对常见SIV疫苗抗原p27Gag的细胞免疫的策略或策略的组合。在我们的方法中，我们正在研究配体前组装结构域(PLAD)的使用，这些结构域对肿瘤坏死因子受体超家族蛋白的功能至关重要。PLAD代表了一类新的肿瘤坏死因子和Fas受体抑制剂，在DNA疫苗接种和初始增强策略中具有重要的优势。我们建议进行结构生物学研究，以解决PLAD结构/功能元件对抑制Fas/FasL至关重要的关键问题。我们的研究将比较应该具有短期效果和高度特异性靶点的FasL信号抑制物，但不应该干扰对疫苗抗原的强功能反应的发展 与公共卫生相关：艾滋病患者携带的一组白细胞破坏了他们对抗机会性感染和预防癌症的能力。试图用持久的解决方案来解决这个问题，将危及血细胞的正常平衡。我们的研究建议测试细胞死亡信号的抑制剂，这些信号将具有短期效果和高度特异性，但不会干扰对癌症或感染的强烈反应的发展。

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.