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的淋巴细胞可抑制细胞介导的免疫并破坏DNA疫苗的功效。它们杀死抗原呈递细胞的能力可以通过几种不同的机制消除，我们正在探索许多这些机制，以找到一种促进细胞介导的SIVGag疫苗应答的最佳机制。我们的假设是，用阻断Fas/FasL信号传导的小分子治疗可以防止抗原呈递细胞（APC）的破坏，并允许产生强有力的抗逆转录病毒免疫。在艾滋病期间，CD4+FasL+细胞的高水平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增强对机会性感染和艾滋病相关癌症的抵抗力。实验计划是开发新的Fas/FasL信号传导小分子抑制剂，以防止疫苗接种后APC裂解。我们确定了三种不同的Fas/FasL抑制策略，将在小鼠免疫研究中进行比较，以确定最适合促进对SIV疫苗常见抗原p27Gag的细胞介导免疫的策略或策略组合。在我们的方法中，我们正在研究对TNF受体超家族蛋白功能至关重要的预配体组装域（PLAD）的使用。PLAD代表了一类新的TNF和Fas受体抑制剂，在DNA疫苗接种和启动-增强策略中具有重要的优势。我们提出结构生物学研究，以解决PLAD结构/功能元件的关键问题，抑制Fas/FasL。我们的研究将比较FasL信号的抑制剂，这些抑制剂应该具有短期效应和高度特异性的靶点，但不应该干扰对疫苗抗原的强功能反应的发展

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.