NOVEL REVERSE ADJUVANT FOR VACCINE ENHANCEMENT

描述（由申请人提供）：我们的研究揭示了模式识别受体TLR-4生物学的一个意想不到的方面。这种分子在肝脏中表达，主要是在库普弗细胞上。来自肠道细菌的内毒素与肝脏TLR-4的结合促进了肝窦内粘附分子的表达。我们的初步数据表明，肝脏中CD8+ T细胞的tlr -4依赖性捕获限制了全身免疫反应的大小，也限制了记忆反应的大小。在本提案中，我们将测试是否可以利用这种机制来提高疫苗的有效性。因此，我们将在先天性缺乏TLR-4的小鼠或用itoran治疗的小鼠中启动流感特异性CD8+ T细胞，itoran是一种TLR-4抑制剂，已被批准用于严重败血症患者。如果这个项目成功，我们将获得概念验证数据，证明疫苗生物学中的新概念是合理的。我们称之为“反向佐剂”策略，因为它通过抑制一种通常起增强免疫反应作用的分子来促进CD8+ T细胞的反应。公共卫生相关性：许多重要疾病，包括疟疾、肝炎和艾滋病，可以通过成功的疫苗加以消灭。然而，这种疫苗是难以捉摸的。该项目旨在开发一种使疫苗更有效的新方法。

DESCRIPTION (provided by applicant): Our research has revealed an unexpected aspect of the biology of the pattern recognition receptor, TLR-4. This molecule is expressed in the liver, principally on Kupffer cells. The engagement of liver TLR-4 by endotoxin derived from the intestinal bacteria promotes the expression of adhesion molecules in the hepatic sinusoids. Our Preliminary Data show that the TLR-4-dependent trapping of CD8+ T cells in the liver limits the size of systemic immune responses, and also of memory responses. In this proposal, we will test whether this mechanism can be exploited to enhance the effectiveness of a vaccine. Thus, we will prime influenza-specific CD8+ T cells either in mice congenitally lacking TLR-4, or in mice treated with Eritoran, a TLR-4 inhibitor that is already sanctioned for use in humans with severe sepsis. If this project is successful, we will have obtained proof-of-concept data that justify a new concept in vaccine biology. We term this the "reverse adjuvant" strategy, since it promotes CD8+ T cell responses via the inhibition of a molecule that more commonly acts to enhance immune responses. PUBLIC HEALTH RELEVANCE: Many important diseases, including malaria, hepatitis and AIDS, could be eliminated by successful vaccines. However, such vaccines are elusive. This project aims to develop a new approach to making vaccines more effective.