NOVEL REVERSE ADJUVANT FOR VACCINE ENHANCEMENT

用于增强疫苗效果的新型反向佐剂

基本信息

批准号：
7573075
负责人：
Ian NICHOLAS Crispe
金额：
$ 22.91万
依托单位：
SEATTLE BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-14 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7573075
关键词：
Acquired Immunodeficiency Syndrome Adjuvant Bacteria Biology CD8B1 gene Cell Adhesion Molecules Clinical Data Disease Drug toxicity Effectiveness Endotoxins Experimental Models Future Genetic HIV Health Hepatic Hepatitis Hepatitis C virus Human Immune Immune response Immunity Immunologic Memory Infection Influenza Influenza A Virus, H5N1 Subtype Intercellular adhesion molecule 1 Intestines Kupffer Cells Liver Malaria Memory Minority Molecular Mononuclear Mus Parasites Pathway interactions Patients Pattern recognition receptor Peptide/MHC Complex Phagocytes Pharmaceutical Preparations Population Radiation Chimera Research Resistance Sepsis Signal Pathway Signal Transduction T memory cell T-Lymphocyte TLR4 gene Testing Vaccination Vaccine Adjuvant Vaccine Clinical Trial Vaccines Vascular Cell Adhesion Molecule-1 base hepatic sinusoid influenza virus strain influenzavirus inhibitor/antagonist liver function mouse model novel novel strategies public health relevance research study response vaccine development vaccine efficacy

项目摘要

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.

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。该分子在肝脏中表达，主要在库普弗细胞上表达。来自肠道细菌的内毒素与肝脏 TLR-4 的结合促进了肝窦中粘附分子的表达。我们的初步数据表明，肝脏中 TLR-4 依赖性 CD8+ T 细胞的捕获限制了全身免疫反应以及记忆反应的大小。在这项提案中，我们将测试是否可以利用这种机制来增强疫苗的有效性。因此，我们将在先天性缺乏 TLR-4 的小鼠或用 Eritoran 治疗的小鼠中启动流感特异性 CD8+ T 细胞，Eritoran 是一种 TLR-4 抑制剂，已被批准用于患有严重脓毒症的人类。如果这个项目成功，我们将获得概念验证数据，证明疫苗生物学新概念的合理性。我们将其称为“反向佐剂”策略，因为它通过抑制更常见的增强免疫反应的分子来促进 CD8+ T 细胞反应。公共卫生相关性：成功的疫苗可以消除许多重要疾病，包括疟疾、肝炎和艾滋病。然而，这样的疫苗是难以捉摸的。该项目旨在开发一种使疫苗更有效的新方法。