权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

OVERCOMING THE DEGRADING EFFECTS OF NICOTINE ON VACCINE USING TLR AGONISTS

使用 TLR 激动剂克服尼古丁对疫苗的降解作用

基本信息

批准号：
8660622
负责人：
MAHYAR NOURI-SHIRAZI
金额：
$ 7.47万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660622
关键词：
Adjuvant Adverse effects Affect Aging Agonist Animal Diseases Antibodies Antibody Formation Antigen-Presenting Cells Antigens Attenuated Live Virus Vaccine Biologic Characteristic Biological Biological Warfare Cell Maturation Cells Centers for Disease Control and Prevention (U.S.)Communicable Diseases Competence Data Defect Dendritic Cells Depressed mood Deterioration Development Disease Disease Outbreaks Drug Formulations Effectiveness Elements Epidemic Exposure to Future Goals Half-Life Hepatitis B Vaccines Herd Immunity Immune Immune response Immune system Immunization Immunologic Adjuvants Immunosuppression Impairment In Vitro Incidence Individual Infection Inflammatory Interferon Type II Interferons Interleukin-12 Interleukin-18 Knockout Mice Knowledge Longevity Memory Military Personnel Modeling Morbidity - disease rate Mus Myelogenous NK Cell Activation Natural Immunity Natural Killer Cells Nicotine Outcome Ovalbumin Patients Population Positioning Attribute Prevalence Process Production Proteins Public Health Recommendation Regulation Reporting Risk Seasons Severities Shapes Signal Transduction Site Smoker Solutions Subunit Vaccines TLR1 gene TLR7 gene Testing Th1 Cells Therapeutic immunosuppression Tobacco Transgenic Mice Vaccinated Vaccination Vaccines Wild Type Mouse Work adaptive immunity base booster vaccine cell mediated immune response cigarette smoking cytokine cytotoxicity design efficacy testing immune function improved in vivo influenzavirus mortality mouse model non-smoker pandemic disease preempt programs prophylactic public health relevance response scientific organization success therapeutic vaccine vaccine efficacy vaccine-induced immunity

项目摘要

DESCRIPTION (provided by applicant): Vaccines aid in saving lives from infectious diseases and biological warfare attacks. They should be safe and effective in all recipients; otherwise, the likelihood that those who are hyporesponsive to vaccines will transmit disease to vulnerable individuals and disrupt herd immunity is greatly increased. There is compelling evidence that smokers, who represent more than one billion people worldwide, are less responsive to vaccines (1-3). However, there currently is no scientific organization and commercial entity offering an enhanced vaccine or working on such optimization. We made progress in our understanding of the mechanisms that underlie the impairment of vaccine-induced immunity and reported that prophylactic and therapeutic vaccines fail to protect and cure animals from disease due to nicotine-induced defects in the biological activities of dendritic cells (DCs) (4). We also reported that the defects observed in DCs are reversible and IFN-g known to be produced by natural killer (NK) cells, is an absolute requirement in this process (5). Hence, we hypothesize that an adjustment of vaccine formulation with immunological adjuvant(s) capable of restoring interactions between DC and NK cells will allow vaccines to also work optimally in this population. Of note, our new preliminary data revealed that among TLR agonists tested, nicotine has limited adverse effect on DC and NK cells responses to a TLR7/8 agonist (Fig. 2). Importantly, addition of this agonist to the vaccine formulation significantly improves antigen-specific effector memory Th1 response in nicotine-exposed mice (Fig. 3C). Based on these findings, we propose to identify the signature of adjuvant(s) that can overcome the degrading effects of nicotine on vaccination outcome. The following aim is designed to accomplish this objective. Aim: Determine the mechanisms by which the TLR7/8 agonist in contrast to other TLR agonists restores the efficacy of vaccines in nicotine-exposed hosts. At the completion of this study, we will have revealed the unknown mechanisms underlying the differential effectiveness of TLR agonists in nicotine-exposed hosts. We envision that such findings could be applied to further development of current and future vaccines.

描述（由申请人提供）：疫苗有助于从传染病和生物战攻击中拯救生命。它们应该在所有接受者中安全有效;否则，那些对疫苗反应迟钝的人将疾病传染给易受伤害的个人和破坏群体免疫力的可能性大大增加。有令人信服的证据表明，吸烟者，谁代表全球超过10亿人，是对疫苗的反应较低（1-3）。然而，目前没有科学组织和商业实体提供增强的疫苗或致力于这种优化。我们在理解疫苗诱导的免疫力受损的机制方面取得了进展，并报告说，由于尼古丁诱导的树突状细胞（DC）生物活性缺陷，预防性和治疗性疫苗未能保护和治愈动物疾病（4）。我们还报道了在DC中观察到的缺陷是可逆的，并且已知由自然杀伤（NK）细胞产生的IFN-g是该过程中的绝对要求（5）。因此，我们假设用能够恢复DC和NK细胞之间相互作用的免疫佐剂调整疫苗制剂将允许疫苗在该群体中也最佳地起作用。值得注意的是，我们的新的初步数据显示，在测试的TLR激动剂中，尼古丁对DC和NK细胞对TLR 7/8激动剂的应答具有有限的不利影响（图2）。重要的是，向疫苗制剂中添加该激动剂显著改善尼古丁暴露小鼠中的抗原特异性效应记忆Th 1应答（图3C）。基于这些发现，我们建议确定可以克服尼古丁对疫苗接种结果的降解作用的佐剂的特征。以下目标旨在实现这一目标。目的：确定TLR 7/8激动剂与其他TLR激动剂相比在尼古丁暴露宿主中恢复疫苗效力的机制。本研究完成后，我们将揭示TLR激动剂在尼古丁暴露宿主中差异有效性的未知机制。我们设想这些发现可以应用于当前和未来疫苗的进一步开发。