Modulating the immune response to adenovirus vectors through NF-kB/IRF3 activatio

通过 NF-kB/IRF3 激活调节对腺病毒载体的免疫反应

• 批准号: 8425546
• 负责人: Amer Aziz Beg
• 金额: $ 25.28万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425546
• 关键词: Adenovirus Vector; Adenoviruses; Adjuvant; Adoptive Transfer; Antibodies; Antigen Targeting; Antigens; Attention; B-Lymphocytes; Cells; Chickens; Clinical; Communicable Diseases; Family; Family member; Future; Gene Expression; Generations; Genetic; Goals; HIV; Human; IFNAR1 gene; IRF3 gene; Immune; Immune response; Immunity; In Vitro; Infection; Infectious Agent; Inflammation; Interferons; Kinetics; Lung; Lymphocyte; Malignant Neoplasms; Mediating; Memory; Mus; NF-kappa B; Natural Immunity; Ovalbumin; Pathway interactions; Pattern recognition receptor; Phosphotransferases; Play; Regulation; Relative (related person); Role; Safety; Signal Transduction; Signaling Molecule; T cell response; Techniques; Testing; Toll-like receptors; Vaccines; adaptive immunity; design; in vivo; pathogen; plasmid DNA; public health relevance; receptor; response; success; transcription factor; vaccine development; vector vaccine; vector-induced

DESCRIPTION (provided by applicant): Despite the tremendous success of vaccines in limiting the spread of infectious diseases, there remains a large unmet need for development of vaccines against major human pathogens such as HIV. Within this context, replication-deficient type 5 adenovirus vector (AdV) vaccines expressing target antigens have received considerable attention because of their relative safety and ability to induce humoral and cell-mediated responses. Host responses against infectious agents or vaccines require highly conserved innate immunity-inducing pattern recognition receptors (PRR), including Toll-like Receptors (TLRs) and RIG-I-like receptors. Despite the presence of multiple PRR, only a few intracellular pathways are thought to be critically important for induction of host responses by PRR. Key amongst them are transcription factors belonging to the NF-kB and IRF families. These transcription factors therefore serve as intracellular adjuvants in promoting immune responses. The main goal of studies proposed here is to determine whether the vaccine potential of AdV can be enhanced through expression of key intracellular adjuvants. To this end, the studies proposed here will systematically evaluate the adjuvant potential and mechanism of action of different key molecules that activate NF-kB and IRF pathways. If successful, our studies can have a major impact on the future design of AdV and potentially non-AdV vaccines for both infectious diseases and cancer. Two specific aims are proposed. Aim 1: Generation, in vitro and in vivo characterization of AdV expressing distinct intracellular adjuvants. Aim 2: Defining the role of type 1 IFN in intracellular adjuvant-induced enhancement of AdV immune responses.

描述（由申请人提供）：尽管疫苗在限制了传染病的传播方面取得了巨大成功，但仍有很大的未满足疫苗开发疫苗对HIV等主要人类病原体的需求。在这种情况下，由于其相对的安全性和诱导体液和细胞介导的反应的能力，表达靶抗原的5型腺病毒载体（ADV）疫苗受到了极大的关注。对传染剂或疫苗的宿主反应需要高度保守的先天免疫识别受体（PRR），包括Toll样受体（TLR）和RIG-I样受体。尽管存在多个PRR，但只有少数细胞内途径对于PRR诱导宿主反应至关重要。其中关键是属于NF-KB和IRF家族的转录因素。因此，这些转录因子是促进免疫反应的细胞内佐剂。此处提出的研究的主要目标是确定ADV的疫苗潜力是否可以通过表达关键细胞内佐剂来增强。为此，此处提出的研究将系统地评估激活NF-KB和IRF途径的不同关键分子的佐剂潜力和机理。如果成功的话，我们的研究可能会对传染病和癌症的ADV和潜在非ADV疫苗的未来设计产生重大影响。提出了两个具体目标。目标1：在表达不同细胞内佐剂的ADV的体外和体内表征。目标2：定义1型IFN在细胞内佐剂引起的ADV免疫反应增强中的作用。