Harnessing Human DC Subsets for Improved Muscosal Vaccines

利用人类 DC 亚群改进粘膜疫苗

• 批准号: 8463956
• 负责人: GERARD ZURAWSKI
• 金额: $ 436.29万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463956
• 关键词: Acute; Adjuvant; Affinity; Agonist; Antibodies; Antigens; Award; B-Lymphocytes; Basic Science; Binding; Bioinformatics; Bioterrorism; Bispecific Antibodies; CD14 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Categories; Cell Surface Receptors; Cell surface; Cells; Chimeric Proteins; Clinical Research; Clinical Trials; Contractor; Data; Databases; Dendritic Cells; Dendritic cell activation; Development; Emerging Communicable Diseases; Funding; Future; Gene Proteins; Generations; Goals; Homing; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunologist; Immunology; In Vitro; Infection; Institution; Knowledge; Langerhans cell; Lectin; Legal patent; Leukocytes; Longevity; Macaca mulatta; Medicine; Memory; Microbe; Mind; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; National Institute of Allergy and Infectious Disease; Phase I Clinical Trials; Physicians; Poliomyelitis; Polyvalent Vaccine; Process; Publications; Receptor Signaling; Research Infrastructure; Resistance; Scientist; Secure; Signal Transduction; Site; Specificity; Staging; Surface; Surface Antigens; T cell response; T-Lymphocyte; TNFRSF5 gene; Technology; Testing; Tetanus; Vaccination; Vaccines; Viral; Viral Proteins; Virus; Work; antigen processing; base; biosignature; burden of illness; flexibility; human subject; improved; in vivo; in vivo Model; influenzavirus; interstitial; langerin; multidisciplinary; novel; novel strategies; novel vaccines; pathogen; programs; receptor; stem; success; uptake; vaccine candidate; vaccine development

Vaccination represents one of the major successes of medicine as it has spared countless people from polio, tetanus and other acute infections. Yet, improved immunization strategies are needed to make vaccines for microbes that cause considerable morbidity . To identify novel strategies for protective vaccination we will study dendritic cells (DCs) which specialized to capture and process antigens in vivo, presenting the MHC molecules to T cells. DCs also present antigens to B cells. Maturation and subsets allow DCs to control diverse immune responses. Our long-term goal is to develop novel human vaccines based on in vivo DC-targeting. Our hypothesis is that Human Dendritic cells subsets express distinct uptake and signaling receptors that need to be mobilized in concert to provide durable immune responses leading to increased resistance to microbes at the mucosal port of entry. To this end, we have made high affinity monoclonal antibodies against several DC surface molecules and conjugated them to several influenza virus proteins. We have shown that antigens delivered to a single type of human DCs through different surface lectins induce distinct types of antigen-specific CD4+ T cell responses. The current focus is on mucosal immunity because mucosa is a major site of invasion as well as replication of pathogens, including influenza virus. Thus, the induction/activation of two major effectors, B cells and CD8+ T cells, with mucosal homing capacity is expected to limit viral replication, resulting in reduced disease burden. Furthermore, induction of CD4+ T cells with helper functions for B cells or CTLs will enhance the longevity of memory cells and the magnitude and the quality of mucosal homing effectors. We view the candidate vaccine as a bispecific antibody a) binding to two different cell surface antigens, such as specific lectin for antigen delivery and CD40 for activation, or to two different DC subsets, to harness their capacity to induce different type of immune effectors, and in addition b)TLR agonists as DC activators. We propose four projects and two technical development components which will be supported by six cores.

疫苗接种代表了医学的主要成功之一，因为它使无数人免于 脊髓灰质炎，破伤风和其他急性感染。然而，需要改进的免疫策略来制定 导致相当发病率的微生物的疫苗。确定保护性的新型策略 疫苗接种我们将研究树突状细胞（DC），该树突状细胞专门捕获和处理体内抗原， 将MHC分子呈现给T细胞。 DC还向B细胞呈现抗原。成熟和子集 允许DC控制各种免疫反应。我们的长期目标是开发新型的人类疫苗 基于体内DC靶向。我们的假设是人树突状细胞亚群表达了独特的吸收 以及需要在协调一致的信号受体中提供持久的免疫反应。 在粘膜入境口中对微生物的抗性增加。为此，我们提高了高亲和力 单克隆抗体对几个DC表面分子，并将它们缀合到几种流感 病毒蛋白。我们已经表明，抗原通过不同的 表面凝集素诱导不同类型的抗原特异性CD4+ T细胞反应。当前的重点是 粘膜免疫，因为粘膜是侵袭和复制病原体的主要部位，包括 流感病毒。因此，具有粘膜的两个主要效应子B细胞和CD8+ T细胞的诱导/激活 预计归因能力将限制病毒复制，从而减轻疾病负担。此外， 诱导B细胞或CTL的辅助功能的CD4+ T细胞将增强记忆的寿命 细胞以及粘膜归巢效应子的大小和质量。我们将候选疫苗视为 双特异性抗体A）与两种不同的细胞表面抗原结合，例如抗原的特异性凝集素 交付和CD40激活或两个不同的DC子集，以利用其诱导不同的能力 免疫效应子的类型，另外b）TLR激动剂作为直流激活剂。我们建议四个项目， 两个技术开发组件将得到六个核心的支持。

项目成果

Blood Interferon Signatures Putatively Link Lack of Protection Conferred by the RTS,S Recombinant Malaria Vaccine to an Antigen-specific IgE Response.

• DOI: 10.12688/f1000research.7093.2
• 发表时间: 2015
• 期刊: F1000Research
• 作者: Rinchai D;Presnell S;Vidal M;Dutta S;Chauhan V;Cavanagh D;Moncunill G;Dobaño C;Chaussabel D
• 通讯作者: Chaussabel D

Detecting specific infections in children through host responses: a paradigm shift.

• DOI: 10.1097/qco.0000000000000065
• 发表时间: 2014-06
• 期刊: Current opinion in infectious diseases
• 影响因子: 3.9
• 作者: Mejias A;Suarez NM;Ramilo O
• 通讯作者: Ramilo O

Serology in the 21st century: the molecular-level analysis of the serum antibody repertoire.

• DOI: 10.1016/j.coi.2015.06.009
• 发表时间: 2015-08
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Wine Y;Horton AP;Ippolito GC;Georgiou G
• 通讯作者: Georgiou G

Translation of genomics research at the bedside: the promise and the challenge.

• DOI: 10.1016/j.clim.2008.09.001
• 发表时间: 2008-11
• 期刊: CLINICAL IMMUNOLOGY
• 影响因子: 8.6
• 作者: Chaussabel, Damien

Opposing Roles of Dectin-1 Expressed on Human Plasmacytoid Dendritic Cells and Myeloid Dendritic Cells in Th2 Polarization.

• DOI: 10.4049/jimmunol.1402276
• 发表时间: 2015-08-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Joo H;Upchurch K;Zhang W;Ni L;Li D;Xue Y;Li XH;Hori T;Zurawski S;Liu YJ;Zurawski G;Oh S
• 通讯作者: Oh S