Boosting PDC and B cell activity to drive SIV immunity

增强 PDC 和 B 细胞活性以驱动 SIV 免疫

• 批准号: 6952677
• 负责人: Melissa J Robbiani
• 金额: $ 23.14万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952677
• 关键词: AIDS vaccines; B lymphocyte; CpG islands; HIV envelope protein; Macaca mulatta; dendritic cells; gut associated lymphoid tissue; immunomodulators; leukocyte activation /transformation; mucosal immunity; neutralizing antibody; oligonucleotides; oral administration; oral mucosa; oral pharyngeal; protein engineering; simian immunodeficiency virus; vaccine development; virus envelope; virus protein; AIDS vaccines; B lymphocyte; CpG islands; HIV envelope protein; Macaca mulatta; dendritic cells; gut associated lymphoid tissue; immunomodulators; leukocyte activation /transformation; mucosal immunity; neutralizing antibody; oligonucleotides; oral administration; oral mucosa; oral pharyngeal; protein engineering; simian immunodeficiency virus; vaccine development; virus envelope; virus protein

DESCRIPTION (provided by applicant): The linings of the oral/nasal cavity contain dendritic cells (DCs) within the epithelia and underlying lymphoid tissues (plasmacytoid and myeloid DCs, PDCs and MDCs) that orchestrate innate and adaptive immune responses to pathogens or vaccines breaching the mucosa. Producing and responding to innate factors, DCs can contribute immediately, while activated DCs (elevated IL-12, IL-15, costimulatory molecules) stimulate strong adaptive T and B cell responses, together affording protective immunity. DC activation mediated by TNF-TNFR and TLR family members is critical for vaccine efficacy. Capitalizing on this, we are exploring CpG-C immunostimulatory oligodeoxynucleotides (ISS-ODNs) that potently activate PDCs as well as B cells to augment immune responses and improve oral/nasal vaccine effectiveness. We propose that CpG-C ISS-ODNs will induce PDCs to secrete type I IFNs to favor MDC and B cell activation and also directly trigger B cells in the tonsils. This activated tonsillar milieu will drive innate and Th1 type adaptive responses needed to control virus infection (systemically and mucosally). Combined with this we are including the chemically inactivated virus vaccine, AT-2 virus, that provides a wealth of antigenic determinants to elicit broad-acting immunity. Specifically, we will employ a mutated form of SIV in which the V1 and V2 regions of envelope have been deleted, (V1V2. This deletion results in the virus being more sensitive to Ab neutralization suggesting that the resulting open conformation of envelope exposes the "neutralization-sensitive epitope" and that the AT-2 form of (V1V2 might induce particularly effective B cell responses in addition to solid T cell responses. This proposal will use the SIV-macaque system to demonstrate that CpG-C ISS-ODNs can be used to effectively activate DCs and B cells of the oral mucosal associated lymphoid tissues to amplify immunity against an orally administered AT-2 SIV vaccine. Within this, we will explore: (i) how these cells respond to native vs (V1V2 SIV in the presence of CpG-C ISS-ODNs and (ii) if CpG-C ISS-ODNs and AT-2 deltaV1V2 applied to the tonsils stimulate potent SIV-specific T and B cell responses in naive and healthy, infected macaques. This proof-of-principle approach will allow us to formally show the feasibility of CpG-C ISS-ODN-activation of mucosal APCs to improve oral/nasopharyngeal vaccination to protect against HIV as well as bolstering existing immunity to eradicate infection. This will provide the basis for future studies in which we plan to extensively explore application of this strategy for vaccine vs therapeutic approaches against HIV.

描述（由申请人提供）：口腔/鼻腔腔的衬里包含上皮细胞和潜在的淋巴组织内的树突状细胞（DCS）（浆细胞类动物和髓样DC，PDC和MDCS），它们使先天性和适应性免疫反应对病原体或疫苗的疫苗刺激性或疫苗刺激了斑点。 DC可以立即产生和响应先天因素，而活化的DC（IL-12，IL-15，IL-15，cotumulation Molecules）刺激了强适应性T和B细胞反应，共同提供了保护性免疫。 TNF-TNFR和TLR家族成员介导的DC激活对于疫苗功效至关重要。利用这一点，我们正在探索CPG-C免疫刺激性寡脱氧核苷酸（ISS-ODN），该核苷酸（ISS-ODN）有效激活PDC和B细胞以增强免疫反应并提高口服/鼻疫苗效果。我们建议CPG-C ISS-ODNS将诱导PDC分泌I型IFN，以偏爱MDC和B细胞激活，并直接触发扁桃体中的B细胞。这种激活的扁桃体环境将驱动控制病毒感染所需的先天和Th1型自适应反应（从系统地和粘膜上）。结合起来，我们包括化学灭活的病毒疫苗AT-2病毒，可提供大量抗原决定因素，以引起广泛的免疫力。 Specifically, we will employ a mutated form of SIV in which the V1 and V2 regions of envelope have been deleted, (V1V2. This deletion results in the virus being more sensitive to Ab neutralization suggesting that the resulting open conformation of envelope exposes the "neutralization-sensitive epitope" and that the AT-2 form of (V1V2 might induce particularly effective B cell responses in addition to solid T cell responses. 该提案将使用SIV-Macaque系统来证明CPG-C ISS-ODN可用于有效激活口服粘膜相关淋巴组织的DC和B细胞，以扩大针对AT-2 SIV疫苗的口服免疫。在此内，我们将探索：（i）这些细胞如何响应天然VS（在存在CPG-C-C ISS-ODN的情况下进行V1V2 SIV以及（ii）如果CPG-C ISS-ODNS和AT-2 deltav1v2应用于扁桃体应用于SIV SIV特异性的T和B细胞响应，则可以在NA型和健康中进行此类证明。 CPG-C ISS-ODN激活粘膜APC改善口服/鼻咽疫苗接种以防止HIV，并增强现有的免疫力来消除感染，这将为我们的未来研究提供基础。