TNFSF APC activators for HIV Vaccines

用于 HIV 疫苗的 TNFSF APC 激活剂

• 批准号: 6648415
• 负责人: Richard Syd Kornbluth
• 金额: $ 21.11万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648415
• 关键词: AIDS vaccines; CD40 molecule; HIV envelope protein gp120; antigen presenting cell; gag protein; immunologic substance development /preparation; immunomodulators; laboratory mouse; leukocyte activation /transformation; nonhuman therapy evaluation; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Activated antigen-presenting cells (APCs) are required in order to induce a strong and long-lasting immune response. For vaccines, APCs are usually activated by either chemical or microbial components in the vaccine formulation. In contrast, normal immune responses rely upon endogenous activators of APCs, mainly CD40 ligand (CD40L, also called CD154 or TNFSF5). While numerous studies have shown how important CD40L is for vaccine responses, an ideal vaccine formulation of this protein has not been determined. Expression plasmids for CD40L result in a very strong immune response, but a soluble trimeric form of the protein is less active. This R03 Small Research Grant will test the feasibility of delivering CD40L in three different forms: as membrane CD40L, as a soluble CD40L trimer, and as a novel 12-chain, four-armed structure formed as a fusion protein with the body of surfactant protein D. Additionally, other members of the TNF superfamily of ligands have been proposed to augment immune responses but have not been tested in a HIV vaccine setting. Two of these TNFSF ligands will also be studied: RANKL (TRANCE, TNFSF11) and CD27L (CD70, TNFSF7). Each TNFSF ligand will be co-administered to mice along with a plasmid DNA construct for either HIV gp120 Env or p24 gag. Vaccine responses will be measured using assays for antibody formation, lymphoproliferative responses, cytokine production, and cytotoxity. Additionally, CD40L constructs will be combined with a fusion protein made from mycobacterial hsp70 and HIV p24 Gag to determine if CD40L has an additive effect when combined with an existing vaccine. Upon the completion of these feasibility studies, it will be clear if these concepts should be advanced into more extensive vaccine studies both for HIV and other pathogens.

描述(由申请人提供)：激活的抗原提呈细胞(APC)是诱导强烈和持久的免疫反应所必需的。对于疫苗，APC通常由疫苗配方中的化学成分或微生物成分激活。相比之下，正常的免疫反应依赖于APC的内源性激活剂，主要是CD40配体(CD40L，也称为CD154或TNFSF5)。虽然大量研究表明CD40L对疫苗反应有多么重要，但这种蛋白的理想疫苗配方尚未确定。CD40L的表达质粒可产生非常强的免疫反应，但可溶的三聚体形式的蛋白质活性较低。这项R03小额研究拨款将测试以三种不同形式输送CD40L的可行性：作为膜CD40L，作为可溶性CD40L三聚体，以及作为一种新的12链四臂结构，作为与表面活性蛋白D主体形成的融合蛋白。此外，已经提出了用于增强免疫反应的肿瘤坏死因子超家族的其他成员，但尚未在艾滋病毒疫苗环境中进行测试。其中两个TNFSF配体也将被研究：RANKL(TRANCE，TNFSF11)和CD27L(CD70，TNFSF7)。每个TNFSF配体将与针对HIV gp120 Env或p24 Gag的质粒DNA构建物一起被共同注射给小鼠。疫苗反应将通过抗体形成、淋巴增殖反应、细胞因子产生和细胞毒性的测定来衡量。此外，CD40L构建物将与分枝杆菌HSP70和HIV p24 Gag制成的融合蛋白结合，以确定CD40L与现有疫苗结合时是否具有相加效应。在这些可行性研究完成后，这些概念是否应该被推进到更广泛的艾滋病毒和其他病原体疫苗研究中就会变得清晰起来。