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）：为了诱导强烈而持久的免疫反应，需要激活的抗原呈递细胞（APC）。 对于疫苗，APC通常在疫苗配方中被化学或微生物成分激活。 相反，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）。 尽管大量研究表明CD40L对于疫苗反应的重要性程度，但尚未确定该蛋白质的理想疫苗制剂。 CD40L的表达质粒会产生非常强的免疫反应，但是蛋白质的可溶性三聚体形式较少。 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疫苗设置。 这些TNFSF配体中的两个也将进行研究：RANKL（TRANCE，TNFSF11）和CD27L（CD70，TNFSF7）。 每个TNFSF配体将与HIV GP120 ENV或P24 GAG的质粒DNA构建体共同采用小鼠。 疫苗反应将使用抗体形成，淋巴增生反应，细胞因子产生和细胞毒性的测定法测量。 此外，CD40L构建体将与由分枝杆菌HSP70和HIV P24 GAG制成的融合蛋白结合使用，以确定与现有疫苗结合使用CD40L是否具有添加效应。 这些可行性研究完成后，清楚是否应该将这些概念提高到更广泛的艾滋病毒和其他病原体的疫苗研究中。