EFFECT OF ANTI-4 1BB ON SIV SPECIFIC CELLULAR IMMUNITY

ANTI-4 1BB 对 SIV 特异性细胞免疫的影响

• 批准号: 7349165
• 负责人: ROBERT S MITTLER
• 金额: $ 5.97万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-09 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349165
• 关键词: Macaca; active immunization; cellular immunity; infection; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The intent of this proposal is to ascertain the effect of in vivo anti-4-1BB treatment on rhesus macaque cellular immune responses to SIV vaccination and/or infection. In so doing, we will explore new ways to stimulate SIV-specific cellular immunity and at the same time, determine the effect of this treatment on the course of disease in SIV-infected animals. Monoclonal antibodies to the 4-1BB receptor (CDw137), a member of the TNF receptor superfamily expressed on activated T cells and NK cells, preferentially stimulate CD8+ T cells in vitro and in vivo. Recent data suggests that ligation of the 4-1BB receptor on CD8+ T cells not only provides necessary co-stimulation and thus activation but may also prolong their survival. The latter effect is intriguing given the importance of CD8+ T cells in controlling viremia in both HIV and SIV infections. This proposal therefore addresses the areas of emphasis of the program announcement in that we are potentially identifying a co-stimulator that may optimize the CD8+ T cell response and ultimately be used as part of a vaccine against HIV. The specific aims are: 1) To test the in vitro effect of anti-4-1BB monoclonals on macaque lymphocytes in terms of activation, proliferation and cytokine secretion. 2) To determine the effect of anti-4-1BB monoclonals on CD8+ T cell responses induced by vaccination of Rhesus macaques with a DNA prime followed by a modified vaccinia Ankara (MVA) boost, both encoding SIVmac239 genes. 3) To administer anti-4-1BB during the course of an acute SIVmac239 infection and thus determine the effect of the treatment on viral loads, CD4 counts, anti-SIV CD8 activity and ultimately disease cours

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。该提案的目的是确定体内抗 4-1BB 治疗对恒河猴细胞免疫反应对 SIV 疫苗接种和/或感染的影响。在此过程中，我们将探索刺激 SIV 特异性细胞免疫的新方法，同时确定这种治疗对 SIV 感染动物病程的影响。 4-1BB 受体 (CDw137) 是在激活的 T 细胞和 NK 细胞上表达的 TNF 受体超家族的成员，针对 4-1BB 受体 (CDw137) 的单克隆抗体优先在体外和体内刺激 CD8+ T 细胞。最近的数据表明，CD8+ T 细胞上 4-1BB 受体的连接不仅提供了必要的共刺激并因此激活，而且还可以延长其存活时间。鉴于 CD8+ T 细胞在控制 HIV 和 SIV 感染中的病毒血症中的重要性，后一种作用很有趣。因此，该提案涉及了该计划公告的重点领域，即我们有可能确定一种可以优化 CD8+ T 细胞反应并最终用作 HIV 疫苗的一部分的共刺激剂。具体目的是：1）体外测试抗4-1BB单克隆抗体对猕猴淋巴细胞活化、增殖和细胞因子分泌的影响。 2) 确定抗 4-1BB 单克隆抗体对恒河猴接种 DNA 初免疫苗后接种改良的安卡拉牛痘 (MVA) 疫苗（均编码 SIVmac239 基因）诱导的 CD8+ T 细胞反应的影响。 3) 在急性SIVmac239感染过程中给予抗4-1BB，从而确定治疗对病毒载量、CD4计数、抗SIV CD8活性和最终疾病进程的影响