ADOPTIVE TRANSFER OF SHIV-SPECIFIC CD8+ T CELLS

SHIV 特异性 CD8 T 细胞的过继转移

• 批准号: 7349352
• 负责人: PHILIP D GREENBERG
• 金额: $ 22.85万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349352
• 关键词: ADOPTIVE; TRANSFER; SHIV; SPECIFIC; CD8+

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. HIV infection is characterized by an inability of the immune system to maintain control of the virus. Experimentally boosting the immune system represents a treatment strategy with the potential to improve the host's ability to control virus. The loss of expression of the co-stimulatory molecule CD28 by CD8+ HIV-specific cells as consequence of differentiation is linked to the inability of CD8 T cells to produce IL-2 as an autocrine proliferation/growth necessary for viral control. Preliminary studies have shown that forcing the expression of CD28 on HIV-specific CD8+ T cell clones confers them the ability to secrete IL-2 upon specific antigen recognition. We predicted that infusing virus-specific CD8+ T cells in vivo might improve persistence and control over viral replication and because such genetic modification of T cells in humans requires evidence of safety, we went on to develop a macaque model and infuse these selected, expanded and genetically modified cells in an autologous macaque. First 108 then 109 cells of both CD8+ CD28+ and CD8+ CD28- subpopulations of the same subclone were infused in a 2-week period. Results from this experiment have shown that the CD28+ population persisted at low levels (0.2-0.6%) of peripheral CD8+ T cells for 6 weeks after transfer then disappeared and that the infusion of cells transiently increased plasma virus in an already viremic macaque. All cells were transduced to express truncated nerve growth factor receptor as a tracking marker. However, the cells rapidly disappeared from the blood potentially due to down-regulation after cell activation. We are determining localization of infused cells in peripheral sites including lymph nodes and gut tissues. The described model offers a unique setting to study the qualitative and quantitative requirements of cellular immunity to maintain control over HIV.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。 HIV感染的特征是免疫系统无法维持对病毒的控制。实验增强免疫系统代表了一种治疗策略，具有提高宿主控制病毒能力的潜力。 CD8+ HIV特异性细胞的共刺激分子CD28的表达丧失与CD8 T细胞无法产生IL-2作为病毒控制所需的自分泌增殖/生长有关。初步研究表明，在HIV特异性CD8+ T细胞克隆上迫使CD28的表达赋予了他们在特定抗原识别时分泌IL-2的能力。我们预测，在体内注入病毒特异性的CD8+ T细胞可能会改善对病毒复制的持久性和控制性，并且因为人类中T细胞的这种遗传修饰需要安全的证据，因此我们继续开发猕猴模型，并在自动猕猴中注入这些选择，扩展和遗传修饰的细胞。第一个108，然后在2周的时间内注入了同一亚克隆的CD8+ CD28+和CD8+ CD28的109个细胞。该实验的结果表明，CD28+种群在转移后的6周内持续了低水平（0.2-0.6％），然后消失了6周，并且细胞在已经病毒的猕猴中的血浆病毒暂时增加。将所有细胞转导，表达截断的神经生长因子受体作为跟踪标记。然而，由于细胞激活后的下调，细胞可能从血液中迅速消失。我们正在确定注入细胞在包括淋巴结和肠道组织在内的外周部位的定位。所描述的模型提供了一个独特的环境，可以研究细胞免疫的定性和定量要求，以保持对艾滋病毒的控制。