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。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。HIV感染的特征是免疫系统无法维持对病毒的控制。实验性地增强免疫系统代表了一种有可能提高宿主控制病毒能力的治疗策略。作为分化的结果，CD 8 + HIV特异性细胞失去共刺激分子CD 28的表达与CD 8 T细胞不能产生IL-2作为病毒控制所必需的自分泌增殖/生长有关。初步研究表明，迫使HIV特异性CD 8 + T细胞克隆表达CD 28，赋予它们在特异性抗原识别后分泌IL-2的能力。我们预测，在体内注入病毒特异性CD 8 + T细胞可能会改善病毒复制的持久性和控制，并且由于人类T细胞的这种遗传修饰需要安全性证据，我们继续开发猕猴模型并将这些选择的，扩增的和遗传修饰的细胞注入自体猕猴。在2周内输注相同亚克隆的CD 8 + CD 28+和CD 8 + CD 28-亚群的最初108个细胞，然后109个细胞。来自该实验的结果表明，在转移后6周，CD 28+群体在外周CD 8 + T细胞的低水平（0.2-0.6%）下持续存在，然后消失，并且细胞的输注在已经有病毒血症的猕猴中瞬时增加血浆病毒。所有细胞被转导以表达截短的神经生长因子受体作为追踪标记。然而，这些细胞可能由于细胞活化后的下调而迅速从血液中消失。我们正在确定输注细胞在外周部位（包括淋巴结和肠道组织）的定位。所描述的模型提供了一个独特的设置来研究细胞免疫的定性和定量要求，以保持对HIV的控制。