STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES

增强 T 细胞克隆过继转移的策略

• 批准号: 8172773
• 负责人: STANLEY R. RIDDELL
• 金额: $ 15.51万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172773
• 关键词: Adoptive Transfer; Aftercare; Animals; Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Death; Cell Survival; Clone Cells; Computer Retrieval of Information on Scientific Projects Database; Disease; Dose; Funding; Grant; Human; Immunity; Immunotherapy; Institution; Interleukin-15; Interleukin-2; Macaca; Maintenance; Malignant - descriptor; Memory; Natural Killer Cells; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Resources; Role; Source; T memory cell; T-Lymphocyte; Toxic effect; United States National Institutes of Health; Viral; cytokine; in vivo; novel; success

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 adoptive transfer of antigen-specific CD8+ effector T cells (TE) is being used to treat human viral and malignant disease with some success. However, the inconsistent or short in vivo persistence of transferred TE has been identified as a limitation of this approach. T cell growth factors such as interleukin (IL)-2 have been used to support the survival of transferred T cells. However, high-dose IL-2 can cause systemic toxicity, induces the expansion of CD4+FoxP3+ regulatory T cells (Treg), which can inhibit antitumor immunity, and may promote activationinduced cell death of transferred TE. IL-15 is a novel cytokine that has a critical role in the maintenance of T-cell memory and may be an alternative to IL-2 for supporting transferred T-cell survival. We administered IL-15 (2.515 ¿g/kg s.c.) to 8 macaques, either daily (n=3) or every 3 days (n= 5), and assessed toxicity and immunological effects. Daily IL-15 increased circulating NK and CD8+ T cells and expanded CD8+CD95+CCR7- effector memory (TEM) and CD95+CCR7+ central memory T cells (TCM). However, daily IL-15 (515 ¿g/kg) accumulated in vivo, causing reversible toxicities. Intermittent IL-15 treatment was safe, increased NK cells and CD8+ TEM or TCM, without boosting the CD4+ Treg. We are currently evaluating the administration of IL-15 to support adoptively transferred CD8+ TE in macaques. As previously reported, TCM-derived CD8+ TE transferred without cytokines persisted in vivo at low levels of 0.20.8% of CD8+ cells. By contrast, TE given with IL-15 persisted for up to 2 years at high levels (up to 10 % of CD8+ lymphocytes) after treatment in 2 animals. The transferred TE reverted to the memory pool and migrated to memory niches. Thus, IL-15 may provide an alternative to IL-2 to support the persistence of transferred TE in human immunotherapy.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 中心，不一定是研究者的机构。 抗原特异性 CD8+ 效应 T 细胞 (TE) 的过继转移被用于治疗人类病毒和恶性疾病，并取得了一些成功，然而，转移的 TE 的体内持久性不一致或较短已被认为是该方法的局限性。白细胞介素 (IL)-2 等 T 细胞生长因子已被用来支持转移的 T 细胞的存活，然而，高剂量的 IL-2 会引起全身毒性，诱导 CD4+FoxP3+ 调节性 T 细胞的扩增。 (Treg) 可以抑制抗肿瘤免疫，并可能促进转移的 TE 激活诱导的细胞死亡。IL-15 是一种新型细胞因子，在维持 T 细胞记忆中发挥着关键作用，可能是 IL-2 的替代品。为了支持转移的 T 细胞存活，我们对 8 只猕猴每天（n=3）或每 3 天（n=5）施用 IL-15（2.5×15 ¿g/kg），并评估毒性。每日 IL-15 增加循环 NK 和 CD8+ T 细胞，并扩大 CD8+CD95+CCR7- 效应记忆 (TEM) 和 CD95+CCR7+ 中央记忆 T 细胞 (TCM)。 g/kg）在体内累积，导致可逆的毒性，间歇性 IL-15 治疗是安全的，可增加 NK 细胞和 CD8+ TEM 或 TCM，而不会增强 CD4+ Treg。我们目前正在评估使用 IL-15 来支持过继转移的 CD8+。猕猴中的 TE 如先前报道，在没有细胞因子的情况下转移的中药来源的 CD8+ TE 在体内持续保持在 CD8+ 细胞的 0.2-0.8% 的低水平。相比之下，给予IL-15的TE在2只动物治疗后持续保持高水平（高达CD8+淋巴细胞的10%），转移的TE恢复到记忆池并迁移到记忆生态位。 -15 可能提供 IL-2 的替代品，以支持人类免疫疗法中转移的 TE 的持续存在。