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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。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。列出的机构是 对于中心，这是调查员的机构。 抗原特异性CD8+效应T细胞（TE）的适应性转移被用于治疗人类病毒和恶性疾病，并有些成功。但是，已将转移的TE的体内持久性不一致或短暂的持久性被确定为这种方法的限制。 T细胞生长因子（例如白介素（IL）-2）已用于支持转移的T细胞的存活。但是，高剂量IL-2会引起全身毒性，诱导CD4+ FOXP3+调节T细胞（Treg）的扩展，该细胞可以抑制抗肿瘤免疫学，并可能促进激活诱导的TE转移TE的细胞死亡。 IL-15是一种新型的细胞因子，在维持T细胞记忆中具有关键作用，并且可能是支持转移的T细胞存活的IL-2的替代方法。我们每天（n = 3）或每3天（n = 5）管理IL-15（2.5 15»g/kg S.C.）至8猕猴，并评估了毒性和免疫学效果。每日IL-15增加了循环NK和CD8+T细胞，并扩展了CD8+CD95+CCR7效应器记忆（TEM）和CD95+CCR7+中央记忆T细胞（TCM）。但是，每日IL-15（5 15 g/kg）在体内积累，导致可逆毒性。间歇性IL-15治疗是安全的，NK细胞增加了，CD8+ TEM或TCM，而无需增强CD4+ Treg。我们目前正在评估IL-15的给药以支持猕猴中适当转移的CD8+ TE。如前所述，TCM衍生的CD8+ TE在没有细胞因子的情况下转移的情况下，在低水平的CD8+细胞中，体内持续存在。相比之下，在2只动物中，用IL-15给予的TE在高水平（高达CD8+淋巴细胞的10％）上持续了2年。转移的TE逆转到内存池并迁移到内存壁ni。 IL-15可以提供IL-2的替代方法，以支持人类免疫疗法中转移的TE的持续性。