STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 抗原特异性CD 8+效应T细胞（TE）的过继转移正被用于治疗人类病毒性和恶性疾病，并取得了一些成功。然而，转移的TE的不一致或短的体内持久性已被确定为这种方法的局限性。T细胞生长因子如白细胞介素（IL）-2已被用于支持转移的T细胞的存活。然而，高剂量IL-2可引起全身毒性，诱导CD 4 + FoxP 3+调节性T细胞（Treg）扩增，抑制抗肿瘤免疫，并可能促进活化诱导转移TE的细胞死亡。IL-15是一种新的细胞因子，在维持T细胞记忆中具有关键作用，并且可能是IL-2的替代物，用于支持转移的T细胞存活。IL-15（2.515微克/千克皮下注射）8只猕猴，每日（n=3）或每3天（n= 5），并评估毒性和免疫学效应。每日IL-15增加循环NK和CD 8 + T细胞，并扩增CD 8 + CD 95 + CCR 7效应记忆（TEM）和CD 95 + CCR 7+中枢记忆T细胞（TCM）。然而，每天IL-15（515 μ g/kg）在体内蓄积，引起可逆毒性。间歇性IL-15治疗是安全的，增加NK细胞和CD 8 + TEM或TCM，而不增加CD 4 + Treg。我们目前正在评估IL-15的施用以支持猕猴中过继转移的CD 8 + TE。如前所述，在无细胞因子的情况下转移的TCM衍生的CD 8 + TE在体内持续在0.2%的低水平。0.8%的CD 8+细胞。相比之下，在2只动物中，给予IL-15的TE在治疗后以高水平（高达10%的CD 8+淋巴细胞）持续长达2年。转移的TE恢复到内存池并迁移到内存利基。因此，IL-15可以提供IL-2的替代方案，以支持转移的TE在人类免疫治疗中的持久性。

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.