Identification of IFN-γ-producing T cells as the main mediators of the side effects associated to mouse interleukin-15 sustained exposure.
Identification of IFN-γ-producing T cells as the main mediators of the side effects associated to mouse interleukin-15 sustained exposure.
复制标题
DOI：
10.18632/oncotarget.10264
复制
发表时间：
2016-08-02
期刊：
影响因子：
--
通讯作者：
González-Aseguinolaza G
中科院分区：
文献类型：
--
作者：
Di Scala M;Gil-Fariña I;Olagüe C;Vales A;Sobrevals L;Fortes P;Corbacho D;González-Aseguinolaza G
白细胞介素 15 (IL-15) 是一种调节淋巴细胞功能和体内平衡的细胞生长因子。其强大的免疫刺激活性加上明显缺乏毒性，使 IL-15 成为癌症治疗的令人兴奋的候选者，但在某种程度上因其循环半衰期短而受到限制。为了提高 IL-15 的生物利用度，我们构建了在肝脏中表达小鼠 IL-15 (AAV-mIL15) 的重组腺相关载体。注射 AAV-mIL15 的小鼠在血清中表现出持续且载体剂量依赖性的 IL-15/IL-15Rα 复合物水平、IFN-γ 的产生以及 CD8+ T 细胞和巨噬细胞的激活。 AAV-mIL15 的抗肿瘤功效在通过注射 MC38 细胞建立的转移性结直肠癌小鼠模型中进行了测试。 AAV-mIL15 治疗可轻微抑制 MC38 肿瘤生长，并显着提高小鼠的存活率。然而，mIL-15的持续表达与肝脾肿大、肝损伤和血液应激等副作用的发生有关，从而导致骨髓中造血前体细胞的扩张。为了阐明这一机制，我们治疗了 IFN-γ 受体、RAG1、CD1d 和 μMT 缺陷小鼠，并将骨髓细胞从 WT 小鼠过继转移到 RAG1 缺陷小鼠。我们证明，小鼠 IL-15 给药的副作用主要是由产生 IFN-γ 的 T 细胞介导的。 IL-15 诱导效应免疫细胞的激活和存活，这是其抗肿瘤活性所必需的；但是，长期暴露于 IL-15 与主要由产生 IFN-γ 的 T 细胞介导的重要副作用的发生有关。调节 T 细胞激活的策略应与 IL-15 给药相结合，以减少继发不良事件，同时保持其抗肿瘤作用。
Interleukin-15 (IL-15) is a cell growth-factor that regulates lymphocyte function and homeostasis. Its strong immunostimulatory activity coupled with an apparent lack of toxicity makes IL-15 an exciting candidate for cancer therapy, somehow limited by its short half-life in circulation. To increase IL-15 bioavailability we constructed a recombinant adeno-associated vector expressing murine IL-15 (AAV-mIL15) in the liver. Mice injected with AAV-mIL15 showed sustained and vector dose-dependent levels of IL-15/IL-15Rα complexes in serum, production of IFN-γ and activation of CD8+ T-cells and macrophages. The antitumoral efficacy of AAV-mIL15 was tested in a mouse model of metastatic colorectal cancer established by injection of MC38 cells. AAV-mIL15 treatment slightly inhibits MC38 tumor-growth and significantly increases the survival of mice. However, mIL-15 sustained expression was associated with development of side effects like hepatosplenomegaly, liver damage and the development of haematological stress, which results in the expansion of hematopoietic precursors in the bone marrow. To elucidate the mechanism, we treated IFN-γ receptor-, RAG1-, CD1d- and μMT-deficient mice and performed adoptive transfer of bone marrow cells from WT mice to RAG1-defcient mice. We demonstrated that the side effects of murine IL-15 administration were mainly mediated by IFN-γ-producing T-cells. IL-15 induces the activation and survival of effector immune cells that are necessary for its antitumoral activity; but, long-term exposure to IL-15 is associated with the development of important side effects mainly mediated by IFN-γ-producing T-cells. Strategies to modulate T-cell activation should be combined with IL-15 administration to reduce secondary adverse events while maintaining its antitumoral effect.