Baxevanis Constantin N, Gritzapis Angelos D, Papamichail Michael
Cancer Immunology and Immunotherapy Center, St. Savas Hospital, Athens, Greece.
J Immunol. 2003 Sep 15;171(6):2953-9. doi: 10.4049/jimmunol.171.6.2953.
Interleukin-12 and IL-18 have been demonstrated to potentiate innate immunity in a variety of experimental tumor models, but the functional roles of NK and/or NKT cells and their mechanism of action in these models have not been fully addressed. Through adoptive transfer of NKT cells activated in vitro with a combination of IL-12 plus IL-18 (IL-12/IL-18 NKT) into syngeneic animals, we demonstrate in this study that IL-12/IL-18 NKT cells are essential and collaborate with the host's own NK cells in natural host immunity against the growth of ALC and MC57X syngeneic tumors. The relative roles of the adoptively transferred IL-12/IL-18 NKT cells and endogenous NK cells in host protection were first shown in normal C57BL/6 (B6) mice treated with anti-asialo GM1 Ab that selectively depletes NK cells; second, in B6.TCRJalpha281(-/-) mice specifically deficient for NKT cells; and third, in B6.scid mice that also lack NKT cells. Furthermore, by injecting normal B6 mice with anti-IL-2 and/or anti-IFN-gamma mAb, we could demonstrate that effective innate immunity against both types of syngeneic tumors was dependent on the production of IL-2 and IFN-gamma by the adoptively transferred NKT cells. In vitro studies confirmed both the secretion of IL-2 and IFN-gamma by the IL-12/IL-18-activated NKT cells and their collaborative role with NK cells for lysis of ALC and MC57X syngeneic tumor targets. This is the first description of an antitumor function of IL-12/IL-18 NKT cells adoptively transferred into syngeneic hosts that provides the basis for a new modality in the cellular immunotherapy of cancer.
白细胞介素-12（IL-12）和IL-18已被证明在多种实验性肿瘤模型中可增强先天免疫，但自然杀伤（NK）细胞和/或自然杀伤T（NKT）细胞在这些模型中的功能作用及其作用机制尚未完全阐明。通过将用IL-12加IL-18（IL-12/IL-18 NKT）组合在体外激活的NKT细胞过继转移到同基因动物中，我们在本研究中证明，IL-12/IL-18 NKT细胞在天然宿主免疫抵抗ALC和MC57X同基因肿瘤生长中至关重要，并与宿主自身的NK细胞协同作用。过继转移的IL-12/IL-18 NKT细胞和内源性NK细胞在宿主保护中的相对作用首先在经抗去唾液酸GM1抗体处理以选择性清除NK细胞的正常C57BL/6（B6）小鼠中得到证实；其次，在特异性缺乏NKT细胞的B6.TCRJα281（-/-）小鼠中得到证实；第三，在也缺乏NKT细胞的B6.scid小鼠中得到证实。此外，通过向正常B6小鼠注射抗IL-2和/或抗干扰素-γ单克隆抗体，我们可以证明针对这两种同基因肿瘤的有效先天免疫依赖于过继转移的NKT细胞产生IL-2和干扰素-γ。体外研究证实了IL-12/IL-18激活的NKT细胞分泌IL-2和干扰素-γ，以及它们与NK细胞协同作用裂解ALC和MC57X同基因肿瘤靶标的作用。这是首次描述过继转移到同基因宿主中的IL-12/IL-18 NKT细胞的抗肿瘤功能，为癌症的细胞免疫治疗提供了一种新方法的基础。
