朱瑞民2006-07-262018-07-092006-07-262018-07-092003http://ntur.lib.ntu.edu.tw//handle/246246/28715IL-6 是一個具多功能性的細胞素，可以調控細胞生長、分化以及細胞存活。許多 腫瘤細胞都會製造TGFβ1 用以躲避cytotoxic T lymphocyte（CTL）所調節的免疫 反應。而IL-6 可以拮抗TGFβ1 抑制CTL的作用。然而IL-6 是否具有恢復被TGFβ1 所抑制的NK 之功能卻仍未知。我們利用可分泌TGFβ1 的犬傳染性花柳性腫瘤 （CTVT）當動物模式進而研究IL-6 是否能恢復NK 活性的機制。在腫瘤生長期 （P 期）CTVT 幾乎不表現MHC 藉此躲避CTL 所引發的免疫反應。在腫瘤消退 期（R 期）細胞表面會有將近1/3 的MHC 分子大量表現。腫瘤細胞缺乏MHC 表現應該會引發NK 細胞的攻擊。在我們的實驗中發現，P 期的CTVT 會藉由 分泌TGFβ1 抑制NK 的毒殺能力，而使腫瘤細胞不被NK 所攻擊。有趣的是，R 期腫瘤浸潤淋巴球（TIL）會分泌高濃度的IL-6 並拮抗TGFβ1 抑制NK 的能力。 P 期TIL 也會分泌IL-6 但是濃度太低不足以阻斷TGFβ1 抑制NK 的能力。IL-6 的濃度可能必須高過閥值才能用以拮抗TGFβ1 而恢復NK 活性。除此之外，缺 乏TGFβ1 的情況下，TIL 所分泌的IL-6 並不具有活化LAK 的NK 毒殺能力。TIL 分泌高濃度的IL-6 用以阻斷腫瘤所分泌的TGFβ1 而讓NK 能力恢復是一個新發 現的機制。這個機制將可有效的應用於免疫治療及腫瘤診斷上。IL-6 is a multifunctional cytokine that regulates cell growth, differentiation and cell survival. Many tumor cells produce TGFβ1, which allows them to evade cytotoxic T lymphocyte (CTL) mediated immune responses. IL-6 antagonizes TGFβ1 inhibition of CTL. However, whether IL-6 restores NK activity, which also is suppressed by TGFβ1, is not known. We used canine transmissible venereal tumor (CTVT), which produces TGFβ1, as a model to determine whether IL-6 restores NK activity. During the progression (P) phase, CTVT cells stop expressing MHC molecules, allowing them to evade the immune response mediated by CTL. During the regression (R) phase, the number of surface MHC molecules increases dramatically on about one third of tumor cells. Tumor cells that loss MHC expression should be targeted by NK cells. In this study, we found that TGFβ1 secreted by CTVT cells suppressed NK cytotoxicity, enabling tumor cells to escape host NK cell attack during P phase. Interestingly, tumor infiltrating lymphocytes (TIL) isolated from regressing CTVT secrete high concentrations of IL-6 and antagonize the anti-NK activity of tumor cell TGFβ1. TIL also produce IL-6 during P phase, but the concentration is too low to block the anti-NK activity of TGFβ1. There is probably a threshold concentration of IL-6 needed to reverse TGFβ1-inhibited NK activity. In addition, in the absence of TGFβ1, IL-6 derived from TIL does not promote the NK killing activity of LAK cells. TIL-derived IL-6 restored the host NK killing activity inhibited by tumor TGFβ1. This new mechanism, in which TIL manufacture high concentrations of IL-6 to block tumor TGF-β1 anti-NK activity, has potential applications in cancer immunotherapy and tumor prognosis.application/pdf395123 bytesapplication/pdfzh-TW國立臺灣大學獸醫學系暨研究所[SDGs]SDG3reporthttp://ntur.lib.ntu.edu.tw/bitstream/246246/28715/1/912313B002375.pdf