行政院國家科學委員會專題研究計畫成果報告:NK細胞受不表現MHC且生產TGF-b之CTVT腫瘤中之細胞素的影響,並開發治療不表現MHC且生產TGF-b腫瘤的基因(3/3)
Date Issued
2005
Date
2005
Author(s)
朱瑞民
DOI
932313B002021
Abstract
Canine transmissible venereal tumor (CTVT) has low levels of MHC molecules on the cell surface. CTVT spontaneously regresses after a 4-6 months of growth. CTVT cells secrete high concentrations of TGF-f3 during tumor growth. TGF-f3 inhibits NK cell cytotoxicity. However, CTVT undergoes regression when TGF-f3 concentration remains high because tumor infiltrating lymphocytes (TIL) produce large amounts of IL-6. IL-6 is a strong TGF-f3 antagonist and is one of the key substances that restore NK cell cytotoxicity against CTVT cells. Based on these findings, we devised and tested a new immuno-gene therapy strategy that uses both IL-6 and IL-15. IL-6 antagonized the inhibitory effect of TGF-f3 on NK cell cytotoxicity. In a cell culture system, we evaluated the role of NK cells in tumor regression and the ability of IL-6 and IL- 15 to restore TGF-f3-inhibited NK cell cytotoxicity. Only the treatment using both IL-6 and IL-iS effectively relieved the inhibitory effect of TGF-f3 and activated NK cell cytotoxicity. The IL-6 and IL- 15 only treatments did not increase, or only slightly increased, NK cell cytotoxicity. Electroporation of IL-6 and IL-iS plasmids into BALB/c mice increased the ratio of NK cells in the spleen and promoted splenocyte NK cell cytotoxicity. The IL-6 and IL-15 only treatments did not significantly change the NK cell ratio or the cytotoxicity of NK cells. However, in the IL-iS treatment, there was a slight elevation of NK cell ratio. In CB17/SCID mice, electroporation with both IL-6 and IL-iS plasmids strongly inhibited the growth and establishment of CTVT. IL-6 or IL-iS alone had no effect. In CB17/SCID mice treated with anti-asialo GM-i antibody, which blocks NK cell function, combined electroporation with
IL-6 and IL-15 was unable to suppress CTVT growth. Thus, NK cells play a key role in suppressing tumors with low MHC expression and high TGF-13 secretion. Gene therapy using both IL-6 and IL-15 effectively suppressed the growth and establishment of the tumor.
Subjects
Anti-asialo GM-i Ab
CTVT IL-6
IL-i5
NK cells
Publisher
臺北市：國立臺灣大學獸醫學系暨研究所
Type
report
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