臺灣博碩士論文加值系統

犬傳染性花柳性腫瘤（以下簡稱CTVT）是一種會經由活的腫瘤細胞直接接種於受傷黏膜而感染之犬隻腫瘤。已知CTVT細胞於實驗接種後會持續生長4-6個月，隨即產生自發性消退。此腫瘤在生長與消退這段期間究竟發生何種免疫機轉躲避宿主的免疫攻擊而持續長期生長？而後宿主本身又是如何對抗腫瘤導致腫瘤細胞快速消退？探討腫瘤細胞與腫瘤浸潤淋巴球之交互作用即為本研究的主題。希望藉以CTVT這獨特的犬隻腫瘤為動物模式，深入瞭解此腫瘤的特性，並試圖找出治療腫瘤的方法。在研究目標（一）我們希望找出腫瘤躲避宿主的免疫機制以及TIL對腫瘤細胞的影響。研究成果發現在腫瘤生長期（P 期）CTVT幾乎不表現MHC抗原，但在接種第十二週時MHC I及II的表現卻戲劇般的急速增加且持續表現至CTVT腫瘤消退。‚R期混合淋巴球-腫瘤反應（MLTR）呈陽性反應，顯示MHC的表現確實能刺激TIL增殖。ƒ進一步發現R期TIL無細胞之上清液可以刺激腫瘤細胞MHC表現，這結果指出腫瘤消退和TIL有密不可分的關係。„ CTVT細胞在不受TIL影響的情況下，腫瘤細胞即沒有表現MHC分子。…加入R期CTVT細胞與TIL共同培養的上清液或TIL單獨培養之上清液之後，CTVT細胞的MHC抗原又會再度的表現。根據研究目標一的結果，CTVT藉由不表現MHC抗原以躲避宿主免疫攻擊的情況下，應該會啟動NK細胞的毒殺作用，然而臨床上可見腫瘤依舊持續生長數個月，似乎並沒有受到NK細胞的影響。在R期腫瘤細胞仍有將近60%不表現MHC抗原的情況下，腫瘤卻快速消退，除了T細胞發揮功能之外，NK細胞的活性似乎也恢復了，究竟R期TIL是如果打贏這場免疫抗爭呢？在研究目標（二）我們對此問題做深入探討。證明了CTVT細胞具有分泌TGF-b的能力，而且不論P或R期都有功能性的TGF-b存在。‚CTVT分泌的TGF-b具有抑制NK細胞的能力。ƒR期TIL分泌IL-6的濃度顯著高過P期。„R期TIL分泌的IL-6具有拮抗TGF-b抑制LAK毒殺能力。… IL-6的濃度必須達到一定的閥值才可以完全拮抗TGF-b的功能。延續目標一及目標二的結果，於研究目標（三），我們希望更進一步探討，R期TIL究竟還會分泌哪種（些）物質刺激宿主MHC的表現？在我們的研究中發現P期和R期的TIL皆會分泌IFN-g，但在TGF-b的作用下，IFN-g刺激MHC表現的功能會被抑制而無法發揮。‚CTVT細胞在經過IL-6 72小時的刺激下，會讓MHC表現顯著增加。ƒ在IFN-g和IL-6共同刺激的情況下，MHC的表現會比單獨加入IL-6或IFN-g高。„ IFN-g和IL-6的協同作用雖可以增加MHC的表現，但IL-6的濃度如果太高則會讓MHC表現下降。…在IFN-g和IL-6的協同作用下會使轉錄因子IRF-1, STAT-1, STAT-3, NF-kB及CREB的表現顯著增加。在具有分泌TGF-b能力的腫瘤，IL-6的存在顯然扮演一個很重要的角色。不僅可以拮抗TGF-b的功能使NK細胞恢復毒殺能力，更可以和IFN-g共同作用刺激MHC的表現。這些發現將有助於研究腫瘤治療上的新方向。

CTVT is a unique tumor of dogs because it can be transplanted to randomly bred recipients by intact, viable cells. Experimentally transplanted CTVT exhibits a predictable growth pattern that includes progressive growth (P phase), stasis (S phase) and regression (R phase). CTVT cells do not express any MHC class I and II molecules during P phase, but express high levels of the molecules during R phase. Which mechanisms occurred between the tumor progression and regression were the interesting things that we want to investigate zealously. The objective of the research described in chapter 2 was to determine the effect of TIL on the expression of MHC I and II molecules in CTVT and on the subsequent regression of this tumor. We found that both MHC I and II molecules suddenly increased 12 weeks after CTVT inoculation, ‚mixed lymphocytes-tumor reaction (MLTR) study provides additional evidence that CTVT cells escape alloreactive T lymphocyte attack by down-regulating MHC I and II expression during P phase; regression follows induction of MHC over-expression and ƒthe increase in MHC expression during R phase was caused by a heat sensitive factor(s) secreted by TIL, and marked the tumor’s transition from P phase to R phase. „R phase CTVT cells lost the ability to express MHC molecules after 1 month of culture in vitro. It is well known that tumors frequently are infiltrated by T lymphocytes and natural killer (NK) cells. The functions of these cell types depend on the level of MHC class I molecules expressed at the surface of tumor cells. Such alteration in MHC I expression consequently should become targets for NK attack, leading tumor regression. However, most tumors maintain their ability to grow in vivo. We discovered that CTVT secretes TGF-b1 at both P and R phases ‚ TGF-b1 inhibited NK activity and escape host immunosurveillance, allowing the tumor to grow vigorously. ƒIn addition, TIL were able to express higher concentrations of IL-6, antagonizing TGF-b1 inhibition of NK activity at tumor regression. CTVT lost expression MHC class I and II in tumor progression phase and TIL secret a heat sensitive factor(s) to induce a re-expression of MHC class I and II during R phase. CTVT cells also secret TGF-b1, a potent inhibitor of immune function, to block the effect of TIL in CTVT growth stage, but high concentration of IL-6 secreted by R phase TIL antagonizes almost completely the immunosuppressive effects of TGF-b1. According to the above results, we further studied which the substances secreted by TIL to induce the MHC expressed. We observed that the TIL secreted IFN-g at both P and R phases. The effect of IFN-g and IL-6 in CTVT cells that secreted TGF-b1 upon the MHC class I and II expression. The changes of levels of involved transcription factors were further studied under the treatment of a variety of concentrations of IFN-g and IL-6 or different combinations of the cytokines. The transcriptional factors IRF-1, STAT-1, STAT-3, NF-k and CREB all increased after treating with IFN-g and IL-6. Our findings will facilitate understanding and further investigation of the mechanisms that initiate host immune surveillance against tumors.

Contents
中文摘要…………………………………………………………………………1
English Abstract ………………………………………………………………4
Chapter 1 Introduction, research objectives and literature Reviews 7
Introduction …………………………………………………………………7
Research objectives…………………………………………………………8
Literature Reviews …………………………………………………………10 Canine transmissible venereal tumor 10
1. Origin and transmission ………………………………………………..10
2. Proliferation characteristics ………………………………………… …12
3. Histological findings ……………………………………………………13
4. Cytology ………………………………………………………………...14
5. Immunity ……………………………………………………………… .15
5-1 CTVT cell
5-1.1 MHC……………………………………………………………..15
5-1.2 Tumor associated antigen ……………………………………….15
5-1.3 Heat shock protein …………………………………………… ..17
5-2 TIL
5-2.1 T cell ……………………………………………………………18
5-2.2 B cell ……………………………………………………………19
5-2.3 Non-T, non-B cells (NK cells) ………………………………… 20
6. Different methods of treatment ………………………………………...20
Tumor cells escape from the immune response 22
1. Loss or down-regulation of MHC class I antigen …………………… ..22
2. Modulation of tumor antigens ………………………………………… 25
3. Defective death receptor signaling ……………………………………..26
4. Lack of co-stimulation …………………………………………………28
5. Immunosuppressive cytokine …………………………………………..28
6. Down regulation of MICA and/or MICB ………………………………30
7. Nonclassical MHC class I --- HLA-G ………………………………….30
References …………………………………………………………………31
Chapter 2 Effect of Tumor Infiltrating Lymphocytes on the Expression of MHC molecules in Canine Transmissible Venereal Tumor Cells ...49
Abstract……………………………………………………………………… .49
Introduction……………………………………………………………………51
Materials and methods………………………………………………………...53
Results…………………………………………………………………………60
Discussions …………………………………………………………………..71 References………………………………………………………………….. .76
Chapter 3 TIL secretion of IL-6 antagonizes tumor-derived TGF-b1 and restores the LAK killing activity 82
Abstract ……………………………………………………………….……82
Introduction………………………………………………………………...83
Materials and methods……………………………………………….…….86
Results……………………………………………………………………...94
Discussions………………………………………………………………..106
References…………………………………………………………………110
Chapter 4 A combinational effect of IL-6 and IFN-g on transcriptional
regulation of MHC expression in TGF-b1-producing tumor
117
Abstract……………………………………………………………………...117 Introduction………………………………………………………………….118
Materials and methods……………………………………………………….121
Results ……………………………………………………………………….128
Discussions…………………………………………………………………...140 References……………………………………………………………………146
Chapter 5 Summary and Discussions 154
Discussions ………………………………………………………………….154
References……………………………………………………………………163
Appendixes I Publications ……………………………………………………..167

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