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研究生:黃敦頌
研究生(外文):Huang, Tun-Sung
論文名稱:研究山葵萃取物在皮膚移植免疫抑制中的構效關係
論文名稱(外文):Investigating the Structure-Activity Relationship of Wasabi Compounds in Immunosuppression for Skin Transplantation
指導教授:蔡東湖蔡東湖引用關係陳裕仁陳裕仁引用關係
指導教授(外文):Tsai, Tung-HuChen, Yu-Jen
口試委員:胡瑞恒陳方佩林麗純林俊昌
口試委員(外文):Hu, Rey-HengChen, Fang-PeyLin, Lie-ChwenLin, Jiunn-Chang
口試日期:2023-03-24
學位類別:博士
校院名稱:國立陽明交通大學
系所名稱:傳統醫藥研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
語文別:中文
論文頁數:60
中文關鍵詞:山葵1-異硫氰基-6-甲亞磺醯基己烷移植樹突細胞調節性T細胞
外文關鍵詞:wasabi6-(methylsulfinyl)hexyl isothiocyanatetransplantationdendritic cellsregulatory T cells
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器官移植是目前最有效的治療末期器官疾病的方法,但移植後的排斥反應仍是移植體損失和移植後死亡的主要原因。雖然Calcineurin Inhibitors (CNIs)是術後抗排斥用藥的主要藥物,但它們有許多副作用,例如腎毒性和神經毒性。此外,有些患者對常規免疫抑制劑具有抗藥性,需要高劑量治療。因此,我們需要更理想有效的免疫抑制策略。Dendritic cells (DCs) 樹突細胞在免疫反應immunity和免疫耐受性immune tolerance方面有著很重要的作用,而從山葵中提取的6-(methylsulfinyl) hexyl isothiocyanate (6-MITC)等天然化合物可以調節DCs的免疫反應。在我們實驗室中,目標藥物6-MITC及其衍生物6-(methylsulfenyl) hexyl isothiocyanate (I7447) 以及6-(methylsulfonyl) hexyl isothiocyanate (I7557) 具有抗癌作用。此外,文獻顯示這些化合物具有抗菌性,暗示其對移植後常見併發症如感染及de novo malignancy原發癌等具有潛在用途。然而,目前對於這些用藥對異體抗原識別和T細胞活化的影響仍不清楚。本研究旨在研究6-MITC及其衍生物I447及I7557對人類myeloid dendritic cells的分化differentiation和成熟maturation的影響,並在實驗大鼠皮膚移植模型中評估其免疫調節效應。本研究的發現可能開發有效的免疫抑制策略,以保護免疫功能並減少移植患者的排斥風險。
本研究進行了對human monocyte-derived Dendritic Cells進行實驗,使用的研究方法包括利用trypan blue exclusion test測定細胞存活率、流式細胞儀flow cytometry測定表面抗原表達、Liu's染色看細胞形態、carboxyfluorescein succinimidyl ester (CFSE)測定CD4+CD45RA+ T cell增殖、ELISA測定不同細胞激素cytokine。在in vivo實驗中將Wistar大鼠的皮膚移植到Sprague Dawley大鼠身上,以此建立組織排斥模型,評估皮膚移植的存活和組織學。通過測量血清中的ALT和creatinine來評估肝臟和腎臟毒性,並使用Foxp3的免疫組織化學染色來評估脾臟內的regulatory T cell表現。我們透過測量細胞增殖和interferon-γ的生成來檢測化合物對allogeneic naive T cells的刺激活性。
結果顯示,這三種化合物對DC存活率沒有顯著影響,但細胞型態在高濃度10μM時減少了樹突的形成。在高濃度10μM時,6-MITC和I7557抑制CD1a和CD83的表達。同時6-MITC和I7557抑制了DC釋放IL-10和TGF-β,但不抑制IL-12的釋放。在動物實驗中,使用6-MITC和I7557治療的大鼠可以延長皮膚移植體的存活時間,改善表皮完整性,減少皮膚內的炎症反應。此外,這兩種化合物還可以在皮膚移植大鼠的脾臟中增加regulatory T cell的表現。使用這些化合物治療不會影響大鼠的肝毒性及腎毒性。
結論是: 6-MITC和I7557能誘導人類突觸細胞DCs分化成tolerogenic phenotype,延長大鼠皮膚移植的生存時間。這些化合物有潛力成為移植抗排斥用藥。
Organ transplantation is the most effective therapy for end-stage organ disease. However, graft rejection remains a major cause of graft loss and mortality after transplant. Calcineurin inhibitors (CNIs) are the mainstay of immunosuppressive therapy, but they have limitations, including side effects such as nephrotoxicity and neurotoxicity. Moreover, some patients are refractory to conventional immunosuppressants, requiring high doses of therapy. Thus, the development of novel and more effective immunosuppressive strategies is necessary. Dendritic cells (DCs) play critical roles in the immune response and immune tolerance, and natural compounds such as 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) extracted from Wasabia japonica can modulate the immune response of DCs. In our laboratory, the target drug 6-MITC and its derivatives 6-(methylsulfenyl)hexyl isothiocyanate (I7447) and 6-(methylsulfonyl) hexyl isothiocyanate (I7557) have anti-cancer effect. Additionally, these compounds have been reported in the literature to possess antimicrobial properties, suggesting their potential use in managing post-transplant complications such as de-novo malignancy and infection. However, their effect on alloantigen recognition and T-cell activation remains unclear. The aim of this study is to investigate the impact of 6-MITC and its derivatives on the differentiation and maturation of human myeloid dendritic cells in vitro and assess their immunomodulatory effects in an experimental rat skin transplantation model. The findings of this study may provide insights into the development of novel and more effective immunosuppressive strategies to preserve immune function and reduce the risk of rejection in transplant patients.
The study involved conducting in vitro experiments on human monocyte- derived DCs using several assays including the trypan blue exclusion test, flow cytometry, Liu’s stain, carboxyfluorescein succinimidyl ester (CFSE) assay, and ELISA. Skin allografts from Wistar rats were transplanted to Sprague Dawley rats to create an experimental tissue rejection model, and the survival and histology of the skin allografts were evaluated. The study also assessed liver and renal toxicity by measuring serum alanine aminotransferase and creatinine, and evaluated regulatory T cells using an immunohistochemical stain for Foxp3 in the spleen. The researchers examined the stimulatory activity of the compounds on allogeneic naive T cells through measuring their proliferation and interferon-γ production. The results showed that the three compounds did not significantly affect DC viability but reduced the formation of dendrites at higher concentrations of 10 μM. At this concentration, 6-MITC and I7557, but not I7447, inhibited the expression of CD1a and CD83. The release of IL-10 and TGF-β, but not IL-12, by DCs was inhibited by 6-MITC and I7557. For stimulatory activity on allogeneic naive T cells in terms of proliferation and interferon-γ production, both 6-MITC and I7557 exhibited dual effects with augmentation at lower concentrations and suppression at higher concentrations. Treatment with 6-MITC and I7557 prolonged skin graft survival, improved the integrity of the epidermis, and reduced dermal inflammatory reactions. Furthermore, both compounds led to an accumulation of regulatory T cells in recipient rat spleens. No evidence of renal or liver toxicity was found with treatment. In conclusion, the use of 6-MITC and I7557 promotes the differentiation of human dendritic cells into a tolerogenic phenotype, resulting in the prolonged survival of rat skin allografts. These compounds hold promise as potential immunosuppressants for the prevention of transplant rejection.
中文摘要...................................................i
Abstract.................................................iii
目錄......................................................vi

1. Introduction............................................1
1.1 Introduction of immunosuppressants in transplantation............................................1
1.2 Unmet medical needs of immunosuppressants..............2
1.3 Different phenotype of dendritic cells lead to either immunostimulatory response or immune tolerance.............3
1.4 Natural products for immunomodulation..................5
1.5 Structural Activity Relationship between 6-MITC and its derivatives................................................6
1.6 Objectives of this study...............................7
2. Materials and Methods...................................8
2.1 The chemical substances in the preparation of Wasabi ( 6-MITC, I7447, I7557)......................................8
2.2 Cultivation of dendritic cells.........................8
2.3 Morphological observation of 6-MITC and derivatives-treated DCs................................................9
2.4 Number of viable cells.................................9
2.5 Analysis through flow cytometry.......................10
2.6 Allogeneic naïve T cell proliferation and cytokines secretion.................................................10
2.7 Detection of cytokines induced by dendritic cells and simulated allogenic Naïve T cells.........................11
2.8 Animals...............................................11
2.9 Skin Transplantation Model............................12
2.10 Drug Preparation and Treatment.......................12
2.11 Histological Evaluation..............................13
2.12 Immunohistochemical Analysis.........................13
2.13 Evaluation of Leukocyte Count, Hepatic, and Renal Function..................................................14
2.14 Statistical analysis.................................14
3. Results................................................14
3.1 Morphological Features................................14
3.2 Effect of 6-MITC and its derivatives on dendritic cell viability.................................................15
3.3 Modulation by 6-MITC and its derivatives on dendritic cell surface marker expression............................15
3.4 Secretion of cytokines from dendritic cell in the presence of 6-MITC and its derivatives....................16
3.5 Effect of 6-MITC and I7557 on dendritic cell stimulation of Allogeneic Naive T Cells...............................16
3.6 Effect of 6-MITC and I7557 on transplanted skin allograft survival........................................17
3.7 Histological analysis of skin allograft treated by 6-MITC and I7557............................................17
3.8 Immunohistochemical study of Fox-p3 in the spleen.....18
3.9 Evaluation of hepatotoxicity and nephrotoxicity by 6-MITC and I7557............................................19
4. Discussion.............................................20
4.1 Potential immunosuppressive agent of 6-MITC and I7557.....................................................20
4.2 6-MITC and I7557 inhibit dendritic cell maturation and induce immunotolerance....................................20
4.3 6-MITC and I7557-treated rats had higher expression of CD4+CD25+Foxp3+ regulatory T cells in the spleen..........21
4.4 Comparable effects of 6-MITC and I7557 with FK-506 on prolonging skin allograft survival and increasing the population of Tregs in the spleen.........................21
4.5 Cytokine profiles and immune tolerance status.........22
4.6 Structure-activity relationship (SAR) of wasabi compounds.................................................23
4.7 The potential use of 6-MITC and I7557 in mitigating the adverse effects associated with CNIs and promoting immunotolerance...........................................24
4.8 Rat Skin Allograft Transplantation Model..............24
4.9 Limitation and future direction.......................25
5. Figures................................................28
Fig.1 Morphological changes in 6-MITC, I7447, and I7557-treated monocyte-derived DCs suggest an immature status during DC development.....................................28
Fig. 2 Histogram from flow cytometric analysis revealed that the average size of the dendritic cells decreased progressively with increasing concentrations of these compounds.................................................29
Fig. 3 There were no statistically significant differences in the viability of dendritic cells treated with 6-MITC, I7447, and I7557..........................................30
Fig. 4 The 6-MITC and I7557 exhibited a dual effect on the CD1a and CD83 expression..................................31
Fig. 5 The secretion of IL-10 and TGF-β was inhibited by 6-MITC and I7557 in a dose-dependent manner, whereas IL-12 in a crescendo-decrescendo pattern...........................33
Fig. 6 6-MITC showed no significant effects on allogeneic CD4+CD45RA+T cells, whereas I7557 had dual effects on T cells.....................................................34
Fig. 7 6-MITC and I7557 maintains skin allograft integrity 14 days after skin transplantation........................35
Fig. 8 6-MITC and I7557 prolongs skin allo-graft survival by maintaining the survival area..........................36
Fig. 9 6-MITC and I7557 reduce the inflammatory reaction with improved integrity of the epidermis and less marked inflammatory cell infiltration compared with the DMSO vehicle controls..........................................37
Fig. 10 The I7557- and 6-MITC-treated groups exhibited higher regulatory T-cell expression compared with the control group.............................................38
Fig. 11 no significant differences between the control, 6-MITC, I7557, and FK506-treated rats in either ALT or creatinine levels.........................................40
6. Tables.................................................41
Table 1 Chemical structure of 6-MITC and derivatives......41
7. References.............................................42
8. Appendix.............................................47
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