半乳醣修飾微脂粒作為標靶式抗原運輸載體應用於癌症免疫治療之研究

Taipei Medical University Institutional Repository > 口腔醫學院 > 生醫材料暨組織工程研究所 > 博碩士論文 > Item 987654321/50964

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題名:	半乳醣修飾微脂粒作為標靶式抗原運輸載體應用於癌症免疫治療之研究 The Study of Galactose-modified Liposome as a Targeted Antigen-delivery Carrier for Cancer Immunotherapy
作者:	林宏潤 Lin, Hung-Jun
貢獻者:	劉得任
關鍵詞:	半乳醣;標靶微脂粒;黏膜途徑;樹突狀細胞;癌症疫苗 Galactose;Targeted liposomes;Mucosal route;Dendritic cells;Cancer vaccine
日期:	2013-06-10
上傳時間:	2018-10-04 15:29:39 (UTC+8)
摘要:	在癌症免疫療法研究中，最常見兩種方法為: (1)體外加入腫瘤相關抗原刺激抗原呈現細胞成熟後，再打回體內抑制腫瘤細胞增生 (2)直接將腫瘤相關抗原送入體內，刺激抗原呈現細胞誘導免疫反應。體外刺激法具有體外培養汙染之風險，培養條件、環境不穩定會造成極大差異性，造成需要控制較多複雜性條件以確保安全性，且刺激後再打回的治療方式，較難引起足夠的免疫反應。體內刺激法則受限於複雜之生理環境，一般抗原在傳輸中容易被體內酵素分解，無法順利傳輸至抗原呈現細胞。因此若利用具生物相容性之載體包覆及保護抗原，並有效地傳遞給抗原呈現細胞以誘導抗原專一性免疫反應，即可達到清除、抑制癌化細胞的目的，此方法目前被認為是極具有潛力之癌症免疫療法。本研究利用微脂粒包覆抗原OVA，同時於表面修飾半乳醣結構以標靶樹突狀細胞膜上C型凝集素受體，藉由專一性辨識將抗原有效地傳遞至樹突狀細胞內，以誘導抗原專一性免疫反應。細胞實驗結果中，小鼠骨髓誘導之樹突狀細胞對半乳醣修飾微脂粒組別有較好的吞噬效率，並在給予半乳醣修飾微脂粒刺激後，樹突狀細胞之成熟化標記CD80/86以及抗原呈現分子MHCⅡ表現量皆有明顯提高，釋放較多細胞激素IL-1β、IL-6和IL-12。在動物實驗中，結果顯示由鼻黏膜途徑給予3次半乳醣修飾微脂粒免疫後之小鼠，血清中OVA專一性IgG抗體生成量明顯增加。取出小鼠脾臟細胞，於體外重新給予OVA刺激，發現培養液中細胞激素IFN-γ和IL-4生成量有明顯提升；同時，觀察到能分泌IFN-γ之CD8+ T淋巴球細胞數量增加，整體脾臟細胞也有增生情形。小鼠給予3次免疫後隔周，於皮下接種表現OVA之淋巴癌細胞E.G7 細胞株，發現給予半乳醣修飾微脂粒組別，腫瘤生長情形有顯著抑制的情況。因此認為利用半乳醣修飾微脂粒當作抗原運輸載體，能有效誘發樹突狀細胞吞噬並成熟化，進一步提升抗原專一性之體液免疫反應和細胞免疫反應，具有應用做為癌症免疫相關治療之潛力。 There are two major methods in cancer immunotherapy. In one approach, antigen presenting cells are stimulated with tumor associated antigens ex vivo, and then re-infused into the body. Another approach is using vaccinal method, which tumor associated antigens are directly delivered to antigen presenting cells in vivo. The first approach needs to take more efforts on controlling the culture conditions and environment to abate the risk of pollution, so it takes more complicatedly for the safety. It is also hard to induce potent and long-term immunity. The second approach is restricted that antigen proteins can be easily dissected by the enzymes in the body. It needs to use high biocompatibility materials as carriers to protect the antigens, which ensuring the antigen presenting cells receive the immune stimulation. Thus, this method would become more efficient to induce the immune system eliminating the tumor cells totally. In the present day, the concept of using antigens encapsulated carriers co-delivered to the antigen presenting cells is thought to be the most potential approach in the cancer immunotherapy. The aim of this study is to develop galactose-modified liposomes as the targeting antigen-delivery carriers that can be specific recognized by C-type lectin receptor. In vitro experiments, the galactose-modified liposomes had a higher uptake rate than unmodified liposomes. Furthermore, bone-marrow derived dendritic cells stimulated with galactosed-modified liposomes displayed a high expression of maturation markers CD80/86, antigen presenting molecular MHCⅡ and elicited the production of IL-1β, IL-6 and IL-12. In vivo experiments, the mice administered of OVA-encapsulated galactosed-modified liposomes via the intranasal route showed higher OVA-specific antibody IgG in serum. Splenocytes from galactose-modified liposomes immunized mice were re-stimulated with OVA and showed significant increased production of IL-4 and IFN-γ. In addition, galactosed-modified liposomes enhanced amounts of IFN-γ producing CD8+ T lymphocytes and the proliferation of splenocytes. Moreover, E.G7 tumor growth was significantly inhibited in mice received galactosed-modified liposomes. Overall, these results indicate that galactosed-modified liposomes can elicit an effective antigen-specific immune response, and might be a potent candidate for further clinical antitumor application.
描述:	碩士指導教授-劉得任委員-張育嘉委員-梁碧惠
資料類型:	thesis
顯示於類別:	[生醫材料暨組織工程研究所] 博碩士論文

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