吲哚胺2,3 雙加氧酶 (Indoleamine 2,3-dioxygenase; IDO) 是色胺酸代謝路徑的速率決定酵素，也被報導是樹突狀細胞 (dendritic cells) 的免疫負向調控因子。當樹狀細胞表現IDO 時，會抑制T 細胞增生與活化，而免疫調節T 細胞 (regulatory T cells)被誘發增殖，進而抑制免疫反應，所以我們假設當樹突狀細胞內的IDO 被抑制時有助於引發抗腫瘤的免疫反應。短髮夾型RNA (short hairpin RNA; shRNA) 是一種有效抑制單一基因表現的方式，因此我們構築可生成對專一抑制IDO 的shRNA 的質體，首先分別確認in vitro 與in vivo 能抑制其mRNA 與蛋白質表現後，接下來利用基因槍從腹部皮膚傳遞的方式送入IDO shRNA。結果發現能可減緩小鼠膀胱癌細胞MBT-2與直腸癌細胞CT-26 的腫瘤生長速度與與延長小鼠生存時間；此外若從接受過IDO shRNA 的小鼠分離CD11c+的細胞過繼轉移 (adoptive transfer) 到植入過MBT-2 的小鼠也能減緩腫瘤的生長，此結果顯示CD11c+樹突狀細胞在引發免疫反應時的確扮演重要角色。而經由T 細胞剔除的實驗，得知對抗腫瘤CD4+與CD8+ T 細胞都參與在IDO shRNA 誘發的免疫反應中，其中CD8+ T 細胞扮演比較重要的角色。除此之外使用針對不同序列的IDO shRNA 也得到相似的治療效用，傳遞能抵抗shRNA 的IDO使其表現在樹突狀細胞則失去了對抗腫瘤的效用，此結果顯示此種抑制腫瘤的免疫反應的確是經由IDO，並且不是因為shRNA 作用在錯誤目標引起。而且使用不同的質體DNA 量去刺激小鼠，也可以發現治療的效果與IDO shRNA 的量呈現正相關，更加強了IDO siRNA 的治療效果不是經由非專一性的作用而誘發。IDO shRNA 與Her2/neu DNA 疫苗融合後，更加強MBT-2 腫瘤治療的效果，也暗示IDO shRNA 具有成為免疫佐劑的潛力。另ㄧ方面，若使用與IDO 相似的蛋白質IDO2 的shRNA，也誘導出相似的免疫反應，腫瘤的免疫細胞浸潤以及細胞毒殺反應都顯示出相似的模式，但IDO 與IDO2 之間的關聯目前仍無法釐清。在本次研究中證明只要經由皮膚傳遞IDO shRNA 就能降低in vivo 的樹突狀細胞IDO 表現並引發免疫反應，而且與Her2/Neu DNA 疫苗合併使用能更增強治療效果。此外，IDO2 功能可能也如同IDO，參與免疫反應的調控。

Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme of tryptophan degradating pathway and a negative immunoregulatory molecule of dendritic cells. IDO-expressing dendritic cells suppress proliferation and activation of effector T cells and induce proliferation of regulatory T cells. We hypothesized that knockdown the IDO expression of dendritic cells could elicit the antitumor response. Besides the IDO specific inhibitor, short hairpin RNA (shRNA) is another approach to silence the IDO expression of dendritic cells. Thus, the IDO specific short hairpin RNA (shRNA) was constructed and evaluated the silencing efficiency on the mRNA and protein expression in vitro and in vivo. We observed the slower tumor growth rate and better survival rate on mouse bladder tumor cell MBT-2 and mouse colon cancer cell CT-26 bearing mice after IDO shRNA vaccinated. Adoptive transfer of CD11c+ cells which were isolated from IDO shRNA vaccinated mice was shown delayed tumor progression. The data indicated that IDO low-expressing CD11c+ cells played a critical role in antitumor response. Depletion the CD8+ and CD4+T cells abolished the IDO shRNA induced antitumor responses. Mice vaccinated with IDO shRNA targeting to different sequence induced similar therapeutic efficacy. IDO shRNA-resistant IDO expression vector delivered into dendritic cells abolished the therapeutic effect. It was suggesting that the therapeutic effect is not due to off-target and is dependent on IDO. In addition, the therapeutic effect was dependent on the vaccinated dose of IDO shRNA plasmid. IDO shRNA fused with Her2/neu DNA vaccine further enhanced the therapeutic effect on the bladder cancer model. On the other hand, IDO2 was an IDO-like protein. IDO2 shRNA induced similar antitumor immune responses with IDO siRNA, but the interaction between IDO and IDO2 was still unknown in this study. In conclusion, we provide a novel and simple approach to induce the antitumor immune response through skin delivery of IDO shRNA. Her2/neu DNA vaccine fused with IDO shRNA further enhanced the therapeutic efficacy. Moreover, the IDO2 might involve in immune regulation of dendritic cells.

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