細胞因子誘導的殺傷細胞

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細胞因子誘導的殺傷細胞Cytokine-induced killer cells, CIK),又稱細胞因子激活殺傷細胞,是一組T細胞-自然殺傷細胞NK)樣表型的適應免疫細胞混合體。醫生通過向外周血單核細胞臍帶血單核細胞中注入干擾素-γ抗CD3單株抗體、重組人體白細胞介素1族2族等細胞因子誘導形成殺傷細胞。

通常情況下,免疫細胞通過識別呈遞在受感染細胞表面的主要組織相容性複合體MHC)而釋放細胞因子,引發細胞裂解英語细胞裂解細胞凋亡。然而,CIK細胞具備不受MHC分子限制的殺傷作用,能夠識別未能呈遞抗原或MHC的受感染細胞甚至惡性腫瘤細胞,並產生迅速及準確的免疫反應。而這些未能呈遞MHC的異常細胞不能被T細胞識別及清除[1][2][3]。這一特殊能力,使得終末分化的CD3+CD56+ CIK細胞能夠具備抗腫瘤細胞毒性,以對抗MHC限制性和非MHC限制性的癌症細胞的能力。該特徵也使得CIK細胞成為治療癌症病毒感染的潛在治療方法之一[4]

命名與歷史[編輯]

「細胞因子誘導的殺傷細胞」的命名,來源於終末分化的CIK細胞成熟必須通過細胞因子刺激。一些資料稱其為「類似T細胞的自然殺傷細胞」,是因為其與自然殺傷細胞有密切關聯。也有人主張將CIK細胞視為自然殺傷細胞的子類[5]

1991年,英戈·G·H·施密特-沃爾夫醫生(G.H. Schmidt-Wolf)首次描述CIK細胞[1],並在1999年開始進行癌症臨床實驗[6]

機制[編輯]

實驗證明淋巴細胞在暴露於干擾素-γ、抗CD3抗體、白細胞介素-1和白細胞介素-2後,能夠裂解新鮮的、非培養的癌症細胞(包括原發性和轉移性癌細胞)。CIK細胞對這些淋巴因子(特別是白細胞介素-2)敏感,並能夠裂解那些對NK細胞或LAK細胞活動產生抗性的腫瘤細胞。

通過抽取外周血或臍帶血(比如簡單的抽血),醫師可以提取出外周血單核細胞臍帶血單核細胞。在一定時效期內,提取出來的細胞在體外暴露於干擾素-γ、抗CD3抗體、白細胞介素-1和白細胞介素-2中;這些細胞因子會強烈刺激CIK細胞的增殖和成熟[1][2][4][7]。之後,成熟的CIK細胞將被回輸給供體或其他異體。

功能[編輯]

因為CIK細胞可以殺死自然殺傷細胞或LAK細胞無法裂解的細胞,所以具備獨特的功能。

CIK細胞同時具備T細胞NK細胞樣表型特徵,二者功能的獨特組合,產生強有力而又廣泛的不受MHC限制的抗腫瘤細胞毒性,具備廣譜抗腫瘤效果[2][4]。CIK細胞識別腫瘤的確切機制和其靶向殺傷作用尚不完全清楚。NK樣細胞除了通過TCR/CD3英語CD3 (immunology),還通過細胞間接觸依賴性的NKG2D英語NKG2DDNAM-1英語DNAM-1NKp30英語NKp30介導來識別腫瘤。這些受體和細胞表面標誌使CIK細胞能夠消滅不呈遞主要組織相容性複合體的細胞,這點可由CIK細胞能夠裂解非免疫原性、異基英語allogeneic同系英語syngeneic的腫瘤細胞證明。特別是實體腫瘤細胞和血液腫瘤細胞均呈遞NKG2D英語NKG2D配體,CIK細胞能夠裂解帶有該標記的癌細胞。此外CIK細胞能夠特異地識別腫瘤細胞和受病毒感染的細胞,而不對健康細胞做出反應[1][2][3][4]

免疫調節性T細胞會抑制CIK細胞的功能[8]

癌症治療的臨床試驗[編輯]

CIK細胞與白細胞介素-2聯合治療癌症療法,已經開始在小鼠和人體臨床實驗中進行,試驗顯示其毒性較低。

在大量的I期和II期臨床試驗中,自體和異體CIK細胞對不同腫瘤實體顯示出廣譜的高毒性潛力,且只有輕微副作用。在許多案例中,CIK細胞治療完全緩解腫瘤,延長患者生存時間並改善生活質量,甚至在癌症晚期也如此。CIK細胞治療的使用限制於臨床研究,但這種治療方法也可能在未來進入一線治療[9][10]

2011年,獨立機構國際CIK細胞臨床實驗目錄(International registry on CIK cells,縮寫IRCC)成立,該機構致力於收集使用CIK細胞的臨床試驗數據和後續分析,以描繪CIK細胞研究的最新狀況,其主要側重於評估CIK細胞治療在臨床試驗中的效果和副作用。[9][10]

發展及挑戰[編輯]

CIK細胞治療仍處於臨床實驗階段[11][12]。在臨床實驗中,研究人員通過細胞因子基因技術(例如白細胞介素-2),成功進行了體外細胞轉染。CIK細胞經過基因改造,增殖率和細胞毒性顯著增加[13]。1999年,基因轉染的CIK細胞首次用於已轉移的癌症治療,共有十例患者參加此次實驗[6]。開始有證據顯示,CIK細胞與樹突細胞相互作用,可以進一步提高抗腫瘤療效;而二者聯合培養更可減少調節性T細胞的數量,從而使CD3+CD56+細胞群體擴增[14][15]。在體外研究顯示,CIK細胞在對特定腫瘤抗原有特異性的嵌合抗原受體英語chimeric antigen receptor引導下,針對呈遞這種抗原的腫瘤細胞的選擇和激活能力有所增加[16][17]。體外實驗和體內實驗還表明,CIK細胞與雙特異性抗體英語bispecific antibodies(能同時與細胞毒性效應細胞和致病抗原結合的抗體)聯合,活性比單獨的CIK細胞要強[18][19]

然而,用於癌症治療的CIK細胞臨床實驗很有限[20][21]。最根本的問題在於,以這種方法培養的免疫細胞靶向性不強[22],CIK細胞無法躲過癌症的免疫抑制、預後效果有限[23];與此同時CAR-T(或聯合使用[24])在實驗中有更好的效果[25]。儘管對於CIK細胞及其治療方法在學術界存有爭議[26],但在中國一些民營醫院(莆田系)已經以高昂收費方式進行、部分省份已將未成熟的CIK治療納入醫保範圍,2016年4月爆發的魏則西事件更將CIK細胞及免疫治療推到風口浪尖[27]

相關條目[編輯]

參考[編輯]

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外部連結[編輯]