细胞因子诱导的杀伤细胞

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细胞因子诱导的杀伤细胞Cytokine-induced killer cells, CIK),又称细胞因子激活杀伤细胞,是一组T细胞-自然杀伤细胞NK)样表型的适应免疫细胞混合体。医生通过向外周血单核细胞脐带血单核细胞中注入干扰素-γ抗CD3单克隆抗体、重组人体白细胞介素1族2族等细胞因子诱导形成杀伤细胞。

通常情况下,免疫细胞通过识别呈递在受感染细胞表面的主要组织相容性复合体MHC)而释放细胞因子,引发细胞裂解英语细胞裂解细胞凋亡。然而,CIK细胞具备不受MHC分子限制的杀伤作用,能够识别未能呈递抗原或MHC的受感染细胞甚至恶性肿瘤细胞,并产生迅速及准确的免疫反应。而这些未能呈递MHC的异常细胞不能被T细胞识别及清除[1][2][3]。这一特殊能力,使得终末分化的CD3+CD56+ CIK细胞能够具备抗肿瘤细胞毒性,以对抗MHC限制性和非MHC限制性的癌症细胞的能力。该特征也使得CIK细胞成为治疗癌症病毒感染的潜在治疗方法之一[4]

命名与历史[编辑]

“细胞因子诱导的杀伤细胞”的命名,来源于终末分化的CIK细胞成熟必须通过细胞因子刺激。一些资料称其为“类似T细胞的自然杀伤细胞”,是因为其与自然杀伤细胞有密切关联。也有人主张将CIK细胞视为自然杀伤细胞的子类[5]

1991年,英戈·G·H·施密特-沃尔夫医生(G.H. Schmidt-Wolf)首次描述CIK细胞[1],并在1999年开始进行癌症临床实验[6]

机制[编辑]

实验证明淋巴细胞在暴露于干扰素-γ、抗CD3抗体、白细胞介素-1和白细胞介素-2后,能够裂解新鲜的、非培养的癌症细胞(包括原发性和转移性癌细胞)。CIK细胞对这些淋巴因子(特别是白细胞介素-2)敏感,并能够裂解那些对NK细胞或LAK细胞活动产生抗性的肿瘤细胞。

通过抽取外周血或脐带血(比如简单的抽血),医师可以提取出外周血单核细胞脐带血单核细胞。在一定时效期内,提取出来的细胞在体外暴露于干扰素-γ、抗CD3抗体、白细胞介素-1和白细胞介素-2中;这些细胞因子会强烈刺激CIK细胞的增殖和成熟[1][2][4][7]。之后,成熟的CIK细胞将被回输给供体或其他异体。

功能[编辑]

因为CIK细胞可以杀死自然杀伤细胞或LAK细胞无法裂解的细胞,所以具备独特的功能。

CIK细胞同时具备T细胞NK细胞样表型特征,二者功能的独特组合,产生强有力而又广泛的不受MHC限制的抗肿瘤细胞毒性,具备广谱抗肿瘤效果[2][4]。CIK细胞识别肿瘤的确切机制和其靶向杀伤作用尚不完全清楚。NK样细胞除了通过TCR/CD3英语CD3 (immunology),还通过细胞间接触依赖性的NKG2D英语NKG2DDNAM-1英语DNAM-1NKp30英语NKp30介导来识别肿瘤。这些受体和细胞表面标志使CIK细胞能够消灭不呈递主要组织相容性复合体的细胞,这点可由CIK细胞能够裂解非免疫原性、异基英语allogeneic同系英语syngeneic的肿瘤细胞证明。特别是实体肿瘤细胞和血液肿瘤细胞均呈递NKG2D英语NKG2D配体,CIK细胞能够裂解带有该标记的癌细胞。此外CIK细胞能够特异地识别肿瘤细胞和受病毒感染的细胞,而不对健康细胞做出反应[1][2][3][4]

免疫调节性T细胞会抑制CIK细胞的功能[8]

癌症治疗的臨床試驗[编辑]

CIK细胞与白细胞介素-2联合治疗癌症疗法,已经开始在小鼠和人体临床实验中进行,试验显示其毒性较低。

在大量的I期和II期臨床試驗中,自体和异体CIK细胞对不同肿瘤实体显示出广谱的高毒性潜力,且只有轻微副作用。在许多案例中,CIK细胞治疗完全缓解肿瘤,延长患者生存时间并改善生活质量,甚至在癌症晚期也如此。CIK细胞治疗的使用限制于临床研究,但这种治疗方法也可能在未来进入一线治疗[9][10]

2011年,独立机构国际CIK细胞临床实验目录(International registry on CIK cells,缩写IRCC)成立,该机构致力于收集使用CIK细胞的临床试验数据和后续分析,以描绘CIK细胞研究的最新状况,其主要侧重于评估CIK细胞治疗在临床试验中的效果和副作用。[9][10]

发展及挑战[编辑]

CIK细胞治疗仍处于临床实验阶段[11][12]。在临床实验中,研究人员通过细胞因子基因技术(例如白细胞介素-2),成功进行了体外细胞转染。CIK细胞经过基因改造,增殖率和细胞毒性显著增加[13]。1999年,基因转染的CIK细胞首次用于已转移的癌症治疗,共有十例患者参加此次实验[6]。开始有证据显示,CIK细胞与树突细胞相互作用,可以进一步提高抗肿瘤疗效;而二者联合培养更可减少调节性T细胞的数量,从而使CD3+CD56+细胞群体扩增[14][15]。在体外研究显示,CIK细胞在对特定肿瘤抗原有特异性的嵌合抗原受体英语chimeric antigen receptor引导下,针对呈递这种抗原的肿瘤细胞的选择和激活能力有所增加[16][17]。体外实验和体内实验还表明,CIK细胞与双特异性抗体英语bispecific antibodies(能同时与细胞毒性效应细胞和致病抗原结合的抗体)联合,活性比单独的CIK细胞要强[18][19]

然而,用于癌症治疗的CIK细胞临床实验很有限[20][21]。最根本的问题在于,以这种方法培养的免疫细胞靶向性不强[22],CIK细胞无法躲过癌症的免疫抑制、预后效果有限[23];与此同时CAR-T(或联合使用[24])在实验中有更好的效果[25]。尽管对于CIK细胞及其治疗方法在学术界存有争议[26],但在中国一些民营医院(莆田系)已经以高昂收费方式进行、部分省份已将未成熟的CIK治疗纳入医保范围,2016年4月爆发的魏则西事件更将CIK细胞及免疫治疗推到风口浪尖[27]

相关条目[编辑]

参考[编辑]

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  2. ^ 2.0 2.1 2.2 2.3 Schmidt-Wolf, IG; Lefterova, P; Mehta, BA; Fernandez, LP; Huhn, D; Blume, KG; Weissman, IL; Negrin, RS. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells.. Experimental hematology. December 1993, 21 (13): 1673–9. PMID 7694868. 
  3. ^ 3.0 3.1 Lu, PH; Negrin, RS. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency.. Journal of immunology (Baltimore, Md. : 1950). 15 August 1994, 153 (4): 1687–96. PMID 7519209. 
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外部链接[编辑]