Cytokine production patterns in cervical intraepithelial neoplasia: Association with human papillomavirus infection
Cytokine production patterns in cervical intraepithelial neoplasia: Association with human papillomavirus infection
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DOI：
10.1093/jnci/89.3.245
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发表时间：
1997-02-05
期刊：
影响因子：
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通讯作者：
Clerici, E
中科院分区：
文献类型：
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作者：
Clerici, M;Merola, M;Clerici, E
背景：生殖器感染某些株人乳头瘤病毒(HPV)与恶变的高风险相关，HPV相关性宫颈上皮内瘤变(CIN)可成为浸润性癌。宿主因素是调节肿瘤生长的关键因素，而调节免疫控制的细胞因子可能特别重要。1型细胞因子白细胞介素2(IL-2)和干扰素γ(干扰素γ)具有免疫刺激作用，因此能够限制肿瘤的生长。2型细胞因子白介素4(IL-4)和白介素10(IL-10)具有免疫抑制作用，因此能够刺激肿瘤生长。目的：分析宫颈上皮内瘤变(CIN)患者外周血单个核细胞(PBMC)分泌细胞因子的情况。方法：30名被诊断为CIN的妇女和10名年龄和性别匹配的健康对照受试者参加了在意大利米兰纳齐奥莱图莫里研究所进行的研究。分析了以下参数：1)镜、细胞学和组织学检查发现宫颈和下生殖道其他部位的HPV感染；2)HPV分型；3)可溶性抗原(流感抗原)或细胞相关的人类白细胞抗原(HLA)同种抗原刺激下PBMC体外产生IL-2；4)有丝分裂原刺激PBMC体外产生1型细胞因子IL-2和干扰素γ，以及2型细胞因子IL-4和IL-10。统计学意义由非参数检验(双侧)确定。结果：30例宫颈鳞癌患者宫颈组织中HPV16、18型感染21例(70%)，均为高度CIN合并HPV感染。在30例CIN患者中，16例(53%)发现HPV感染已扩散到下生殖道的其他部位，从而导致更广泛的疾病，而14例(47%)HPV感染仅限于门静脉。广泛性疾病组PBMC对可溶性抗原或同种异体抗原刺激产生IL-2的能力明显低于局限性疾病组和健康对照组。相反，广泛性疾病组的IL-4和IL-10水平明显高于局限性疾病组和健康对照组。在HPV感染患者中检测到的IL-4和IL-10的产量最高，这些患者已经扩展到生殖道之外。结论：CIN具有不同的免疫学特征，其中HPV感染是否局限于门静脉。在观察到HPV持续感染的妇女中，主要增强潜在保护性细胞介导免疫的细胞因子的产生是有缺陷的。从1型到2型细胞因子的显著转变与更广泛的HPV感染有关。提示：这些数据加强了对CIN患者免疫失调进行详细分析的必要性。他们还提示，细胞因子检测在确定预后或决定是否需要细胞因子治疗方面有潜在的用处。
Background: Genital infection with certain strains of human papillomavirus (HPV) is associated with a high risk of malignant transformation, and HPV-associated cervical intraepithelial neoplasia (CIN) can become invasive cancer. Host factors are critical in regulating tumor growth, and cytokines that modulate immunologic control may be of particular importance. The type 1 cytokines interleukin 2 (IL-2) and interferon gamma (IFN gamma) are immunostimulatory and are thus capable of limiting tumor growth. The type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10) are immunoinhibitory and are thus capable of stimulating tumor growth. Purpose: We analyzed the production of cytokines by peripheral blood mononuclear cells (PBMCs) in women with CIN associated with localized or extensively spread HPV infection. Methods: Thirty women diagnosed with CIN and 10 age- and sex-matched healthy control subjects were enrolled in the study conducted at Istituto Nazionale Tumori, Milan, Italy. The following parameters were analyzed: 1) HPV infection of the cervix and other sites of the lower genital tract by colposcopic, cytologic, and histologic examinations; 2) HPV typing; 3) in vitro production of IL-2 by PBMCs in response to stimulation with soluble antigen (influenza [FLU] antigen) or to cell-associated human leukocyte antigen (HLA) alloantigen; and 4) in vitro production of the type 1 cytokines IL-2 and IFN gamma and of the type 2 cytokines IL-4 and IL-10 by PBMCs in response to mitogen stimulation. Statistical significance was determined by nonparametric tests (two-sided). Results: High-grade CIN associated with HPV infection was detected in all case patients, and HPV type 16 or 18 infection was detected in cervical tissue of 21 (70%) of 30 case patients. HPV infection that had spread to other sites of the lower genital tract, thus resulting in more extensive disease, was detected in 16 (53%) of the 30 individuals with CIN, whereas HPV infection was limited to the portio in 14 (47%). IL-2 production by PBMCs in response to stimulation with soluble antigen or HLA alloantigen was reduced in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. In contrast, IL-4 and IL-10 production in response to mitogen stimulation was elevated in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. The highest production of IL-4 and IL-10 was detected in patients with HPV infection that had extended beyond the genital tract. Conclusions: CIN is characterized by different immunologic profiles, in which HPV infection is or is not confined to the portio. Production of cytokines that mainly enhance potentially protective cell-mediated immunity is defective in the women in whom extended HPV infection was observed. A pronounced shift from type 1 to type 2 cytokine production is associated with more extensive HPV infection. Implications: These data reinforce the need for detailed analyses of immune dysregulation in CIN patients. They also suggest the potential usefulness of the cytokine assays for determining prognosis or deciding whether cytokine-based therapy is indicated.