细胞毒性T淋巴细胞相关抗原4的研究进展

细胞毒性T淋巴细胞相关抗原4（CTLA-4）属于B7／CD28家族成员，具有下调免疫应答为主的多种免疫学效应。CTLA-4有多个位点基因多态性，其基因多态性可影响CTLA-4分子的表达和功能，同某些免疫因素相关性疾病有关。CTLA-4可表达于免疫细胞为主的多种细胞，有膜结合和可溶性等两种形式。CTLA-4Ig和抗单抗是CTLA-4用于防治自身免疫性疾病、移植排斥及肿瘤的两种分子，其效能在动物试验及临床应用中已得到证实.     

基因多态与胃癌遗传易感性的关系

基因多态性是一组由遗传决定的性状,它们已显示在中间水平上影响疾病的遗传易患性。胃癌是由环境因素和遗传因素共同引发的恶性肿瘤,研究发现许多基因多态与胃癌的遗传易感性有关。本将就与胃癌遗传易感性有关的几个功能基因的多态性作一综述。     

基因多态与胃癌遗传易感性的关系

基因多态性是一组由遗传决定的性状 ,它们已显示在中间水平上影响疾病的遗传易患性。胃癌是由环境因素和遗传因素共同引发的恶性肿瘤 ,研究发现许多基因多态与胃癌的遗传易感性有关。本文将就与胃癌遗传易感性有关的几个功能基因的多态性作一综述     

细胞毒T淋巴细胞相关抗原4基因C-658T多态性与溃疡性结肠炎相关性研究

,与UC患者的病变范围有显著相关(P=0.037;P=0.0067);UC组C61T基因型频率与对照组相比,差异无统计学意义(P=0.192).结论 CTLA-4基因启动子区C-658T位点T等位基因与中国汉族UC存在显著相关性.     

乙醇代谢酶遗传多态与癌易感性关系的研究

少量至中等量饮酒，可降低人类患某些心血管疾病和肿瘤的危险性，但过量饮酒已确定为上呼吸道化道、乳腺和大肠等的癌危险因素。个体对过量饮酒诱发乙醇相关吕的易感性，与其乙醇代谢酶的遗传多态性密切相关。现已确定乙醛为乙醇代谢的终致癌物，使乙醛易在体内积累的乙醇脱氯酶和乙醛脱氢酶的等位基因型ＡＤＨ２（１）、ＡＤＨ３（１）和ＡＬＤＨ２（２）可使癌易感性增加，并在人癌病例对照研究得到证实。本同时还简述了乙醇诱导     

抗原特异性细胞毒性T细胞体外扩增方法的研究近展

抗原特异性细胞毒性T细胞(cytoxicTlymphocytes,CTLs)在细胞免疫应答中起着重要的效应功能,从而在抗肿瘤和抗感染免疫中发挥着重要作用。由于受到各种因素的限制和影响,抗原特异性CTLs无法在体内有效地诱导和扩增,因此,通过体外诱导和扩增CTLs后再将此CTLs回输到体内是一个比较理想的方法,且具有重要的应用价值,如何高效激活和扩增抗原特异性CTLs是此法能否成功应用的关键。     

稳定表达细胞毒性T淋巴细胞相关抗原CTLA-4的293T细胞株的建立

目的：构建稳定表达细胞毒性 T 淋巴细胞相关抗原-4（cytotoxic T lymphocyte antigen-4, CTLA-4）的293T 细胞株。方法首先从人外周血获取 PBMC 加以 T 细胞活化; PCR 扩增 CTLA-4转录本,连接pUCm-T 质粒引入 HindⅢ和 EcoRⅠ双酶切位点后转入真核细胞表达质粒 pcDNA3．1;重组质粒 pcDNA3．1-CTLA-4经脂质体转染293T 细胞,以抗生素 G418筛选表达 CTLA-4的293T 细胞;定量 PCR、免疫荧光分别检测293T 细胞 CTLA-4表达与细胞定位。结果血样来源 T 细胞经活化后表达 CTLA-4转录本。 HindⅢ和EcoRⅠ双酶切证实重组质粒内 CTLA-4插入序列正确; RT-PCR 及免疫荧光检测证实293T 细胞能够稳定表达目的蛋白 CTLA-4,并定位于细胞膜表面。结论成功构建的 pcDNA3．1-CTLA-4重组真核表达载体,在293T 细胞膜表面实现了稳定表达,为进行相关生物学理论与应用研究打下基础。     

细胞毒性T淋巴细胞相关抗原4（CTLA—4）的研究进展

ＣＴＬＡ－４是Ｔ细胞上的一种跨膜受体，与ＣＤ２８共同享有Ｂ７分子配体，而ＣＴＬＡ－４与Ｂ７分子结合后诱导Ｔ细胞无反应性，参与免疫反应的负调节。基因重组的ＣＴＬＡ－４Ｉｇ可在体内外有效、特异地抑制细胞和体液免疫反应，对移植排斥反应及各种自身免疫性疾病有显著的治疗作用，毒副作用极低，是目前被认为较有希望的新的免疫抑制药物。     

艾灸干预免疫抑制兔细胞毒性T淋巴细胞抗原-4的作用效应分析

目的：比较不同艾灸干预下免疫抑制兔细胞毒性T淋巴细胞相关抗原4(CTLA-4)及程序性死亡受体1(PD-1表达变化的异同。方法：20只大耳白兔随机分为空白组、模型组、艾条灸（MSM）组与隔药饼灸（HPM）组,每组5只,连续7 d腹腔注射环磷酰胺（CTX）诱导免疫抑制模型。造模成功后分别进行MSM与HPM干预,均为隔日灸,共治疗10次。治疗结束后麻醉白兔,取血清、肝脏与脾脏,ELISA检测血清中PD-1、PD-L1含量,免疫组化法检测肝组织PD-1含量,RT-qPCR检测肝、脾组织CTLA-4 mRNA含量。结果：HPM和MSM均可降低免疫抑制下PD-1及PD-L1水平,并可有效抑制脾脏CTLA-4和肝脏PD-1、CTLA-4水平升高,与免疫抑制模型组相比差异均存在统计学意义（P<0.05）,且Pearson相关性检验表明肝组织中CTLA-4与PD-1呈显著正相关（r=0.780 7,P<0.001）。结论：HPM可通过调控多个免疫抑制位点改善机体免疫功能。     

细胞毒性T淋巴细胞相关抗原-4Ig和anti-CD154单抗在移植中的研究进展

细胞毒性T淋巴细胞相关抗原(CTLA)-4Ig和anti-CD154单抗是目前器官移植的新型生物免疫抑制剂.两者均通过阻断协同刺激信号来抑制T淋巴细胞的活化,从而起到免疫耐受作用,在器官移植中有很好的应用前景.CTLA-4 Ig和anti-CD154单抗在动物模型实验中研究发现单用或联用有长久强效的免疫耐受作用能延长移植物的存活期.在临床中的应用尚处于初期,其临床副作用、安全性及长期的疗效有待进一步观察.     

Cytotoxic T-lymphocyte antigen-4 and programmed death-1 function as negative regulators of lymphocyte activation

The B7 family of ligands and receptors plays a critical role in the modulation of immune responses. The B7/cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the more recently identified programmed death ligand/programmed death-1 (PD-L/PD-1) ligand/receptor pairs define pathways that function as rheostats of lymphocyte activation. Analysis of receptor and ligand expression patterns, as well as the phenotype of CTLA-4 or PD-1-deficient mice, strongly suggests that these pathways are nonredundant. Current data suggest that the B7/CTLA-4 pathway functions primarily to attenuate, limit, and/or terminate naïve T-cell activation in secondary lymphoid organs. The PD-L/PD-1 pathway, on the other hand, may primarily attenuate, limit, and/or terminate T-, B-, and myeloid cell activation/effector function at sites of inflammation in the periphery.     

Cytotoxic T lymphocyte-associated antigen-4 polymorphism in patients with rheumatic heart disease

Acute rheumatic fever (ARF) is a systemic inflammatory disease occurring as a consequence of an exaggerated immune response to group A, beta haemolytic streptococcal pharyngitis. The molecular mimicry between human target organs/tissues and specific components of the infectious organism leads to the development of autoimmune reactions and cardiac tissue damage in rheumatic heart disease (RHD). Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T cell activation and proliferation during the immune response. CTLA-4 gene polymorphism has been shown to affect the inhibitory function of CTLA-4. We aimed to analyze the association of CTLA-4 gene locus at position 49 of exon 1 with susceptibility to ARF/RHD. This study included a total of 98 patients with RHD as a sequela of ARF, who fulfilled the revised classification criteria of Jones and 154 healthy unrelated controls. CTLA-4 +49 A/G polymorphism was genotyped by using PCR-RLFP technique. Data was analyzed by binary logistic regression models. The frequencies of GG, GA and AA genotypes were found to be 14%, 47% and 39%, respectively, in patients and 6%, 45% and 49%, respectively, in controls. The GG genotype was found to be significantly different between patients and controls (OR: 3.11; P = 0.016). GA and AA genotypes did not statistically differ between patients and controls. Our data showed a significant association of +49G /G polymorphism in a small patient group with RHD.     

Cytotoxic T-lymphocyte antigen-4-CT60 polymorphism in rheumatoid arthritis

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a functional candidate gene with susceptibility to rheumatoid arthritis (RA). The aim of this work was to investigate the possible influence of the recently described CT60A/G dimorphism of the CTLA-4 gene in the susceptibility to RA in Spanish patients. A total of 433 RA patients and 398 control subjects were included in the study. Genotyping of CTLA-4 CT60 was performed using two different methods: polymerase chain reaction restriction fragment length polymorphism system using an amplification-created restriction site and a TaqMan 5'-allelic discrimination assay. In order to validate results obtained by different methods, a quality-control exercise was performed. No significant deviation in the distribution of the alleles or genotypes of the CT60 was found when we compared RA patient and control groups. In addition, no differences in CTLA-4 CT60 genotypic distribution was found when RA patients and controls were stratified by the presence or absence of the shared epitope. In conclusion, our results do not support an association between CT60A/G polymorphism and susceptibility to RA in the Spanish population, although the contribution of other positions located within the 3' region of the CTLA-4 gene to RA susceptibility cannot be discarded.     

血清可溶性 CTLA-4表达与重症肌无力的相关性研究

目的探讨血清可溶性细胞毒性T淋巴细胞相关抗原-4（CTLA-4）表达与福建地区重症肌无力（ myasthenia gravis ,MG）患者的相关性。方法 ELISA法检测福建地区80例MG患者（ MG患者分为激素未治疗组及激素治疗组,且激素治疗组进一步分为免疫抑制剂治疗组和胸腺切除组）和80例正常对照组血清可溶性CTLA-4（ sCTLA-4）水平。结果 MG激素未治疗组、激素治疗组的sCTLA-4均高于正常对照组[（6．03±3．58） ng/ml、（3．44±2．36） ng/ml vs （0．49±0．95） ng/ml],它们之间的差别具有统计学意义（χ2＝100．67,P＜0．001）;其中激素治疗组sCTLA-4表达水平高于正常对照组（Z＝-9．03,P＜0．001）,而 MG激素未治疗组sCTLA-4表达高于激素治疗组（Z＝-3．37,P＝0．001）;并且激素未治疗组激素治疗前后血清sCTLA-4水平差异有统计学意义（t＝3．10,P＝0．005）;胸腺切除术后sCTLA-4低于手术前（Z＝-2．21,P＝0．04）,而免疫抑制剂治疗前后差异却没有统计学意义（Z＝-1．26,P＝0．21）。结论 sCTLA-4参与MG的发病机制,激素治疗、胸腺切除治疗减少sCT-LA-4表达。     

Meta-Analysis: The Relationship Between CTLA-4 +49 A/G Polymorphism and Primary Biliary Cirrhosis and Type I Autoimmune Hepatitis

Objectives: CTLA-4 exon-1 +49A?>?G (rs231775) polymorphism has been reported to influence the risk for primary biliary cirrhosis (PBC) as well as type I autoimmune hepatitis (AIH-1) in many studies; however, the results still remain controversial and ambiguous. This study aimed to determine more precise estimations for the relationship between CTLA-4 +49 A?>?G polymorphism and the risk for PBC and AIH-1 by using a meta-analysis.

Design and Methods: PubMed, EMBASE and MEDLINE were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association.

Results: Fifteen studies including 3661 patients with PBC and 4427 controls as well as seven studies including 1270 patients with AIH-1 and 1614 controls were identified. Our pooled analysis revealed that G allele of CTLA-4 gene +49A/G polymorphism may confer an increased risk of PBC in overall (p?=?0.001, OR?=?1.29; 95% CI?=?1.13–1.47) and Caucasians (p?=?0.001, OR?=?1.32; 95% CI?=?1.21–1.44). At genotypic level, the codominant, dominant and recessive models showed no significant association with PBC. With respect to AIH-1, the AG genotype demonstrated a trend for association with increased risk of AIH-1 (p?=?0.04, AG vs. AA, OR?=?1.20; 95% CI?=?1.01–1.43). However, the CTLA-4 alleles as well as genotypes in dominant and recessive models were not associated with a risk for AIH-1 in both Caucasians and Asians.

Conclusions: This meta-analysis concluded that the CTLA-4 G allele and the AG genotype were associated with an increased risk for PBC and AIH-1, respectively, suggesting the CTLA-4 +49 A/G polymorphism as a candidate of susceptibility locus to PBC and AIH-1.     

Polymorphisms in Cytotoxic T-lymphocyte Associated Antigen 4 Gene Does Not Affect sCytotoxic T-lymphocyte Associated Antigen 4 Levels in Human Papillomavirus-Infected Women with or without Cervical Cancer

Background: Cervical cancer (CaCx) is the second most common cancer in Indian women. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) + 49 AA polymorphism is known to be associated with CaCx. Current attempt is to use immunotherapy for the treatment of metastatic melanoma and metastatic castration-resistant prostate cancer, i.e., blocking of CTLA-4 using a fully human monoclonal CTLA-4 antibody to disrupt its inhibitory signal. This allows the CTLs to destroy the cancer cells. There is no information available on the soluble level of CTLA-4 on which the immunotherapy is targeted. This is specifically in Indian population including cases with CaCx. Objective: The aim of this study is to evaluate the levels of soluble CTLA-4 (sCTLA-4) in human papillomavirus (HPV)-infected women with or without CaCx and their association with the polymorphism at CTLA-4 + 49 A/G and CTLA-4 −318 C/T genotypes. Materials and Methods: This is an exploratory case–control study involving two groups of HPV-infected women, the cases were with invasive CaCx and the control group was women with the healthy cervix. sCTLA-4 levels were measured using ELISA in 92 CaCx cases and 57 HPV-positive women with the healthy cervix. Results: Both cases and controls have similar sCTLA-4 levels. Comparison of CTLA-4 + 49A/G and −318 C/T genotypes with sCTLA-4 levels among cases and control also did not show any statistically significant difference. Conclusion: The present study suggests sCTLA-4 levels are not affected by a polymorphism at + 49 A>G CTLA-4. Hence, levels of CTLA-4 are similar in both CaCx cases and control group.     

Cytotoxic T-Lymphocyte Antigen-4 Single Nucleotide Polymorphisms Are Not Associated with Outcomes after Unrelated Donor Transplantation: A Center for International Blood and Marrow Transplant Research Analysis

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor hematopoietic stem cell transplantations (HSCT) have been shown to be an independent predictor of inferior relapse-free survival (RFS) and overall survival (OS) compared with those with the AA genotype, in single-center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, nonrelapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in adults with acute myeloid leukemia and advanced myelodysplastic syndrome undergoing a first 8/8 or 7/8 HLA-matched unrelated donor HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of acute and chronic GVHD. An exploratory analysis of other CTLA-4 SNPs, as well as studying the interaction with antithymocyte globulin, also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes.     

Correlation of CTLA-4 polymorphism and the risk of gastric cancer in a Chinese Bai population

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is involved in the regulation of immune responses mediated by T cells. This study aimed to explore the correlation between CTLA-4 gene polymorphisms and the risk of gastric cancer (GC) in the Bai minority population of southwestern China. A total of 422 GC patients and 397 healthy controls (HC) were included in this case–control study. Four single nucleotide polymorphism sites of CTLA-4 gene (rs231775, rs733618, rs16840252 and rs3087243) were selected and analysed. The results showed a significant difference in the rs733618 loci between GC and HC groups. The frequency of the rs733618 polymorphism ‘TC’ genotype was significantly lower in GC group compared to the HC group [odds ratio (OR), 95% confidence interval (CI): .47 (.35–.63), p < .001]. GC cases with dominant genetic model ‘TC + CC’ had a 47% reduced risk of GC [OR, 95%CI: .53 (.40–.71), p < .001]. Subgroup analyses revealed that the rs733618 ‘TC + CC’ genotype was associated with a lower risk of GC in male patients [OR, 95%CI: .42 (.31–.58), p < .001], those aged ≤60 years old [OR, 95%CI: .27 (.18–.42), p < .001], non-drinkers [OR, 95%CI: .21 (.13–.33), p < .001], non-smokers [OR, 95%CI: .38 (.25–.57), p < .001] and individuals without Helicobacter pylori infection [OR, 95%CI: .16 (.10–.26), p < .001]. Further multivariated analyses indicated that individuals with the ‘TC + CC’ rs733618 genotype who were aged ≤60 years old [OR, 95%CI: .42 (.29–.83), p = .032] and had no H. pylori infection [OR, 95%CI: .35 (.28–.76), p = .018] were found to have a protective effect against GC. Additionally, soluble CTLA-4 were significantly lower in GC patients with ‘TC’ and ‘TC + CC’ genotypes (all p < .05). Our findings suggest that the rs733618 polymorphism of CTLA-4 gene may play a critical role in the prevention of GC.     

Association of the A/G polymorphism at position 49 in exon 1 of CTLA-4 with the susceptibility to unexplained recurrent spontaneous abortion in the Chinese population

PROBLEM: To investigate whether the A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, which delivers a negative signal to T-cell activation, confers the susceptibility to unexplained recurrent spontaneous abortion in the Chinese population. METHOD OF STUDY: A total of 168 patients with unexplained recurrent spontaneous abortion (RSA), who were treated in the Renji Hospital affiliated to the Shanghai Second Medical University, were matched against 117 women with normal pregnancy history. Case-control study to compare the frequency of G/A alleles, AA/AG/GG genotypes and A + (AA + AG) /G+ (GG + AG) phenotypes of CTLA-4 between RSA patients and controls were performed. After amplification of CTLA-4 exon-1 region by polymerase chain reaction (PCR), restriction fragment-length polymorphism (RFLP) was used to detect the polymorphism at position 49 in exon-1 of CTLA-4 gene. Statistical significance was tested by SPSS software. RESULTS: There were dissimilar distributions of G/A alleles, AA/AG/GG genotypes and A+/G+ phenotypes of CTLA-4 between RSA patients and controls. The frequencies of G allele (P = 0.032) and GG genotype (P = 0.011) in RSA patients were significantly higher than those in controls, while the frequencies of AG genotype (P = 0.039) and A + (AA + AG) phenotype in RSA patients were decreased significantly (P = 0.011). CONCLUSIONS: Our findings suggest that A/G polymorphism in exon-1 of CTLA-4 is associated with the immunopathogenesis of RSA, and it confers susceptibility to RSA in Chinese population.     

ADAM33基因遗传多态性与支气管哮喘易感性关系的Meta分析

目的:综合评价解整合素金属蛋白酶33 (ADAM33)基因Met764Thr和Pro774Ser位点多态性与哮喘易感性的关系.方法:按照统一的检索策略,检索Pubmed、Ovid-Medline、CNKI及维普数据库中有关ADAM33基因多态性与哮喘易感性关系的病例-对照研究,按照纳入和排除标准选择文献提取相关信息,应用Review Manager 5.0软件进行Meta分析.结果:本研究纳入国内外14篇合格文献,其中Met764Thr位点12篇,共3 418例哮喘病例和3 520例对照;Pro774Ser位点8篇,共2 793例哮喘病例和3 207例对照.Meta分析结果显示,携带764位点Met/Thr或Thr/Thr突变基因型患哮喘的危险性是野生型的1.56倍(OR=1.56,95％CI=1.09～2.22),Pro774Ser位点突变基因型也与哮喘危险性升高有关(OR=1.39,95％CI=1.00～ 1.93).将人群分层后,该两个位点多态性与哮喘的关联均仅见于中国人群(764位点:OR=2.73,95％CI=1.79 ～4.17,774位点:OR =2.32,95％CI=1.30 ～4.15).结论:ADAM33基因764和774位点的突变与哮喘的易感性升高有关.