白细胞介素4和白细胞介素13与M2型肺泡巨噬细胞在肺纤维化中的作用研究进展

2型辅助性T细胞(Th2)是CD4+T细胞经抗原刺激后分化的细胞群,其分泌的白细胞介素4(IL-4)/IL-13作用于巨噬细胞,使其经"替代激活"活化为M2型巨噬细胞,从而发挥特定作用;肺组织在受到抗原持续刺激后,存在于肺泡及间充质中的巨噬细胞在经Th2细胞分泌的IL-4和IL-13激活形成M2型肺泡巨噬细胞,从而参与肺纤维化(PF)的进程,可见M2肺泡巨噬细胞在PF中起着重要的作用。本综述以PF为背景,探讨Th2型细胞因子IL-4和IL-13在PF中的作用,M2型肺泡巨噬细胞的抗炎和促纤维化作用,IL-4和IL-13受体在治疗PF中的作用,IL-4和IL-13激活的M2型肺泡巨噬细胞对PF的双重作用,为抗PF药物研究提供思路。     

白细胞介素21的基础与临床研究进展

白细胞介素21是一种新近发现的细胞因子,与其受体结合后可以调节T细胞的增殖,促进B细胞、NK细胞的增殖、分化并能提高NK细胞杀伤活性。本文就IL-21及其受体结构、生物学作用及临床疾病作一综述。     

IL-7及IL-15在肿瘤免疫疗法中的应用

嵌合抗原受体T细胞(CAR-T)免疫疗法经过体外将正常T细胞进行基因修饰后,再回输入患者体内,以非人类白细胞抗原(HLA)依赖性方式识别肿瘤细胞并进行杀伤。自2017年美国食品药品监督管理局(FDA)批准了诺华及Kite公司两款嵌合抗原受体T细胞产品上市以来,嵌合抗原受体T细胞疗法在全球展开蓬勃发展。白细胞介素-2(IL-2)、白细胞介素-4(IL-4)、白细胞介素-7(IL-7)、白细胞介素-15(IL-15)、白细胞介素-21(IL-21)等细胞因子可促使嵌合抗原受体T细胞在体外有效增殖。本文主要对白细胞介素-7及白细胞介素-15进行阐述,探讨其作用机理以及临床应用。     

IL-23与肿瘤关系的研究进展

IL-23是主要由活化的树突状细胞分泌的白细胞介素,它具有多种生物学功能,主要能促进CD4 T细胞增殖,促进T细胞和抗原提呈细胞产生细胞因子,可以调节树突状细胞的共刺激功能。近年来,许多研究发现IL-23参与许多炎症、肿瘤及自身免疫病。本文主要综述IL-23在肿瘤中作用的研究进展。     

白细胞介素-21的基础与临床

白细胞介素(IL)-21主要来源于CD4 T细胞,与IL-2,IL-15有较高的同源性;其对应的受体由IL-21R和γc两个亚单位构成,前者在氨基酸序列上与IL-2Rβ或IL-4Rα具有很高的一致性,后者则为IL-2,IL-4,IL-15等细胞因子受体的共用γ(commonγ,γc)链,是IL-21启动信号转导中不可缺少的亚单位。通常,γc介导的IL-21信号转导通过JAK1,JAK3,以及STAT1和STAT3途径而得到执行,影响B细胞、NK细胞和T细胞等免疫功能的发挥,表现出复杂的生物学效应。鉴于IL-21所具有的多种免疫活性,推测其在肿瘤的防御机制中扮演着重要角色。本文就IL-21及其受体结构、生物学作用、抗肿瘤作用及临床应用作一简介。     

白细胞介素17及其与多种疾病的关系

白细胞介素17（IL-17）是近年来发现的一种前炎性细胞因子,主要由辅助性T细胞17（Th17）特异性分泌,也可由多种固有免疫细胞等分泌。虽然IL-17的作用至今仍未完全明确,但已发现其具有强大的招募中性粒细胞、诱导多种细胞分泌炎症细胞因子和趋化因子等多种生物学功能,并与人体多种疾病有着密切的联系。本文对IL-17的来源、生物学活性及其与人体各系统临床常见疾病的关系作一简要综述。     

人白细胞介素10 cDNA的克隆及其真核表达载体的构建

<正>白细胞介素10(interlekin-10,IL-10)是已知的细胞因子网络中为数不多的一种抑制性细胞因子,主要由Ⅱ型辅助T细胞分泌产生,具有重要的免疫调节功能和抗炎作用,其生物学效应在重症感染、自身免疫性疾病和器官移植等疾病的发生、发展和转归过程中发挥着重要的调节作用,已有的研究资料显示IL-10有望成为临床相关疾病治疗的新选择。本文旨在利用RT-PCR技术从人外周血单个核细胞中克隆人IL-10的cDNA并构建其真核表达质粒,为进一步研究IL-10基因在细胞内的表达特征及其影响因素和探讨临床     

氨茶碱对大鼠哮喘模型支气管肺泡灌洗液IL-12、IL-13 mRNA表达的影响

细胞因子白细胞介素-12(IL-12)和IL-13是由多种炎症细胞产生,调节T淋巴细胞的增殖和分化,肺内IL-12和IL-13被认为是两个关键细胞因子调节哮喘发病时异常的免疫过程[1].     

IL-2对免疫激活和免疫耐受的双向调节作用

白细胞介素2(interleukin-2,IL-2)从被发现迄今已有30余年,但仍然是最受关注和被广泛研究的细胞因子之一。IL-2最初是从T细胞培养上清液中分离获得,并对体外培养的T细胞具有促进增殖作用,因此传统认为IL-2是一种激活T细胞,并维持T细胞分化和增殖的T细胞生长因子,同时也参与炎症或自身免疫性反应。近年来,人们在IL-2或IL-2R缺陷小鼠动物模型等的研究中发现IL-2的主要功能不仅是提升免疫反应,更重要的是维持Treg细胞的稳定及其介导的免疫耐受,故具有双向免疫调节作用,这些对IL-2生物学活性的新发现,也促使人们开始重新评价和认识临床使用IL-2的疗效、适应症和给药方式。     

临床联合使用白介素Ⅱ概况

白介素(interleukin, IL)是一类介导白细胞间相互作用的细胞因子,迄今发现的IL已多达15种以上,命名为IL-1,IL-2……IL-15等.IL-2(T细胞生长因子)是在巨噬细胞或单核细胞分泌的IL-1参与下,通过促细胞分裂剂(如ConA、PHA等)或特异性抗原刺激,由辅助T细胞产生的一种淋巴因子,目前在临床上主要用于肾细胞癌、恶性黑色素瘤、恶性淋巴瘤及其他恶性肿瘤的治疗,对免疫缺陷病(如AIDS)、病毒、细菌、真菌或原虫感染(如肝炎、结核病、麻风病)及中毒性休克、烧伤后感染等均有一定疗效.近年来IL-2在联合使用方面具有更大的价值,现将有关情况综述如下.     

Role of interleukin-21 in inflammation and allergy

Interleukin-21 (IL-21) is a newly described cytokine, produced by activated CD4+ T cells. Since the discovery in 2000, IL-21 has been the object of intensive research because of its homology to IL-2, IL-4 and IL-15, and its ability to modulate both innate and adaptive immune responses. IL-21 mediates its functions through a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL-21R) and the common gamma-chain, that is shared with IL-2, IL-4, IL-7, IL-9, IL-13, and IL-15 receptors. IL-21R is originally described on T, B and NK cells, which is in accordance with the cell types that mostly respond to IL-21. Indeed, IL-21 augments the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and terminally differentiated plasma cells, and moreover, enhances the activity of natural killer cells. More recently, IL-21R has also been documented on non-immune cells, raising the possibility that IL-21 is an important mediator in the cross-talk between immune and non-immune cells. As discussed in this review, the potential role of IL-21 in immune-mediated and allergic diseases would seem to suggest that either disrupting or enhancing IL-21 signaling may be useful in specific clinical settings.     

Interleukin-21 in immune and allergic diseases

Interleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, plays a major role in the control of innate and adaptive immune responses. IL-21 biological activity is mediated by binding of the cytokine to a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL-21R), and the common γ-chain, that is shared with IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. IL-21 stimulates the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, and enhances the activity of natural killer cells. IL-21 controls also the activity of non-immune cells, such as epithelial cells and stromal cells. The demonstration that IL-21 is involved in the immune responses occurring in chronic inflammatory and allergic diseases suggests that either disrupting or enhancing IL-21 signalling may be useful in specific clinical settings.     

白细胞介素7受体在淋巴细胞发育和多发性硬化中的研究进展

摘要： 白细胞介素 7 受体 （IL7R） 属于Ⅰ型细胞因子受体家族成员的跨膜受体, 由特异性α链和γ链组成, 在淋巴前体细胞、 祖 B 细胞、 T 细胞、 胸腺细胞、 树突状细胞、 髓样细胞及单核细胞中均可表达。生理情况下, IL7R 是淋巴细胞发育中的关键调控分子。IL7R 在多发性硬化 （MS） 的发生中发挥了重要的作用, 其多态性与 MS 密切相关; IL7Rα 中和抗体可显著改善实验性变态反应脑脊髓炎小鼠模型的表型。上述研究提示 IL7R 可能是 MS 新的治疗靶点。     

IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues

IL-22, also termed IL-TIF, is a member of the IL-10 family of cytokines. Its principal source appears to be memory CD4 T cells with a Th1 polarized phenotype. IL-22 induces its signals through a two-component receptor comprised of IL-22R1 and CRF2-4/IL10Rb. Both of these receptor components also participate in separate receptor complexes specific for other IL-10 family cytokines. Because CRF2-4 exhibits ubiquitous expression, the tropism of IL-22 action appears to be dictated by the expression of IL-22R1. IL-22R1 has a highly restricted expression pattern. Its highest expression, by far, is in the acinar cell population of the pancreas. Lower, but still functional, levels of expression are also observed in skin, colon, liver, and kidney. The responses that have been observed to date for IL-22 resemble the "acute phase" type responses elicited by IL-6, suggesting that IL-22 might be appropriately considered as a T cell-derived IL-6-like activity having distinct target cell specificity. The functional role of this system remains unclear, but it is likely that the responses elicited by this cytokine serve to contribute both to acute host defense against pathogens and to safeguard vulnerable target tissues under conditions of stress.     

Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2

Interleukin 22 (IL-22) is a cytokine induced during both innate and adaptive immune responses. It can effect an acute phase response, implicating a role for IL-22 in mechanisms of inflammation. IL-22 requires the presence of the IL-22 receptor (IL-22R) and IL-10 receptor 2 (IL-10R2) chains, two members of the class II cytokine receptor family (CRF2), to effect signal transduction within a cell. We studied the interaction between human IL-22 and the extracellular domains (ECD) of its receptor chains in an enzyme-linked immunoabsorbant assay (ELISA)-based format, using biotinylated IL-22 (bio-IL-22) and receptor-fusions containing the ECD of a receptor fused to the Fc of hIgG1 (IL-22R-Fc and IL-10R2-Fc). IL-22 has measurable affinity for IL-22R-Fc homodimer and undetectable affinity for IL-10R2. IL-22 has substantially greater affinity for IL-22R/IL-10R2-Fc heterodimers. Further analyses involving sequential additions of receptor homodimers and cytokine indicates that the IL-10R2(ECD) binds to a surface created by the interaction between IL-22 and the IL-22R(ECD), and thereby further stabilizes the association of IL-22 within this cytokine-receptor-Fc complex. Both a neutralizing rat monoclonal antibody, specific for human IL-22, and human IL-22BP-Fc, an Fc-fusion of the secreted IL-22 binding-protein and proposed natural antagonist for IL-22, bind to similar cytokine epitopes that may overlap the binding site for IL-22R(ECD). Another rat monoclonal antibody, specific for IL-22, binds to an epitope that may overlap a separate binding site for IL-10R2(ECD). We propose, based on this data, a temporal model for the development of a functional IL-22 cytokine-receptor complex.     

Targeting interleukin-21 in inflammatory diseases

INTRODUCTION: IL-21, a new member of the type 1 cytokine superfamily, is produced by various subsets of CD4(+) T cells and binds to a composite receptor that consists of a specific receptor, termed IL-21 receptor and the common γ-chain subunit. Initially considered to be a critical regulator of T and B cell function, IL-21 is now known to regulate the activity of many other cell types, including both immune and non-immune cells. AREAS COVERED: In this review, we discuss the biological features of IL-21 and summarize recent advances in the pathogenic role of IL-21 in chronic inflammatory diseases. Moreover, we discuss why IL-21 blockers can have a place in the therapeutic armamentarium for patients with immune-mediated diseases and the potential risks of such treatments. EXPERT OPINION: Data emerging from studies in human and experimental models of autoimmunity suggest that IL-21 is critically involved in the initiation and/or progression of inflammatory reactions where self-reactive immune cells or antibodies cause damage in tissue. Thus, theoretically, targeting IL-21 could help attenuate the activation of inflammatory pathways and facilitate the resolution of tissue damaging immune responses. However, one should also take into consideration some potential risks that could derive from the blockade of IL-21.     

IL-17 cytokine/receptor families: emerging targets for the modulation of inflammatory responses

IL-17 was identified a decade ago as a pro-inflammatory cytokine produced by activated T cells that stimulates the secretion of other cytokines from various non-lymphoid cells by acting through a unique cell surface receptor, IL17R. Evidence that IL-17 may contribute to several immune-mediated diseases, such as rheumatoid arthritis and airway inflammation, prompted much interest in this cytokine. Recently, the large-scale analysis of expressed sequence tags (EST) led to the discovery of novel genes dispersed in the human genome that encode at least five additional cytokines structurally related to IL-17. Screening of EST databases also uncovered at least four novel genes encoding Type I transmembrane proteins with significant homology to IL-17R, thereby forming a family of receptors whose cognate ligands are likely to belong to the IL-17 cytokine family. Initial characterisation of some of these cytokines and one IL-17R homologue demonstrated their involvement in regulating inflammatory responses in a manner similar to, albeit distinct from, that of prototypic IL-17. The IL-17 cytokine/receptor families appear therefore to represent unique signalling systems within the cytokine network that might offer innovative approaches to manipulate immune and inflammatory responses. The prospect of targeting these molecules for therapeutic purposes has generated a substantial volume of patent literature that will be reviewed here.     

重组人白介素21的表达、分离纯化及其体外生物活性的检测

白介素21(IL-21)是最新发现的与白介素2,白介素14和白介素15结构和序列同源的细胞因子.对于T细胞、B细胞和NK细胞有提高免疫应答等多种生物学活性.所以白介素21特别是人源白介素是一个抗肿瘤治疗和其他免疫治疗的一个潜在活性蛋白.为进一步研究IL-21,从刺激过的人外周血单核细胞中成功克隆成熟人白介素21编码基因,经过大肠杆菌密码子偏好的生物信息学分析、突变密码子、转化、诱导和CM-52阳离子交换柱分离纯化,实现了重组人白介素21蛋白在pET22b系统中的无标签表达.并将重组蛋白应用于淋巴细胞增殖实验和直接抗肿瘤(HepG2,K562和MDA)活性检测体外活性检测.结果表明,淋巴细胞增殖与重组人白介素21浓度成正相关,而r hIL-21对人肿瘤细胞无直接抗肿瘤活性.