IL-23及其相关细胞因子在慢性特发性血小板减少性紫癜中的表达与作用探讨

本研究旨在探讨lL-23及其它的IL-12家族成员在慢性特发性血小板减少性紫癜(ITP)的表达及其免疫调节功能。运用反转录实时PCR方法检测30例慢性ITP患者和15例正常对照者外周血单个核细胞(PBMNC)中IL-23p19、IL-12p35、IL-12p40、IL-27、IL-17 mRNA的表达水平,用ELISA方法检测血浆IL-23、IL-12、IL-17含量并分析其在慢性ITP中的表达规律及与T亚群的关系。结果表明,慢性ITP患者及正常人PBMNC均低水平表达IL-23p19、IL-12p35、IL-27、IL-12p40 mRNA;部分患者及正常人PBMNC微量表达IL-17 mRNA。IL-12p35、IL-27、IL-17mRNA的表达水平与正常对照相比无显著差异,IL-23p19、IL-12p40 mRNA的表达水平比正常对照明显减低(p<0.01)。慢性ITP患者血浆IL-12水平高于正常对照者(p<0.01),IL-23、IL-17水平与正常对照者相比无显著差异。结论:ITP患者体内T淋巴细胞异常主要与IL-12相关,可能与IL-23/IL-17调节轴无直接关系。     

Targeting the IL-23/IL-17 axis for the treatment of psoriasis and psoriatic arthritis

Introduction: A growing amount of data supporting the pathogenic role of the IL-23/IL-17 axis in inflammatory/autoimmune disorders has provided the rationale to target the system for therapeutic purpose. Several compounds have been and are currently under intense investigation in psoriasis and psoriatic arthritis (PsA) yielding impressive results.

Areas covered: In this review article, we provide an overview of currently available data on the IL-23/IL-17 system as a target for treatment for psoriasis and PsA. We searched MEDLINE for articles on drug therapy for psoriasis and PsA published between 1 January 2010 and 31 May 2015. One of these agents, ustekinumab, has been recently approved for the treatment of psoriasis and PsA, and a number of IL-23/IL-17-targeted compounds under investigation in these diseases.

Expert opinion: As our knowledge of the role of the IL-23/IL-17 axis in the pathogenesis of psoriasis and PsA deepens, it enables the development of more targeted therapies in the management of these conditions. Early data on IL-23/IL-17 targeting drugs appear promising, although incomplete. Given the key role IL-23/IL-17 in host defence, the safety profile of targeted drugs should be thoroughly assessed in future studies.     

Biological therapy targeting the IL-23/IL-17 axis in inflammatory bowel disease

Introduction: As many inflammatory bowel disease (IBD) patients do not benefit from long-term anti-tumour necrosis factor treatment, new anti-inflammatories are urgently needed. After the discovery of the interleukin (IL) 23/17 axis being pivotal in IBD pathogenesis, many different compounds were developed, targeting different components within this pathway.

Areas covered: A literature search to March 2016 was performed to identify the most relevant reports on the role of the IL-23/IL-17 axis in IBD and on the different molecules targeting this pathway. First, the authors briefly summarize the immunology of the IL-23/IL-17 pathway to elucidate the mode of action of all different agents. Second, they describe all different molecules targeting this pathway. Besides discussing efficacy and safety data, they also explore immunogenicity, exposure during pregnancy and pharmacokinetics.

Expert opinion: A new era in IBD treatment has recently been initiated: besides immunomodulators and TNF-antagonists, anti-adhesion molecules and monoclonal antibodies targeting the IL-23/IL-17 pathway have been developed. Biomarkers for personalized medicine are urgently needed. This therapeutic (r)evolution will further improve disease-related and patient-reported outcome, though a lot of questions should still be addressed in future years.     

Anti-CD6 mAbs for the treatment of psoriasis

ABSTRACT

Introduction

Psoriasis is a chronic inflammatory skin condition known to affect about 1%-3% of the global population. Psoriasis can be a serious burden to the patients, having deleterious effect on their physical, social and mental wellbeing. Systemic therapies consisting of methotrexate, cyclosporine, acitretin, PUVA, etc. used in moderate to severe psoriasis, are associated with end organ toxicity with long term use.     

双歧杆菌对过敏性哮喘儿童DC成熟及其分泌细胞因子的影响

目的研究青春型双歧杆菌对过敏性哮喘儿童外周血单个核细胞（PBMC）来源的树突状细胞（DC）表达CD86和HLA-DR及其分泌IL-1βI、L-6I、L-10、IL-12、IL-23和IFN-γ的影响。方法从15名过敏性哮喘儿童和15名非哮喘儿童的外周血单个核细胞诱导生成未成熟DC,分别加入青春型双歧杆菌或脂多糖（LPS）后继续培养DC 2天,①每天于倒置显微镜下观察DC形态;②用流式细胞仪检测各组DC表面CD86和HLA-DR的分子表达;③用ELISA方法检测培养上清中IL-1βI、L-6I、L-10、IL-12I、L-23和IFN-γ的水平。结果①DC经双歧杆菌和LPS分组处理后第2天,于倒置显微镜下观察到双歧杆菌组和LPS组的DC突起均较空白组明显,具有突起的细胞数量较空白组增多,而双歧杆菌组与LPS组比较,LPS组有突起的细胞数量明显增多,提示DC过度生长。②双歧杆菌刺激后,哮喘儿童DC表面CD86表达明显增高,HLA-DR表达无明显变化,非哮喘儿童CD86和HLA-DR表达均无明显变化;LPS刺激可明显增加哮喘儿童和非哮喘儿童CD86和HLA-DR的表达。③双歧杆菌刺激哮喘儿童DC分泌IL-12、IFN-γI、L-1β及IL-6水平增高,刺激非哮喘儿童DC分泌IL-12I、L-10I、L-1β及IL-23水平增高。结论①过敏性哮喘儿童DC表面CD86的表达可能存在缺陷,双歧杆菌能适度上调其表达,在DC的成熟过程中可能起调节作用。②双歧杆菌能刺激过敏性哮喘儿童DC分泌IL-12和IFN-γ,从而改变Th2优势分化,纠正Th1/Th2失衡。③过敏性哮喘儿童DC分泌IL-10可能存在缺陷,从而影响免疫耐受的形成。④双歧杆菌可能通过刺激哮喘儿童DC分泌IL-1β及IL-6增高,达到促进Th17细胞分化的作用。     

Immunomodulatory neural stem cells for brain tumour therapy

Advances in the understanding of stem cells have enabled the development of novel therapies for brain tumours. Neural stem cells (NSCs) possess the ability to migrate throughout the CNS. By exploiting the tropism of NSCs to various neural pathologies (e.g., glioma, degeneration, stroke and so on) and the delivery of various immunomodulatory cytokines, new treatments for brain tumours have been investigated. These new strategies offer significantly more specificity than existing treatment regimens, such as surgery, radiation and chemotherapy. As methods in isolating and culturing NSCs are better understood, clinical applications of this therapeutic strategy may inevitably emerge. Here, the preclinical advances and the results supporting the effectiveness of stem cell therapies are reviewed. In addition, the obstacles to clinical development and methods to circumvent these caveats are discussed.     

Psoriatic transversal nail grooves on biologics

We noticed transverse grooves on the nails of a psoriasis vulgaris patient being treated with ixekizumab. The indentation might have appeared during the period when the effective concentration of ixekizumab was low and psoriasis activity in the nail matrix had increased shortly before the monthly dose.     

Positioning ustekinumab in moderate-to-severe ulcerative colitis: new kid on the block

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract. Dysregulated innate and adaptive immune pathways contribute to intestinal inflammation in IBD, and cytokines, including IL-12 and IL-23, play a key role. The blockade of both IL-12 and IL-23 may have an impact on different pathways of inflammation and could be effective for the treatment of inflammatory bowel diseases.

Ustekinumab is a fully human IgG1κ monoclonal antibody which binds to the shared p40 protein subunit of IL-12 and ?23. It is currently approved for several immune-mediated diseases such as moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn’s disease, and has shown promising results in UC.

Areas covered: A review of the literature was performed to understand several aspects including the role of IL-12 and ?23 in UC, the potential therapeutic role of ustekinumab in inflammatory bowel disease, and the positioning of ustekinumab in the therapeutic algorithm of UC, based on extrapolated data from available randomized clinical trials.

Expert opinion: Ustekinumab is effective and safe in UC, and shows potential advantages compared to other drugs in moderate-to-severe UC.     

Ustekinumab: targeting the IL-17 pathway to improve outcomes in psoriatic arthritis

ABSTRACT

Introduction: Autologous Stem Cell Transplantation (ASCT) represents the standard treatment in eligible “de-novo” multiple myeloma (MM) patients.

Areas covered: ASCT may be single or tandem, and a single ASCT can be followed by an allogeneic (Allo)-SCT. A systematic review has been conducted to examine the current evidence for the efficacy of using a tandem transplant strategy in MM.

Expert opinion: A tandem ASCT approach should be considered for all patients, although the benefit from the second ASCT in patients who are in complete remission or experience a very good partial response should be answered in a clinical trial. Recent results with the new induction regimens indicate that there is a role for tandem ASCT in the presence of adverse cytogenetic abnormalities. Planned AlloSCT after ASCT has not been found to be superior in the majority of studies and is not recommended outside of a clinical trial. However, single or tandem ASCT are both appropriate options and participation in prospective clinical trials should be encouraged to resolve the debate in the era of novel agents for MM.     

Efficacy and safety of ustekinumab and etanercept for the treatment of psoriasis

Importance of the field: TNF-α inhibitors such as etanercept have been used for psoriasis for years. A fairly well defined efficacy and safety profile has developed. A new biologic agent, ustekinumab, an IL-12 and IL-23 inhibitor, has recently been released in the US for the treatment of moderate-to-severe psoriasis. The purpose of this article is to compare the efficacy and safety profiles of ustekinumab and etanercept.

Areas covered in this review: We examined safety and efficacy data regarding ustekinumab and etanercept from clinical reports, a head-to-head trial, review articles, and databases and registries from the last 20 years.

What the reader will gain: Evidence is reviewed about the efficacy for the treatment of psoriasis as well as the safety profiles for both agents, ustekinumab and etanercept.

Take home message: Both drugs have data to confirm efficacy and safety in patients with moderate-to-severe psoriasis in the short-term. The limited long-term data on the safety profile of ustekinumab requires careful judgment on the clinician's part, weighing well-defined benefits and potential unknown risks.     

IL-23 and IL-27: new members of the growing family of IL-12-related cytokines with important implications for therapeutics

The recent discoveries of the two interleukin (IL)-12-related cytokines, IL-23 and IL-27, reveal that the regulation of cellular immunity is more complex than originally thought. Until these discoveries, the role of IL-12 in modulating cellular immune responses had been overestimated due to the belief that the IL-12 p40 subunit was unique to IL-12. However, because p40 is shared between IL-12 and IL-23, it would be expected that p40^-/- mice are doubly deficient in IL-12 and IL-23. Indeed, the essential role previously attributed to IL-12 in experimental autoimmune encephalitis during studies of p40^-/- mice has been shown to be due to IL-23 instead. The newest addition to the IL-12 cytokine family, IL-27, has unique features as well. Its specific action on naive CD4+ T cells in both mice and humans appears to distinguish it from the other IL-12 family members. Although related, the IL-12 family of cytokines and their receptors have distinct patterns of expression and unique effects on developing immune responses. This review summarises much of the pertinent literature on the IL-12 cytokine family and provides predictions regarding their potential therapeutic roles based on what has been learned about their functions in vitro and in vivo in gene-deficient mice.     

In situ gene therapy for prostate cancer: immunomodulatory approaches

The development of effective treatments for prostate cancer is thwarted by the natural history of the disease. The biological and clinical potential of most individual cancers is uncertain. In many cases the disease will not progress to clinical significance but experimental and clinical studies indicate that prostate cancer can and may metastasise early in the course of the disease from relatively small foci (i.e., not necessarily the largest or index cancer). Localised prostate cancer is potentially curable with localised therapies (radical prostatectomy or irradiation therapy). However, there are no curative therapies for metastatic prostate cancer. Gene therapy, especially those approaches with an immunomodulatory component, may provide additional therapeutic options with the potential to affect both localised and systemic disease. We have pioneered the development and application of in situ gene therapy protocols using adenoviral vectors to transduce specific genes that generate cytotoxic activity and/or a systemic antitumour immune response. In addition we have completed initial studies that demonstrate the therapeutic potential of adenoviral vector-mediated gene modified cell-based vaccines. Our review discusses preclinical studies focused on the development of immunostimulatory in situ gene therapy approaches that hopefully will provide novel and effective treatments for localised and metastatic prostate cancer.     

慢性病毒性肝炎患者血清IL-12水平T细胞亚群的变化及意义

目的研究慢性病毒性肝炎患者血清IL-12水平、T细胞亚群变化及意义.方法分别采用双抗体夹心ELISA法与抗体致敏的红细胞花环试验法,对55例慢性病毒性肝炎患者血清LI-12水平及T细胞亚群进行了测定.结果慢性病毒性肝炎患者IL-12水平、CD 4细胞、CD 4/CD 8比值明显低于正常对照组,而CD 8细胞则明显增高;HBV-DNA阳性组CD 4细胞、CD 4/CD 8比值明显低于HBV-DNA阴性组,而CD 8细胞则明显高于HBV-DNA阴性组,IL-12水平则无显著差别.结论慢性病毒性肝炎患者存在细胞免疫功能低下,免疫调节功能紊乱,IL-12及T细胞亚群的检测对监测慢性病毒性肝炎患者不同临床类型的疾病活动,病毒复制,指导治疗都具有一定的意义.     

结直肠癌患者血清IL-23和IL-10水平的检测及其意义

目的探讨结直肠癌进展过程中,患者血清中几种细胞因子水平的变化及其在肿瘤进程中的意义。方法纳入50例患者及20例健康志愿者,运用ELISA方法检测各组血清IL-23I、L-17I、L-10和IFN-α水平的变化。结果结直肠癌患者血清IL-23和IL-10水平显著高于对照组,而且Ⅳ期患者血清IL-10水平显著高于Ⅰ、Ⅱ、Ⅲ期。结论与IL-17和IFN-α相比,患者血清中IL-23和IL-10表达水平显著增加;此外,患者血清中IL-10的高水平表达可能促进了结直肠癌的发展。     

IL-12及IL-12P40对NK抗肿瘤功能的免疫调节

目的　通过对正常人及肿瘤患者血清中IL 12以及IL 12P4 0含量的检测 ,观察其分子对NK细胞抗肿瘤细胞细胞毒效应的影响 ,探讨IL 12、IL 12P4 0分子在NK细胞抗肿瘤功能上的免疫调节作用。方法　ELISA酶联免疫法检测IL 12、IL 12P4 0分泌水平以及MTT释放法检测NK细胞毒活性。结果　①肿瘤患者外周血PBMC中CD3 、CD5 6 细胞阳性率低于对照组 (P <0 0 5 )。②肿瘤患者NK细胞对NK敏感细胞K5 6 2以及NK不敏感细胞Raji和Ddaudi的杀伤活性均低于正常对照组 (P <0 0 5 )。③正常人外周血NK细胞经含肿瘤患者血清培养后 ,NK细胞杀伤活性明显下降 (P <0 0 5 )。④在肿瘤患者血清中 ,IL 12分泌水平为 14 3 31± 0 93pg ml,高于对照组 84 97± 3 7pg ml(P <0 0 5 ) ;IL 12P4 0含量为 2 2 4 90± 0 7pg ml,高于对照组 32 5 6± 0 7pg ml(P <0 0 5 )。⑤正常人NK细胞经不同浓度 ( 1μg ml、5 μg ml以及 10 μg ml)IL 12诱导后 ,在 5 μg ml、10 μg ml浓度NK细胞杀伤率均高于对照组 ;在肿瘤患者中 ,仅高剂量( 10g ml)IL 12组的杀伤率高于对照组。⑥这种诱导增高的NK细胞杀伤率可被外源性IL 12P4 0的加入而下调。结论　肿瘤患者血清中IL 12P4 0含量的增高可能与肿瘤密切相关的NK细胞功能下降有关。     

~(131)I治疗Graves甲亢前后血清IL-17A/IL-23的动态变化及临床意义

目的通过测定Graves病(GD)患者131I治疗前后血清IL-23/Th17轴相关因子水平,探讨IL-17A、IL-23的动态变化在131I治疗Graves甲亢中的临床意义。方法随机选取本院未接受治疗的GD住院患者30例作为T0组,经131I治疗后1、3、6月分别作为T1组、T3组、T6组,同期健康体检者30例作为对照组,组间在年龄、性别、病程等方面差异无统计学意义(P0.05),具有可比性。采用ELISA法检测GD各组和对照组血清IL-17A和IL-23水平,并结合临床检查FT3、FT4、TSH的结果分析其临床意义。结果 30例Graves甲亢患者在131I治疗前血清IL-17A、IL-23水平显著高于对照组(P0.05);随着治疗的进行,1、3、6月血清IL-17A、IL-23水平逐渐下降,差异均有统计学意义(P0.05);GD患者131I治疗6个月后,T6组患者IL-17A、IL-23双阴性的疗效好于单阴性,双阴性和单阴性的疗效好于双阳性,差异存在统计学意义(Fisher值为13.273,P0.05)。结论动态观察Graves甲亢患者131I治疗前后IL-23/Th17轴相关因子水平的变化具有指导治疗、判断疗效、预测复发等临床意义。     

Brodalumab-an IL-17RA monoclonal antibody for psoriasis and psoriatic arthritis

Introduction: IL-17 is a growing target for autoimmune and inflammatory diseases. Brodalumab is a fully human anti-IL-17RA monoclonal antibody that has been investigated in a range of disease including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease and asthma.

Areas covered: This review aims to summarize up-to-date pharmacological properties of brodalumab and the clinical efficacy and safety data presented in clinical trials. The focus of this review will be on psoriasis, psoriatic arthritis and rheumatoid arthritis although we will briefly touch on the other indications in which the drug has been studied as we feel it adds to our understanding of the IL-17 pathway and highlights areas where research is still needed.

Expert opinion: Brodalumab has shown good efficacy in psoriasis in small but extended studies with a moderate effect on psoriatic arthritis. Brodalumab studies are clearly negative in rheumatoid arthritis and inflammatory bowel disease. The data are equivocal in asthma; however, further studies in this disease are justifiable. The safety profile of this drug thus far is not worrisome although longer studies in more patients are needed.     

Inflammatory cytokines: from discoveries to therapies in IBD

ABSTRACT

Introduction: Although the etiology of inflammatory bowel diseases (IBD) remains unknown, accumulating evidence suggests that the intestinal tissue damage in these disorders is due to a dynamic interplay between immune cells and non-immune cells, which is mediated by cytokines produced within the inflammatory microenvironment.

Areas covered: We review the available data about the role of inflammatory cytokines in IBD pathophysiology and provide an overview of the therapeutic options to block the function of such molecules.

Expert opinion: Genome studies, in vitro experiments with patients’ samples and animal models of colitis, have largely advanced our understanding of how cytokines modulate the ongoing mucosal inflammation in IBD. However, not all the cytokines produced within the damaged gut seem to play a major role in the amplification and perpetuation of the IBD-associated inflammatory cascade. Indeed, while some of the anti-cytokine compounds are effective in some subgroups of IBD patients, others have no benefit. In this complex scenario, a major unmet need is the identification of biomarkers that can predict response to therapy and facilitate a personalized therapeutic approach, which maximizes the benefits and limits the adverse events.     

胸腺肽α_1联合舒利迭治疗哮喘的前瞻性研究

目前认为,哮喘的免疫学改变的核心是辅助T细胞(Th)的2个亚群Th1/Th2比例和功能失衡,表现为Th2细胞的数目增多和功能亢进,而Th1细胞所占比例和应答水平减弱[1].胸腺肽α1具有双向免疫调节作用,它可以使Th1类细胞因子如IL-2、IFN-γ等分泌增加,增强Th1类细胞功能,使Th2类细胞因子如IL-4等分泌减少,抑制过激的体液免疫[2-4].本研究采用胸腺肽α1联合舒利迭治疗哮喘,旨在研究其调节哮喘患者Th1/Th2平衡的机制和临床疗效.     

患者血清IL-12、IFN-γ及LDH在急性髓细胞性白血病化疗中的意义

目的探讨急性髓细胞性白血病（AML）患者化疗前、后血清白细胞介素-12（IL-12）、γ干扰素（IFN-γ）及乳酸脱氢酶（LDH）的变化及其意义。方法按照化疗后是否完全缓解分为完全缓解组（CR）和未完全缓解组（UCR）。采用酶联免疫吸附试法（ELISA）法和全自动生化分析仪酶法,分别测定并比较AML患者化疗前、后血清IL-12、IFN-γ及LDH的变化。结果初诊患者化疗前血清IL-12、IFN-γ含量显著低于正常,LDH高于正常;血清IL-12、IFN-γ、LDH含量与化疗的疗效相关,化疗过程中IL-12、IFN-γ持续降低和LDH持续升高者预后不良。化疗后CR组血清IL-12、IFN-γ含量较化疗前明显增高,LDH明显降低;化疗后UCR组血清IL-12和IFN-γ没有明显增高,LDH无明显下降;而化疗后CR组与UCR组比较,血清IL-12、IFN-γ、LDH差异有显著性（P＜0.05）。结论（1）化疗效果与化疗后血清IL-12、IFN-γ和LDH的含量相关。（2）血清IL-12、IFN-γ等细胞因子的免疫学失衡可能是AML发病的重要因素,也为急性白血病对化疗的原发性耐药研究提供了一条新的途径。（3）血清IL-12IFN-γ和LDH在一定程度上反映了AML的预后。