Agonists for the Chemokine Receptor CXCR4

The development of agonists for the chemokine receptor CXCR4 could provide promising therapeutic candidates. On the basis of previously forwarded two site model of chemokine-receptor interactions, we hypothesized that linking the agonistic N-terminus of SDF-1 to the T140 backbone would yield new high-affinity agonists of CXCR4. We developed chimeras with the agonistic SDF-1 N-terminus grafted to a T140 side chain and tested their binding affinity and chemotactic agonist activity. While chimeras with the peptide grafted onto position 12 of T140 remained high-affinity antagonists, those bearing the peptide on position 14 were in part agonists. One chimera was a full CXCR4 agonist with 25 nM affinity, and several chimeras showed low nanomolar affinities with partial agonist activity. Our results confirmed that we have developed high-affinity agonists of CXCR4.     

Atopic Dermatitis and Cytokines: The Immunoregulatory and Therapeutic Implications of Cytokines in Atopic Dermatitis - Part II: Negative Regulation and Cytokine Therapy in Atopic Dermatitis

Atopic dermatitis is an immunologic disease that results in allergic inflammations of the skin. Cytokines are involved in the negative regulation of immunopathogenesis of atopic dermatitis. Negative immune regulation is also achieved by immune cells in addition to cytokines which are subsequently regulated by a counter-regulatory mechanism. Allergen tolerance is an important aspect of the treatment of atopic dermatitis. Recently, the IL-27, IL-21, and IL-10 cytokines were found to be important components of the counter regulatory mechanism that terminates immune response, and protects the host from excessive immune responses. IL-10 and TGF-β are well-known to be involved in the immune tolerance. IL-10 and IFN-γ are promising cytokines with respect to the prevention of allergen sensitization and the induction of allergen-specific tolerance. In particular, IFN-γ has unique tolerogenic effects with respect to pre-sensitized allergens, especially in atopic dermatitis. In this review, the role of cytokines in the immune tolerance and relevant patents are reviewed, and therapeutic strategies are presented based on the immunologic architecture of AD.     

The Antistaphylococcal Effect of Nisin in a Suitable Vehicle: A Potential Therapy for Atopic Dermatitis in Man

Staphylococcus aureus plays a central role in the pathogenesis of atopic dermatitis and is the predominant microorganism both in the lesions and in adjacent clinically normal skin. Chronic infection might aggravate the underlying lesion and serve as a source for further S. aureus infection. Nisin is a non-toxic and non-irritant peptide with no antibiotic-like side effects. In this study the antistaphylococcal activity of nisin in six topical formulations was investigated in diffusion tests and is shown to depend both on the water content and on the technological system. Because topical products often adhere to the stratum corneum for only a short time, the kinetics of antimicrobial activity were examined using a membrane filter technique. Thirty minutes after nisin addition almost no living microorganisms were detectable in different aqueous samples. The results demonstrate the potential of nisin preparations as an alternative to common antibiotics in the treatment of S. aureus infections in atopic dermatitis.     

特应性皮炎的靶向治疗药物研究进展

特应性皮炎(atopic dermatitis,AD)是一种与遗传、免疫功能异常有关的慢性、复发性、炎症性皮肤病,常在婴儿和儿童期即开始发病。     

Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2

To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure–activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.     

Discovery of 1,5-Dihydro-4H-imidazol-4-one Derivatives as Potent,Selective Antagonists of CXC Chemokine Receptor 2

CXC chemokine receptors 1 (CXCR1) and 2 (CXCR2) have been demonstrated to have critical roles in cancer metastasis. Because they share high homology sequences, it is still unclear how to design selective CXCR1 or CXCR2 antagonists. Based on a pharmacophore model we built, compound 2 bearing a 1,5-dihydro-4H-imidazol-4-one scaffold was identified as a selective CXCR2 antagonist with a low CXCR1 antagonism preference. Further optimization and structure–activity relationship studies led to compound C5 that overcame the disadvantages of compound 2 and performed with higher selectivity. It showed excellent oral bioavailability and in vitro anticancer metastasis activity. Further dynamic simulation of the molecular protein complex showed that the amino acid residue K320 of CXCR2 contributed most to the selectivity of C5. This study provides important clues for the design of new CXCR2 selective antagonists, and C5 can be a molecular tool for investigating the difference in the biological function of CXCR1 and CXCR2.     

异位性皮炎患者血清牛磺酸水平的测定

目的:探讨血清牛磺酸水平与异位性皮炎发生的关系。方法:采用高效液相方法,对门诊收集的30例异位性皮炎患者(患者组)和30例正常对照者(对照组)行血清牛磺酸水平的测定。结果:患者组血清牛磺酸水平为(6.25±0.79)mg/L,对照组水平为(10.32±0.65)mg/L,2组牛磺酸水平差别有统计学意义(P<0.01)。结论:异位性皮炎的发生可能与患者血清中牛磺酸水平降低有关。     

CD4+IL-10+调节性T细胞在特应性皮炎患者中的改变

摘要 目的 探讨特应性皮炎患者CD4+IL-10+调节性T细胞及其细胞因子的改变。方法 用流氏细胞仪直接免疫荧光法检测AD患者外周血CD4+IL-10+T细胞的绝对计数和百分率;用酶联免疫吸附试验检测外周血细胞因子IL-10、TGF-β的浓度。 结果AD患者CD4+IL-10+T细胞绝对计数为0.26+0.126×109/L,占CD4+T细胞的百分率是12.76+4.85%;而对照组CD4+IL-10+T细胞绝对计数为0.016+0.007×109/L,占CD4+T细胞的百分率是3.27+1.03%。经t检验,AD患者CD4+IL-10+T细胞绝对计数和百分率均高于对照组,有统计学差异（p <0.05）。 AD患者外周血IL-10浓度为126.59+59.46 pg/ml,高于正常对照组（31.47+10.96 pg/ml）,经t检验,有统计学差异（p<0.05）。AD患者外周血TGF-β浓度为407.23+155.88 pg/ml,高于正常对照组（359.47+99.21 pg/ml）,但经t检验,没有统计学差异（p>0.05）。CD4+IL-10+T细胞绝对计数、百分率均与外周血IL-10浓度呈正相关,有统计学意义（r=0.47,r=0.65, p <0.05）;而与外周血TGF-β无统计学相关性（r=0.15,r=0.21 , p >0.05）。结论 IL-10可能是Trl发挥功能的主要因子,通过下调由Thl和Th2细胞介导的炎症反应过程,参与免疫调节。     

微生态制剂防治特应性皮炎研究进展

研究发现过敏性疾病患儿大便中乳酸杆菌和双歧杆菌数量较健康者减少,有临床试验提示微生态制剂对预防和治疗AD有积极作用。因此,安全的微生态制剂可能为AD的防治提供有效途径。     

婴幼儿异位性皮炎的健康教育与干预研究

<正>异位性皮炎发病率逐步升高,正在成为公共健康的主要问题之一。由于导致异位性皮炎的因素是多方面的,如遗传、年龄、环境、精神、生活习惯等。对异位性皮炎患者仅用药物治疗,只能达到缓解症状的目的,不能祛除引发异位性皮炎的     

A Novel CC Chemokine Receptor 4 Antagonist RS‐1269 Inhibits Ovalbumin‐Induced Ear Swelling and Lipopolysaccharide‐Induced Endotoxic Shock in Mice

Abstract: There is growing evidence that chemokines recruit leukocytes in allergic, inflammatory and immune responses. CC chemokine receptor 4 (CCR4) is implicated as a preferential marker for T helper 2 cells, and the cells selectively respond to CC chemokine ligand 17 (CCL17) and CCL22. We searched for compounds having a profile as a CCR4 antagonist from an in‐house library and have previously reported that 3‐{2‐[(2R)‐2‐phenyl‐4‐(4‐pyridin‐4‐ylbenzyl)morpholin‐2‐yl]ethyl}quinazoline‐2,4(1H,3H)‐dione (named RS‐1154) was capable of significantly inhibiting the binding of [¹²⁵I]CCL17 to human CCR4‐expressing CHO cells. From further synthesis of its derivatives, we newly focused on 3‐(isobutyrylamino)‐N‐{2‐[(2R)‐2‐phenyl‐4‐(4‐pyridin‐4‐ylbenzyl)morpholin‐2‐yl]ethyl}benzamide (RS‐1269), which showed potency comparable to RS‐1154 in inhibiting CCL17‐induced migration of DO11.10 mice‐derived T helper 2 cells with an IC₅₀ value of 5.5 nM in vitro. We then investigated the pharmacological effects of RS‐1269 on ovalbumin‐induced ear swelling and lipopolysaccharide‐induced endotoxic shock in mice. The ear thickness was significantly decreased by oral administration of RS‐1269 at the dose of 30 mg/kg. Treatment with lipopolysaccharide significantly increased the serum level of tumour necrosis factor‐α. Compared with an anti‐CCL17 antibody, RS‐1269 significantly inhibited the production at the dose of 100 mg/kg. These results raise the possibility that RS‐1269 or one of its derivatives has potential to serve as a prototype compound to develop therapeutic agents for atopic dermatitis and inflammatory diseases.     

树突状细胞在特应性皮炎发病机制中的作用

特应性皮炎(atopic dermatitis,AD)是一种慢性复发性、瘙痒性、炎症性皮肤病,其病因复杂.目前虽然已明确遗传学背景、环境因素及免疫学异常在AD发病机制中起着重要作用,但其确切的病理生理过程尚不完全清楚.近年来的研究证实,树突状细胞(dendritic cells,DCs)在调节AD Th1/Th2失衡、维持AD炎症发展上起着决定性的作用.     

食物干预儿童特应性皮炎50例临床观察

目的:观察食物干预对儿童特应性皮炎患者临床症状改善情况.方法:采用随机对照临床试验,共纳入儿童特应性皮炎患者100例,随机分成食物干预组和对照组,每组50例进行临床对照观察.结果:食物干预组的疗效明显高于对照组.结论:通过特异性IgG的检测,指导干预儿童特应性皮炎的食物结构,能有效地治疗儿童的特应性皮炎.     

基于特应性皮炎严重程度的临床生物标志物研究进展

特应性皮炎（atopic dermatitis,AD）是一种慢性炎症性皮肤病,具有异质性的特点,临床根据AD轻、中、重度患者,采取不同的治疗方案。准确地判断出AD的严重程度对提出治疗方案极为重要,目前对于AD严重程度的判断还是依赖于特应性皮炎评分和湿疹面积和严重程度指数,这难以准确预测疾病的转归和复发。近年来,关于AD严重程度的临床生物标志物研究取得了一定的进展,研究主要集中在趋化因子类（如CCL17）、白细胞介素类（如IL-31、IL-17）等,本文从相关生物标志物与AD发病机制的关系及严重程度的相关性角度,总结了相关标志物的研究进展,希望为临床诊断及治疗提供一定的依据。     

儿童特应性皮炎皮肤屏障功能相关蛋白表达情况

目的:了解特应性皮炎患儿皮肤屏障功能相关蛋白的表达情况。方法:应用免疫组化方法检测特应性皮炎患儿和正常儿童的中间丝聚合蛋白、内披蛋白、兜甲蛋白等皮肤屏障功能相关蛋白(表皮终端分化蛋白)的表达差异,采用染色强度(0~5 分)反映相关蛋白的表达水平。结果:正常儿童皮肤的中间丝聚合蛋白、内披蛋白、兜甲蛋白的染色强度分别为(4.49±0.14)分、(4.39±0.14)分、(4.56±0.15)分,特应性皮炎患儿受累部分皮肤分别为(2.19±0.17)分、(2.29±0.11)分、(1.89±0±22)分,两组比较差异均有统计学意义(P均<0.01)。特应性皮炎患儿和正常儿童的中间丝聚合蛋白、兜甲蛋白均主要表达于颗粒层,正常儿童内披蛋白主要表达于棘细胞上层和颗粒层,特应性皮炎患儿内披蛋白主要表达于棘细胞上层。结论:特应性皮炎患儿皮肤屏障功能相关蛋白表达下降,提示存在皮肤屏障功能障碍。     

特应性皮炎患者严重程度与免疫偏移的相关性研究

目的探讨特应性皮炎患者病情严重程度与Th1、Th2免疫偏移的相关性,以期对特应性皮炎的治疗提供新的思路。方法收集2006年9月至2011年9月年于我院就诊的特应性皮炎患者80例,收集同期健康志愿者80例最为对照,采用EASI对患者严重程度进行评分;采集患者血液标本,ELISA法检测细胞因子IFN-γ、IL-2、IL-4、IL-5、IL-31的表达。比较特应性皮炎患者与健康志愿者体内不同细胞因子的表达,并对细胞因子与EASI进行相关性分析。结果 AD患者IFN-γ、IL-2等Th1细胞因子的表达均低于健康对照组(P<0.05);而IL-4、IL-5、IL-31等Th2细胞因子的表达均高于健康对照组(P<0.05);AD患者IL-4、IL-5、IL-31的表达与EASI均呈正相关性(P<0.05)。结论 AD患者存在不同程度的Th1/Th2免疫偏移,纠正此免疫偏移状态,有望成为AD治疗的新思路。     

HLA-DR3基因对特应性皮炎患者免疫应答的调节

目的:探讨HLA-DR3基因对特应性皮炎(AD)患者免疫应答的调节机制。方法:采用序列特异性引物聚合酶链反应(PCR-SSP)检测特应性皮炎患者的HLA-DRB等位基因型,采用放射变应原吸附实验(RAST)检测血清特异性IgE。结果:外源性特应性皮炎(EAD)组HLA-DR3基因频率高于对照组(P<0.05,RR=5.27),而HLA-DR6基因频率低于对照组(P<0.05,RR=0.10)。内源性特应性皮炎(IAD)组各等位基因与对照组比较均无统计学意义。在HLA-DR3阳性的10例EAD患者中,1例抗h1sIgE阳性,1例抗d1sIgE阳性,7例抗d2sIgE阳性,2例抗mx2sIgE阳性,2例抗fx5EsIgE阳性,HLA-DR3与抗d2sIgE有关,列联系数为0.48(P<0.05)。结论:HLA-DR3可能是AD的易感基因,而HLA-DR6可能是AD的抗性基因,同时携带有HLA-DR3的个体对粉尘螨的特异性变态反应可能是引发AD的病理机制之一。     

恶性淋巴瘤靶向治疗

近年,淋巴瘤的治疗有了革命性的进展,除常规化疗和造血干细胞移植的进展之外,最引人注目的方面是淋巴瘤靶向治疗,主要是单克隆抗体和放射免疫治疗。单克隆抗体治疗单克隆抗体的靶向治疗至关重要的环节是抗原的选择。理想的靶抗原应为肿瘤特异性抗原,仅在肿瘤细胞中表达,而正常细胞不表达或很少表达,并且靶抗原应在肿瘤细胞中表达稳定均一,不产生分泌型抗原,避免抗体与血循环中的抗原结合并清除;理想的靶抗原应参与细胞凋亡或细胞生长信号的调节,抗体与抗原结合后能阻断肿瘤细胞生长,诱导凋亡,增加肿瘤细胞对化疗或其他治疗的敏感性。抗体选…     

氯霉素泼尼松搽剂治疗小鼠特应性皮炎的实验研究

目的:研究氯霉素泼尼松搽剂对小鼠急性特应性皮炎的治疗效果.方法:选取48只小鼠,分为空白组、模型组、对照组及实验低、中、高剂量组共6组,每组8只,除空白组外,其余5组小鼠均用二硝基氯苯丙酮溶液建立特应性皮炎模型,空白组、模型组给予生理盐水,对照组给予1％吡美莫司乳膏,实验组低、中、高剂量组分别给予相应浓度的氯霉素泼尼松...