银屑病生物治疗研究进展

 当前医学界一致认为，银屑病是一种 T 细胞引发并维持的自身免疫性疾病，病人机体免疫系统紊乱，健康细胞受到攻击，造成临床上典型的皮肤鳞屑性炎症病变^[1]。这种慢性炎症性疾病的病理过程包括T细胞浸润、真皮血管的改变、表皮角质细胞过度增生和异常分化 。其中参与银屑病发病的 T 细胞大致经历3个阶段的变化：T细胞（CD45RO+）的初始活化；T 细胞迁移至病变皮肤；活化T 细胞释放细胞因子发挥促增殖功能。真皮内的 CD4+ T细胞及其产生的细胞因子是银屑病发病的中心环节，角质细胞与血管内皮细胞的变化只是继发于细胞免疫机制异常的一种改变^[2]。随着对银屑病发病机制及免疫学机制研究的不断深入，人们陆续开发出多种生物制剂。这些生物制剂与传统的化学制药制造出来的具有严格化学分子式的小分子药品完全不同，它们都是蛋白质大分子，可以特异性作用于T细胞活化过程中不同的信号转导分子及途径，从而阻断疾病进程。此类生物制剂均通过生物工程技术获得，按性质大致可以划分为重组单克隆抗体（单抗）、重组抗体融合蛋白、重组细胞因子或生长因子等 3 大类；根据作用于 T 细胞活化靶点的不同，又可以分为针对原发性刺激、阻断共刺激分子作用、抑制T细胞增殖、抑制有炎症介导活性细胞因子和平衡有免疫调节活性的细胞因子等 5 大类^[3-4]。生物制剂的出现，为银屑病治疗提供了新的选择，正逐步改变着皮肤科医师治疗银屑病的传统模式。本文就近几年来银屑病生物治疗方面的最新研究进展做一综述。......     

Long-term inhibition of intimal hyperplasia using vascular photodynamic therapy in balloon-injured carotid arteries

Flexible treatments for intimal hyperplasia after angioplasty are still needed. The aim of this study was to demonstrate the long-term effects of vascular photodynamic therapy with talaporfin sodium on intimal hyperplasia following interventional injury. Intimal hyperplasia was induced by balloon distension injury to the carotid artery in 31 rabbits. Talaporfin, 5.0 mg/kg, was delivered systemically immediately after balloon injury. The injury site was irradiated with a diode laser light of wavelength 664 nm using a fluence of 50 J/cm² after 30 min. At day 3 and weeks 3, 6, 9, 15, and 25 after photodynamic therapy, the treated artery of each rabbit was excised and examined immunohistochemically. Thirty minutes after talaporfin administration, drug fluorescence was found only in the balloon-injured carotid artery wall. At 3 days, no smooth muscle cells were seen in the media of the photodynamic therapy-treated arterial segments. Intimal hyperplasia developed progressively in the balloon-injured and untreated segments; however, in the segments treated with photodynamic therapy, intimal hyperplasia was markedly suppressed until 25 weeks and the media was repopulated by smooth muscle cells without macrophages. Vascular photodynamic therapy with talaporfin may be used to inhibit restenosis after vascular intervention. An erratum to this article is available at .     

阴道镜下高频电灼术联合α-2a干扰素凝膏治疗尖锐湿疣疗效分析

目的探讨阴道镜下高频电灼术联合重组人干扰素α-2a治疗尖锐湿疣（CA）的效果。方法将165例CA分为3组，A组应用阴道镜下高频电灼术联合重组人干扰素α-2a；B组单纯采用阴道镜下高频电灼治疗；C组应用NS-FII型多功能光谱治疗仪联合肌注重组人干扰素α-2a。结果治疗后3-6个月A、B、C组复发率分别为0％、4．4％、65．4％：半年后人乳头瘤病毒（HPV）转阴率分别为93．5％、85．4％、43．8％，A组明显优于B组，B组明显优于C组，3组比较差异有统计学意义（P〈0．01）。结论阴道镜下高频电灼术联合重组人干扰素α-2a治疗CA可明显降低CA复发率和提高HPV转阴率。     

含人基质金属蛋白酶组织抑制因子-1重组腺病毒的构建与体外表达

从人肝癌组织中提取总RNA，RT—PCR合成hTIMP-1的全长cDNA，克隆到腺病毒载体AdEasy系统的穿梭质粒pAdTraek—CMV上，与骨架质粒pAdEasy-1在BJ5183受体菌中进行同源重组，成功构建含hTIMP-1全长eDNA的重组腺病毒载体，经293细胞的包装、扩增，生成含hTIMP-1基因的重组腺病毒AdhTIMP-1并实现体外表达，为进一步研究肝癌浸润和转移机理以及肝癌的基因治疗提供实验基础。     

荷EL4肿瘤小鼠模型的建立及美法仑抑瘤作用免疫机制的探讨

目的:建立荷小鼠淋巴瘤EL4的野生型C57BL/6小鼠及其裸鼠模型,探讨美法仑(melphalan)抑瘤作用的免疫机制。方法:给正常野生型C57BL/6小鼠皮下接种小鼠淋巴瘤EL4细胞,建立荷EL4肿瘤的小鼠模型。于野生型C57BL/6小鼠皮下接种瘤细胞后12d,经腹腔给荷瘤小鼠单次注射不同剂量的美法仑,找出美法仑可发挥最大的抑瘤作用,并能致使肿瘤消退、不再复发的最小使用剂量。然后再给野生型C57BL/6小鼠及其裸鼠(遗传背景相同)皮下同时接种小鼠淋巴瘤EL4细胞建立两种荷瘤小鼠模型。同样于接种瘤细胞后12d,经腹腔给两种荷瘤小鼠模型均注射可使野生型C57BL/6小鼠肿瘤消退、不再复发的最低剂量的美法仑,以正常野生型C57BL/6小鼠为对照,观察在T淋巴细胞缺陷的裸鼠体内美法仑的抑瘤作用。结果:注射7.5mg/kg美法仑治疗后,免疫功能正常的野生型C57BL/6荷瘤小鼠的肿瘤消退;而荷瘤C57BL/6裸鼠的肿瘤仍继续生长。结论:单一剂量的美法仑对荷淋巴瘤EL4小鼠具有明显的治疗作用,其作用的发挥需要T淋巴细胞的参与,可能与T细胞的杀伤作用有关。     

Role of ventricular assist devices in the German heart allocation system

The Eurotransplant (ET) allocation algorithm, newly implemented in 2000, gives priority for heart transplantation (HTx) to patients with high urgency (HU) status, but now this status is rescinded upon ventricular assist device (VAD) implantation and only regained if severe complications occur during mechanical circulatory support (MCS). We studied the effects of this change on the patients in our institute who were waiting for HTx with MCS. The median duration of MCS until HTx in adult patients gradually increased from 3.1 months in 1994, reaching a peak of 16.7 months in 2000, and then gradually decreased to 6.0 months in 2003. Among the patients with VAD implantation as a bridge to HTx, two patients were on MCS for more than 1 year (the longest duration of MCS being 1.6 years) at the end of 1999, and this figure increased to nine patients and a maximum MCS duration of 3.7 years at the end of 2003. These data imply that the patients in whom a complication occurred in the early phase of MCS and who had overcome this complication underwent HTx early with HU status, and those who were stable during MCS waited a long time for HTx. Furthermore, the number of patients in the latter group is increasing. The new allocation algorithm imposes on patients with MCS waiting for HTx who are relatively young and free from complications and serious coexisting disease, very long-term MCS without an end to VAD bridging, which is almost equivalent to destination therapy. Part of this paper was presented at the 42nd JSAO Conference (Tokyo, October 5–7, 2004)     

Imbalances in serum proinflammatory cytokines and their soluble receptors: a putative role in the progression of idiopathic IgA nephropathy (IgAN) and Henoch–Schönlein purpura nephritis,and a potential target of immunoglobulin therapy?

Following recent experimental data suggesting an aggravating effect of circulating proinflammatory cytokines on the histological lesions of IgAN, we studied changes in serum proinflammatory cytokines and their soluble receptors and antagonists in patients treated with polyvalent immunoglobulins (15 with severe nephropathy who had indicators of poor prognosis: heavy proteinuria, hypertension, altered renal function and Lee's histological grade III or IV; and 14 with moderate forms of IgAN who had permanent albuminuria > 300 mg/day and < 2000 mg/day, Lee's histological grade II and a glomerular filtration rate > 70 ml/min) in comparison with healthy controls (n = 20) and patients with non-IgA nephritides (n = 50). These were measured by means of specific immunometric assays before and after 9 months of immunoglobulin therapy. Total tumour necrosis factor (TNF) serum and IL-6 levels were elevated in IgAN patients before therapy, relative to controls, and normalized after immunoglobulin therapy. Levels of soluble TNF receptor of type I (sR55) and type II (sR75) increased on immunoglobulin therapy. TNF index α-55,75 used to assess biologically available TNF-α (ratio of total TNF-α divided by levels of soluble TNF receptors sR55 and sR75) was elevated before therapy and was below healthy control values after 9 months of immunoglobulin administration. Levels of serum IL-1 receptor antagonist were low prior to immunoglobulin administration in patients with severe forms of IgAN, and normalized on therapy. Serum interferon-gamma was unmodified. The histological activity index correlated with serum total TNF-α, TNF index α-55,75 and serum IL-6 levels, whereas proteinuria correlated with serum total TNF-α and TNF index α-55,75 but not with serum IL-6. These data suggest that the overproduction of proinflammatory cytokine is unbalanced by their natural antagonists in IgAN and Henoch–Schönlein syndrome. This process may play a role in the progression of the disease and be one of the targets of immunoglobulin therapy.     

实验性犬心肌梗塞和溶栓后再闭塞时血浆中GMP—140,TXB2的变化

本文采用放免法测定实验性犬心肌梗塞和溶栓后再闭塞时血浆中ＧＭＰ－１４０、ＴＸＢ２、６－Ｋ－ＰＧＦ１α的含量变化，并探讨其与心肌梗塞溶栓后再闭塞的关系。结果表明，在血栓形成时血浆中ＴＸＡ２稳定代谢产物ＴＸＢ２水平显著升高（ｐ〈０．０５），在溶栓后再闭塞率高（８７．５％）的非治疗组（Ｂ组）。在溶栓后４小时至溶栓后３天期间呈进行性升高（ｐ〈０．０１），而在再 埘经低（１６．７％）的ＡＰＩ０１３４治疗组（     

Recurrent high level parvovirus B19/genotype 2 viremia in a renal transplant recipient analyzed by real-time PCR for simultaneous detection of genotypes 1 to 3

Organ transplant recipients infected with parvovirus B19 frequently develop persistent viremia associated with chronic anemia and pure red cell aplasia. In this study, a male renal transplant recipient who had been infected with parvovirus B19/genotype 2 after renal transplantation at the age of 34 years is described. The patient was repeatedly treated with high dose intravenous immunoglobulin (IVIG) that resulted in the resolvement of symptoms but not in virus eradication. During an observation period of 33 months after transplantation three phases associated with high parvovirus B19 viremia were observed. Both the first and the second viremic phases were combined with severe anemia. Parvovirus B19 specific IgM-antibodies were initially detected at the beginning of the second phase in continually rising concentrations. Initially eradication of the virus by immunoglobulin therapy was reported after the first viremic phase [Liefeldt et al. (2002): Nephrol Dial Transplant 17:1840-1842]. Retrospectively this statement has to be corrected. It was based on the use of a qualitative PCR assay specific for parvovirus B19 genotype 1 associated with reduced sensitivity for detection of genotype 2. After sequence analysis of the viral DNA and adjustment of a real-time PCR assay (TaqMan) for quantitative detection of all three B19 virus genotypes analysis of consecutive serum samples allowed the demonstration of long lasting phases with reduced viral loads following IVIG-treatment. These results demonstrate that IVIG treatment of parvovirus B19-triggered anemia in transplant recipients offers an opportunity to resolve symptoms, but does not guarantee eradication of the virus. Since reactivation of parvovirus B19 infection can result in high virus load associated with the recurrence of symptoms repeated screening for viral DNA is recommended using the TaqMan system established for quantitative detection of all three genotypes of parvovirus B19.     

Gene therapy of amyotrophic lateral sclerosis

Two-year experiments were performed to evaluate the neurotrophic effect of hypoxia-inducible factors (vascular endothelial growth factor and angiogenin) expressed in recombinant human adenoviruses in amyotrophic lateral sclerosis. Randomized placebo-controlled trial demonstrated safety and good tolerability of the recombinant antiviral drugs. The life span of patients under conditions of hypoxia increased after treatment with the test drug, which was probably related to improved resistance of motoneurons. The presence of virus-neutralizing antibodies decreases the effectiveness of adenoviral vectors, which necessitates differential approach to the selection of patients and continuous monitoring of gene therapy. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 467–470, April, 2008