Cytokine-targeted therapy for the management of solid organ transplant recipients

IntroductionThe number of solid organ transplants completed annually continues to trend upwards each year. Despite this, maintenance immunosuppression available on the market has remained relatively stagnant. Standard triple immunosuppression, composed typically of tacrolimus, mycophenolate, and steroids, lead to many side effects that limit the use of these medications. Tacrolimus, specifically, causes nephrotoxicity that can lead to renal dysfunction requiring a kidney transplant down the road. Alternative therapies for the management of immunosuppression need to be identified to try to mitigate these adverse effects.BodyCytokines are responsible for facilitating T cell differentiation and lead to the activation of inflammatory mediators that can contribute to graft damage and ultimately rejection. IL-4, IL-6, IL-12/23, and IL-15 are attractive targets for medications to try to ameliorate graft rejection. Various cytokine-targeted medications are currently available on the market for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, psoriatic arthritis, Crohn’s, and multiple sclerosis.ConclusionThis article reviews cytokine involvement in alloimmunity and the potential role cytokine-targeted therapy may play in prevention of allograft rejection in solid organ transplant recipients.     

缺血性脑卒中治疗时间窗后辅助溶栓治疗的进展

组织纤溶酶原激活物（tPA）溶栓是缺血性脑卒中治疗的金标准,然而,tPA的治疗时间窗和超过治疗时间窗后再应用所致的致命性副作用限制其的临床应用。为了解决tPA应用的限制性,可联合应用tPA与其他药物或非药物的介入方式治疗,且部分联合治疗方案经实验验证可以减轻治疗时间窗外应用tPA所致并发症,尤其是出血性转化（HT）。联合应用药物的作用机制包括保护血脑屏障,增强血管生成作用和保护脑血管。非药物介入方式则包括干细胞移植和有多方面生物效应的气体治疗。tPA与上述治疗方式的联合应用旨在减轻滞后tPA治疗所致的副作用和脑卒中所诱发的神经性缺损和行为损伤。因此,辅助治疗是一种创新的治疗形式,可解决tPA治疗的限制因素,并可能延长缺血性脑卒中的治疗时间窗。     

治疗慢性心力衰竭的鸟苷酸环化酶激活剂维利西呱

维利西呱是一种口服的可溶性鸟苷酸环化酶激活剂,用于治疗恶性慢性心力衰竭和左心室射血分数(LVEF)降低的患者。其通过一氧化氮–环鸟苷酸–蛋白激酶(NO-c GMP-PK)信号通路新机制,改善心肌收缩性,从而治疗心力衰竭。临床研究表明,维利西呱对慢性心力衰竭和LVEF降低的患者虽不能显著改善12周后NT-proBNP水平,但有降低NT-proBNP水平,改善LVEF和降低不良反应事件的趋势,同时该药物耐受性较好,具有很好的安全性。     

Effect of tension-force on plasminogen activator activity from human periodontal ligament cells

The plasminogen activator (PA)-plasmin proteolytic system has recently received considerable attention because of its participation in a wide variety of biological activities and in pathological conditions involving tissue destruction. Excessive mechanical stress such as occlusal trauma is associated with alveolar bone loss in severe periodontitis. Therefore, mechanical stress may involve degradation of the extracellular matrix by occlusal trauma through activation of the PA-plasmin proteolytic system. We examined the effects of mechanical stress on PA activity, gene expressions of tissue type (t) PA, urokinase type (u) PA and PA inhibitor-1 (PAI-1) in human PDL cells. Human PDL cells were cultured on flexible-bottomed culture plates and placed on a Flexercell Strain Unit. The cells were flexed at 6 cycles (5 s strain, 5 s relaxation) at 9% and 18% elongation for 5 d. Application of tension-force induced significantly higher PA activity in stressed PDL cells than in non-stressed controls, and did so in a time- and magnitude-dependent manner (p<0.001, ANOVA). Western-blot analysis revealed that the high level of activity was due to tPA and not uPA. Gene expression of tPA mRNA in stressed PDL cells, as examined by RT-PCR, increased on d 5. These findings suggest that tPA may be involved in periodontal metabolism in response to mechanical stress.     

小鼠骨髓细胞和脾细胞诱导形成破骨细胞潜能的比较

目的在体外破骨细胞分化因子(RANKL)和巨噬细胞集落刺激因子(M-CSF)联合应用的情况下,比较小鼠骨髓细胞和脾细胞形成破骨细胞的能力。方法选用小鼠M-CSF依赖性非附着性骨髓细胞和脾细胞,以不同的细胞密度在含有25ng/mlsM-CSF和30ng/mlsRANKL的(-MEM培养液中培养5、9天后,计数形成的抗酒石酸酸性磷酸酶染色(TRAP)阳性多核细胞的数目和骨吸收面积。结果脾细胞形成的破骨样细胞与骨髓形成的细胞形态与功能均无明显差异,但所需的细胞密度为骨髓细胞的10~20倍。结论在特殊情况下,脾细胞可替代骨髓细胞进行体外破骨细胞实验,但培养条件应适当调整。     

An acute injection of Porphyromonas gingivalis lipopolysaccharide modulates the OPG/RANKL system and interleukin‐6 in an ovariectomized mouse model

Background/aims: In the present study, we attempted to develop a simulated model to explore the causal effects of periodontal pathogens on skeletal homeostasis in postmenopausal osteoporosis. Methods: Fifty‐three female adult ICR mice were randomly assigned to an experimental group (ovariectomized) or a control group. A single injection of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis‐LPS, ATCC 33277) or Escherichia coli lipopolysaccharide (E. coli‐LPS) was administered intraperitoneally 4 weeks after an ovariectomy. Concentrations of interleukin‐6 (IL‐6), osteoprotegerin (OPG), and the receptor activator of nuclear factor‐κB ligand (RANKL) in serum were subsequently analyzed using an enzyme‐linked immunosorbent assay (ELISA). Results: Under stimulation with P. gingivalis‐LPS or E. coli‐LPS, the concentration of OPG rose in both groups. The serum level of RANKL showed a decreasing trend 24 h after the injection in both groups. After injection of P. gingivalis‐LPS in both the experimental and control animals, the OPG : RANKL ratio increased 24 h after the booster (22.26–620.99, P < 0.05). The serum level of IL‐6 in the experimental group significantly increased 1–6 h after administration of E. coli‐LPS and 1–3 h after administration of P. gingivalis‐LPS (P < 0.05). Conclusions: A single booster injection of P. gingivalis‐LPS induced short‐term changes in OPG, RANKL, and IL‐6 serum levels in this ovariectomized mouse model.     

An acute injection of Porphyromonas gingivalis lipopolysaccharide modulates the OPG/RANKL system and interleukin-6 in an ovariectomized mouse model

Background/aims:  In the present study, we attempted to develop a simulated model to explore the causal effects of periodontal pathogens on skeletal homeostasis in postmenopausal osteoporosis.
Methods:  Fifty-three female adult ICR mice were randomly assigned to an experimental group (ovariectomized) or a control group. A single injection of Porphyromonas gingivalis lipopolysaccharide ( P. gingivalis -LPS, ATCC 33277) or Escherichia coli lipopolysaccharide ( E. coli -LPS) was administered intraperitoneally 4 weeks after an ovariectomy. Concentrations of interleukin-6 (IL-6), osteoprotegerin (OPG), and the receptor activator of nuclear factor-κB ligand (RANKL) in serum were subsequently analyzed using an enzyme-linked immunosorbent assay (ELISA).
Results:  Under stimulation with P. gingivalis -LPS or E. coli -LPS, the concentration of OPG rose in both groups. The serum level of RANKL showed a decreasing trend 24 h after the injection in both groups. After injection of P. gingivalis -LPS in both the experimental and control animals, the OPG : RANKL ratio increased 24 h after the booster (22.26–620.99, P  < 0.05). The serum level of IL-6 in the experimental group significantly increased 1–6 h after administration of E. coli -LPS and 1–3 h after administration of P. gingivalis -LPS ( P  < 0.05).
Conclusions:  A single booster injection of P. gingivalis -LPS induced short-term changes in OPG, RANKL, and IL-6 serum levels in this ovariectomized mouse model.     

The plasminogen-activating system in gingival fluid from adults

High concentrations of tissue plasminogen activator (t-PA) and placental type plasminogen activator inhibitor (PAI-2) have previously been found in gingival crevicular fluid (GCF) of adults and children. In the present study, intra-individual comparisons were made of the concentrations of t-PA, urokinase type plasminogen activator (u-PA), PAI-1, and PAI-2 in GCF from the same sites before and after periodontal treatment in eight healthy male volunteers aged 35–46 yr. The gingival state was assessed by exudate measurement, bleeding on standardized probing, and the gingival index of Löe & Silness 3 days before the start of the trial and on the day after completing a 21-day preventive program consisting of instruction and professional cleaning once a week. Eight sites per subject were selected for enzyme analyses, all showing improvement in gingival state during the period. Sampling of GCF at the start and at the end of the trial was done with small disks of Millipore-filter. t-PA and PAI-2 were analyzed with enzyme-linked immunosorbent assays with low method errors. The mean concentrations of t-PA were 0.73 mg/1 before treatment and 0.49 mg/1 after treatment. The mean concentrations of u-PA were 84.4 ug/1 before treatment and 101.6 μg/1 after treatment. PAI-1 was found in three subjects at the detection level. The mean PAI-2 concentrations were 2.19 mg/1 before and 1.13 mg/1 after treatment. The mean molar ratio PAs/PAI-2 was 0.47 before and 0.48 after treatment. This insignificant change implies a maintained proteolytic balance and indicates that PAI-2 is an important inhibitor of tissue proteolysis.