Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation

Introduction: Acute and chronic graft rejection continues to be an important problem after solid organ transplantation. With the introduction of potent immunosuppressive agents such as calcineurin inhibitors, the risk of rejection has been significantly reduced. However, the adverse effects of life-long immunosuppression remain a concern, and there exist a fine balance between over-immunosuppression and risk of rejection.

Areas covered: In this review, the current standard of care in immunosuppressive therapy, including the use of steroids, calcineurin inhibitors, mycophenolate prodrugs and mammalian target of rapamycin inhibitors, will be discussed. Newer immunosuppressive agents showing promising early data after liver and kidney transplantation will also be explored.

Expert Opinion: Currently, calcineurin inhibitors continue to be a vital component of immunosuppressive therapy after solid organ transplantation. Although minimization and avoidance strategies have been developed, the ultimate goal of inducing tolerance remains elusive. Newer emerging agents should have potent and specific immunosuppressive activity, with minimal associated side effects. An individualized approach should be adopted to tailor immunosuppression according to the different needs of recipients.     

Unique changes in interstitial extracellular matrix composition are associated with rejection and cyclosporine toxicity in human renal allograft biopsies

Renal allograft loss from chronic rejection or cyclosporine toxicity (CsAT) is characterized by progressive interstitial fibrosis, yet the protein composition of these lesions is unknown. The normal tubular basement membrane (TBM) contains laminin (LM), collagen IV (containing collagen IV alpha chain 1 [COL4A1] and COL4A2), thrombospondin (TSP), and fibronectin (FN). Only TSP and FN extend beyond the TBM into the interstitial space. Very scanty amounts of interstitial collagens (I and III) are detected in the interstitium. In a pilot study of human renal allograft biopsy specimens, three patterns of extracellular matrix (ECM) composition were identified. Pattern 1 showed no change in ECM composition; pattern 2 showed generalized accumulation of collagens I and III in the interstitium; and pattern 3 showed new expression of COL4A3 and LM-beta2 in the proximal TBM. Criteria were established for the clinicopathological diagnosis of CsAT and rejection. These diagnoses were correlated with the ECM composition in 22 renal allograft biopsy specimens. Control groups were examined in a similar manner and included native kidney biopsy specimens from patients with other allografts (n = 7), renal biopsy specimens from patients with glomerular disease (n = 9), and renal allograft biopsy specimens from patients without clinicopathological evidence of renal disease. These data show that rejection is associated with pattern 3 and CsAT is associated with pattern 2. Thus, detection of ECM composition may be a useful adjunct to standard microscopy in distinguishing rejection from CsAT in renal allograft biopsy specimens. These data suggest that interstitial fibrosis associated with rejection and CsAT result from different pathogenic mechanisms.     

开放性结肠直肠切除术后的腹内游离气体

立位Ｘ线胸片可敏感而特异地显示膈下游离气体 ,对开放性结肠直肠切除术后空腔脏器出现破损是一项有效的检查 ,但由于剖腹术后气腹自然吸收所需要的时间未知 ,其作用尚未被确定。本次试验的目的即在于确定这一时间。　　 3个月内连续 92例接受了连续性结肠直肠切除术的病人 (8例拒绝合作 ,9例采用了腹腔镜技术 )中的 75例参与了这次试验 (平均年龄 6 2 1岁 ,男∶女 =1 3∶1) ,手术指征分别为直肠癌 6例 ,憩室病 2例 ,肠道炎症 2例 ,放疗引起狭窄 3例 ,功能性疾患 (慢性运输性便秘 ,直肠脱垂 ) 2例 ,其它 (家族性腺瘤息肉、乙状结肠扭转、短…     

树突状细胞与肝脏疾病

免疫反应的产生首先是由抗原提呈细胞(antigenpresenting cells,APC)捕获抗原,经其加工处理后将抗原信息传递给T,B淋巴细胞,从而引发一系列的特异性免疫应答.APC包括树突状细胞(dendritic cells,DC)、巨噬细胞(MΦ)、B细胞等,其中DC是人体内最具潜能的抗原提呈细胞(APC),能在体内外直接激活纯真(naive)T细胞,提呈抗原给MHC-Ⅰ类限制性CD8+和MHC-Ⅱ类限制性CD4+T淋巴细胞,诱导特异性免疫应答[1-6].     

Traditional Chinese manual acupuncture for management of obesity: A systematic review

AIM: To evaluate the effectiveness and safety of acupuncture for the treatment of obesity by reviewing currently available randomised controlled trials. METHODS: This review followed the Cochrane Handbook for Systematic Reviews of Interventions. Fifteen English and three Chinese databases were searched from their respective inceptions until July 2014. Key words used in the search consisted of acupuncture, needles, obesity, overweight, randomised trial and their synonyms. The risk of bias of included studies was assessed. The differences in effect size between acupuncture and control (including sham, no treatment, western medicine and dietary therapy/exercise) groups were compared using Cochrane Collaboration’s RevMan 5.3 software. RESULTS: Two thousand six hundred and twenty-one records were identified; after full-text articles assessed for eligibility, 9 of them met inclusion criteria. Majority of included studies had unclear or high risk of bias across all domains. All included studies had high or unclear risk of bias in randomisation, blinding and outcome data. Meta-analysis showed that acupuncture was more effective for reducing body weight and body mass index than no treatment group. Manual acupuncture was also superior to dietary therapy alone for decreasing body weight. With dietary therapy as co-intervention, combined acupuncture group achieved lower body mass index than combined sham acupuncture group or dietary therapy alone group at the end of treatment period. No severe adverse events from acupuncture group were reported from all included studies. CONCLUSION: Due to the poor quality of included studies the effectiveness of acupuncture cannot be concluded. Better-designed, large-scale, randomised, sham-controlled clinical trials with long-term follow-up are needed.     

The anti-nausea effects of CB1 agonists are mediated by an action at the visceral insular cortex

BACKGROUND AND PURPOSE

Conditioned gaping reactions reflect nausea-induced behaviour in rats. Cannabinoid 1 receptor (CB₁) agonists interfere with the establishment of nausea-induced conditioned gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB₁ receptors.

EXPERIMENTAL APPROACH

We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB₁ agonist, CB13, on the establishment of LiCl-induced gaping in rats. We further evaluated the ability of HU-210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl-induced conditioned gaping and determined if this effect was mediated by CB₁ receptors.

KEY RESULTS

Central, but not peripheral, CB13 suppressed LiCl-induced conditioned gaping. Central administration of the potent CB₁ agonist, HU-210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl-induced gaping reactions, but not LiCl-induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU-210 delivered to the VIC prevented LiCl-induced nausea, but not learning per se. The suppression of LiCl-induced conditioned gaping by HU-210 was mediated by CB₁ receptors because it was prevented by co-administration of CB₁ antagonist/inverse agonist, AM-251, into the VIC. A high dose of AM-251 (20 µg) administered alone into the VIC did not produce conditioned gaping reactions.

CONCLUSIONS AND IMPLICATIONS

The nausea-relieving effects of CB₁ agonists, but not the nausea-inducing effects of CB₁ inverse agonists, are mediated, at least in part, by their action at the VIC in rats.