Polyclonal hypergammaglobulinemia in a case of B-cell chronic lymphocytic leukaemia: the result of IL-2 production by the proliferating monoclonal B cells?

Summary. CLL is typically characterized by acquired hypogammaglobulinemia. We report the case of a female patient suffering from B-CLL who developed polyclonal hypergammaglobulinaemia: 38-3 g/I polyclonal IgG, 0.97g/1 IgA and 0.33 g/1 IgM. Immunophenotyping showed a monoclonal lymphocytic population CD19⁺ CD5⁺ CD40⁺ CD23+, low slg⁺ (95%), K type in the great majority (96%). RT-PCR of immunoglobulin genes gave evidence of monoclonal rearrangement of the IgM type. Our tests showed that IL-2 was produced when leukaemic B cells were stimulated with phorbol myristate acetate, ionomycin and lipopoly-saccharide. In addition, transfections with the full IL-2 promoter or elements thereof revealed that IL-2 expression is inducible and mediated through the NF-kB-promoter element. Finally, the amount of IL-2 secreted by these cells is about 39ng/ml/10⁶ cells, which is remarkably high for non-T cells. These results suggest that the large amounts of polyclonal IgG seen in this case of B-CLL are secreted by normal B cells which are in turn stimulated by IL-2 produced by proliferating monoclonal (leukaemic) B cells. Under cyclosporin A treatment, immunoglobulin secretion and B cell count remained low.     

药物性牙龈肥大发病机制的研究进展

药物性牙龈肥大(DIGO)主要由长期服用苯妥英钠、环孢素A、硝苯地平引起,不仅影响牙面的清洁与美观和牙齿正常生理功能,而且可能造成患者心理上的障碍。然而,DIGO发病机制复杂,无法明确,导致治疗较为棘手。许多学者对其进行了多方面的研究,提出许多观点与假设,包括胶原生成与降解失衡机制、炎症等。该文从分子机制与药物具体机制两方面总结了近几年对DIGO发病的研究,并对DIGO未来的研究方向进行探讨,希望能够对DIGO的预防与临床治疗有所帮助。     

Immunosuppressive Effect of Cyclosporin A in Two Lymphocyte Transfer Models in Rats: Comparison of in Vivo and in Vitro Treatment

The immunosuppressive effect of CS-A was first studied in the assay for local GvHR. 3 x 10⁶ viable spleen cells from LEW rats were injected into one foot pad of LEW x BN hybrids and both PLN were weighed 7 days later. Treatment of the recipients with 3 doses of 50 mg/kg/day of CS-A suppressed this local GvHR. The effect was more pronounced when treatment started at the time of cell transfer rather than a few days before peak response. In-vitro incubation of the cellular inoculum with CS-A also prevented local GvHR. Histology of the PLN confirmed the quantitative results expressed by the PLN index. CS-A was further investigated in the EAE model in LEW rats. It protected rats sensitised with spinal cord emulsified in complete Freund's adjuvant for as long as they were treated with CS-A. Treatment delayed until after the appearance of EAE also markedly improved their condition. Oral treatment of recipients with 50 mg/kg/day CS-A prevented the development of adoptive EAE following the transfer of lymphoid cells conditioned in vitro. The presence of 0.1-1.0 μg CS-A in the medium of the sensitised lymphoid cells also inhibited the adoptive transfer of EAE. Finally, if the cells for the adoptive transfer were derived from CS-A-treated sensitised donors, they failed to induce EAE. Histological examination supported the symptomatic findings     

Calcineurin inhibitor minimization in pediatric liver allograft recipients

Abstract:  The use of CNI in pediatric LTx has dramatically improved the outcome for children with end-stage liver disease by significantly reducing the rate of acute and chronic rejection. Long-term concerns about CNI-induced nephrotoxicity and other adverse effects remain an issue, particularly as the emphasis moves from short-term survival to long-term quality of life. This review summarizes lessons learnt from pediatric and adult solid organ transplantation in minimizing CNI use in immunosuppression protocols in children following LTx. There are three models for CNI minimization: dose reduction, withdrawal or avoidance, supplemented by the use of IL-2 receptor blocking antibodies in the peri-transplant period, and early transition to alternate drugs such as MMF or SRL. Prospective studies evaluating reduction or withdrawal protocols in adult and pediatric LTx indicate that rejection rates are comparable with traditional CNI-based immunosuppression and that two and five yr patient and graft survival are similar, with recovery in renal function. There are few studies evaluating complete avoidance of CNI, apart from that in renal transplantation, although the benefits of long-term reduction in cardiovascular, metabolic, and possibly neoplastic side effects may justify this approach. It is not clear yet how CNI minimization will affect the development of tolerance but experimental and preliminary clinical studies indicate that CNI and steroid avoidance or minimization in the peri-operative period may favor the development of long-term graft tolerance. In summary, CNI minimization may be safe and effective in the short term but large-scale pediatric randomized studies are required to evaluate the long-term efficacy of these regimes in the development of chronic rejection, PTLD, and graft tolerance.     

New developments in immunosuppressive therapy in renal transplantation

The introduction of new immunosuppressive agents and protocols has improved outcomes for renal transplant recipients by decreasing the risk of rejection and by increasing the function and lifespan of the allograft. This article reviews the major changes in the combinations of therapies used: calcineurin inhibitors, target of rapamycin inhibitors, mycophenolate mofetil, non-depleting monoclonal versus depleting monoclonal and polyclonal antibodies for induction and increasing emphasis on protocols for reduction or avoidance of steroids and calcineurin inhibitors. The new agents with novel immunological targets such as anti-CD40 ligand, LEA29Y, FTY720, anti-CD20 (rituximab, Rituxan?, Mabthera?) and anti-CH52 (alemtuzumab, Campath?), which are under development but have yet to survive the rigors of clinical trials are also discussed. In the presence of low early rejection rates, immunosuppressive therapy is setting new goals such as better graft function (glomerular filtration rates), reduction in adverse effects such as hypertension, hyperlipidaemia and drug toxicity and, above all, the prevention of late graft deterioration.     

3种不同厂家环孢素A胶囊在健康人体的药动学和生物等效性

 目的研究3种环孢素A胶囊在健康中国人体内的药动学和生物等效性。方法健康志愿者18名,采用简化三交叉试验设计,单剂量口服试验或参比制剂200mg;于服药后48h内,抽取静脉血;用高效液相色谱法测定全血中环孢素A的含量;用DAS软件计算药动学参数并评价3种制剂的生物等效性。结果参比制剂新山地明及两种试验制剂因普兰他和田可的主要药动学参数:ρ_max分别为(947.161±174.985),(758.869±193.539)和(938.711±202.379)μg·L^-1;t_max分别为(1.694±0.645),(2.472±0.581)和(1.861±0.564)h;t_1/2分别为(25.014±17.692),(28.032±14.602)和(28.056±22.927)h;AUC_0-48h分别为(6563.683±1342.601),(6152.483±1066.901)和(6594.165±927.042)μg·h·L^-1;AUC_0-∞分别为(7113.479±1655.657),(6771.877±1240.034)和(7253.950±1228.181)μg·h·L^-1。结论经统计学分析,3种制剂具有生物等效性。     

Atopic dermatitis: review of immunopathogenesis and advances in immunosuppressive therapy

This paper reviews the theories of the pathogenesis of atopic dermatitis (AD), with a particular emphasis on its immunopathogenesis. The contribution of predisposing factors, immunopathogenic factors and provoking factors in the pathogenesis of AD are considered. Predisposing factors explored in this article include genetics and the disturbance of skin function. Immunopathogenic factors reviewed include T cell dysfunction, biphasic cytokine expression and the role of immunoglobulin E. Provoking factors considered include microbial factors, psychosomatic interactions, contact allergens and irritants, inhalant allergens, food and climate. Immunosuppressive treatments reviewed include cyclosporin, azathioprine, methotrexate, tacrolimus, interferon-gamma, phosphodiesterase inhibitors and pimecrolimus (SDZ ASM 981).     

肝移植患者术后环孢素A血药浓度分析

目的探讨肝移植患者术后环孢素A(CsA)的合适用量及有效血药浓度范围。方法采用荧光偏振免疫法对7例肝移植患者术后1～790dCsA全血谷浓度进行监测,共136次,并对监测结果进行分析。结果肝移植患者术后出现不良反应的谷浓度为(542.09±97.36)ng/mL,出现排斥反应的谷浓度为(67.05±33.92)ng/mL。结论跟踪监测肝移植患者术后不同时间段的CsA血药浓度,对临床提高肝移植患者的生存率,减少CsA的不良反应具有积极意义。     

神农33注射液减轻环孢素A肾毒性的实验研究

目的 观察神农33注射液减轻环孢素A（CsA)肾毒性的作用效果。方法 建立大鼠急性CsA肾毒性模型。观察神农33注射液治疗前后病理学改变和体重，血清尿素氮（BUN）及肌酐（Cr)的动态变化；用硫代巴比妥法，放免法及Western Blot法检测组织内丙二醛（MDA），前列腺素I2/血管紧张素A2（PGI2/TXA2）及热休克蛋白70（HSP70）的含量。结果 神农33注射液治疗后的组织病理改变较轻，未见明显的体重减轻及血清BUN，Cr的进行性增高，局部组织MDA，PGI2/TXA2及HSP70的含量明显低于CsA肾中毒组。结论 神农33注射液能有效减轻CsA所致的肾毒性损伤。     

Conversion from cyclosporin A to tacrolimus in pediatric liver transplantation

The dosing regimen for conversion from cyclosporin A (CsA) to tacrolimus immunosuppression was studied in 12 pediatric liver allograft recipients. Patients were stratified according to their age. Tacrolimus was started orally at a dosage of 0.05 mg/kg b.i.d., 12 h after stopping CsA administration and increased thereafter if needed. Tacrolimus and CsA concentrations were assayed by immunoassay using, respectively, an IMx and a TDx autoanalyzer (Abbott-France). Mean CsA concentration was in the therapeutic range 12 h prior to and at the time of introduction of tacrolimus. After 72 h of tacrolimus therapy, CsA concentrations were undetectable whereas mean tacrolimus concentration was 10.4 ng/mL with a mean dose of 0.09 mg/ kg b.i.d. The decline of CsA concentration was clearly biphasic. A slower decline in CsA concentration was detected after initiation of tacrolimus therapy, suggesting an inhibition of CsA metabolism by tacrolimus. No nephrotoxicity was observed. This dosage regimen allowed effective immunosuppression while avoiding additive nephrotoxicity.