Assessment of immunosuppression by serum inhibition of alloreaction and measurement of cyclosporin A (CyA) serum levels in kidney graft recipients under CyA

The immunosuppressive effect of kidney graft recipient sera was studied on T-lymphocyte alloreactive line (4H) proliferation and compared to native cyclosporin A (CyA) and CyA metabolite concentrations determined by radioimmunoassay (RIA) using specific or nonspecific monoclonal antibodies. Three clinical groups were studied: (1) patients experiencing acute renal rejection episodes (CyA-R), (2) patients experiencing CyA-dependent nephrotoxicity episodes (CyA-TOX) and (3) patients in a clinically steady state (CyA-ST), according to their therapeutic regimen i.e., monotherapy (CyA alone) or polytherapy (CyA associated with prednisolone and/or azathioprine). Regardless of the clinical state, sera of patients in polytherapy displayed more inhibitory activity than those of monotherapy patients (24% and 40% inhibition of 4H proliferation, respectively, at sera dilution of 1:2), something which was no doubt due to the inhibitory activity of prednisolone on T-lymphocyte growth. In the two therapeutic regimens, CyA-ST patient sera exhibited the lowest inhibitory activity on the 4H line (45% and 65% inhibition of 4H proliferation in mono-and polytherapy, respectively, at sera dilution of 1:2). Sera from CyA-TOX patients were highly inhibitory (74% and 86% inhibition of 4H proliferation in mono-and polytherapy, respectively, at sera dilution of 1:2), in agreement with RIA assays showing increased native circulating CyA and CyA metabolites and daily CyA intake in this group as compared to CyA-St. Surprisingly, CyA-R patient sera were no less inhibitory than those of CyA-ST patients on 4H-line, antigen-induced proliferation. This clinical group did not differ from others for CyA intake or level of circulating immunosuppressive molecules, suggesting that rejection could be associated with a state of interindividual variation in sensitivity to CyA. In addition, a polytherapeutic regimen seemed to modify CyA bioavailability in CyA-ST group patients, with a decreased CyA metabolite level as compared to their monotherapy counterparts (native CyA plus metabolite/native CyA ratio being 2.73 and 3.73, respectively). In contrast, in the CyA-R patient group, polytherapy appeared to be associated with an increase in CyA metabolite circulating levels (ratio 4.79). In view of the low inhibitory activity of CyA metabolites, this profile might lead to rejection.     

视盘血管炎的治疗

目的：研究视盘血管炎的发病机制,病因,病程经过,治疗方法及预后。方法：系统治疗和观察了视盘血管炎４６例,其中视乳头水肿２６例、３０眼,中央静脉血栓型２０例、２０眼。对患者视力、视野、眼压、视乳头改变、眼底荧光血管造影及血象等进行了检查。对视乳头水肿型行ＣＴ颅脑扫描,眼压测量和脑脊液检查以除外颅内病变。所有患者均予以抗感染和抑制免疫反应疗法。结果：患者均在１８个月内治愈。视乳头水肿型视盘血管炎半数视     

Abbreviated cyclosporine AUCs on Neoral – the search continues!

 Cyclosporine is a powerful immunosuppressant with a narrow therapeutic window and considerable inter- and intrapatient variability. The pre-dose trough concentration (C_min) is commonly used for therapeutic drug monitoring. With the new microemulsion (Neoral), intrapatient variability was reduced. However, the usefulness of Neoral C_min was questioned. Firstly, because of the improved and more-rapid absorption, accidental intake before blood sampling has a greater impact on C_min than with classic cyclosporine. Secondly, C_min may be low despite high drug exposure, due to rapid clearance in children. A full pharmacokinetic (PK) profile with determination of the area under the curve (AUC) is expensive and cumbersome, and therefore a search for an abbreviated AUC began. Here, we present a retrospective analysis of 84 PK profiles from 78 pediatric renal transplant recipients. By analysis of rejection episodes and toxicity, we estimated a target AUC above 5,000 ng×h/ml in the early post-transplant period and 3,900 ng×h/ml beyond 100 days. The abbreviated AUC using the 2- and 6-h concentrations (C2 and C6) and a simple estimate derived from the 3-h concentration (C3) were equally well correlated with the AUC. From our data, we recommend a target C3 at approximately 800 ng/ml early after transplantation and 450–550 ng/ml beyond 100 days. Received: 28 January 1998 / Revised: 10 June 1998 / Accepted: 15 June 1998     

Human nonspecific suppressive lymphokines

Since the term lymphokine first appeared in print over 20 years ago, a tremendous number of these soluble mediators of the immune system have been described. Within the past few years, many human nonspecific suppressive lymphokines have been identified. This review discusses the historical basis of immunologic suppression and suppressor factors. Later reports describing suppressive human lymphokines are then grouped into four categories: primarily stimulatory lymphokines that also mediate certain suppressive activities, suppressive lymphokines produced during altered states of immunity, suppressive lymphokines produced by exogenously stimulated lymphocytes, and suppressive lymphokines produced by unstimulated lymphocytes. Recent work I have been involved in focusing on the human suppressive lymphokine soluble suppressor factor (SSF) is also discussed.     

Perspectives in transplantation immunology 1991

Summary The clinical success of organ transplantation depends to a large degree on the immunological acceptance of the grafted organ. This paper summarizes from an immunological point of view the recent progress that has been made to improve graft acceptance, and discusses some future aspects in the field. Over the last few years, major emphasis has been put on the development of new immunosuppressive drugs, including FK 506, rapamycin, and Deoxyspergualin. Together with monoclonal antibodies against defined T-cell surface antigens, there are now new and effective means available to prevent or treat rejection episodes. Progress has also been made in the field of HLA typing, where the introduction of molecular biology-based methods significantly increased the accuracy of HLA class II typing. The ultimate goal of transplantation immunology is the induction of (donor-) specific tolerance. While some protocols are effective in inducing peripheral tolerance in experimental animals, these regimens are at present not yet applicable in the clinical situation. To overcome the shortage of donor organs, alternative strategies are currently being considered. Among these, xenotransplantation may eventually prove successful, despite the massive immunological problems such as, e.g., the presence of preformed xenoreactive antibodies.Abbreviations CTL cytolytic T lymphocyte - HLA human leukocyte antigen - MHC major histocompatibility complex - PCR polymerase chain reaction - mAB monoclonal antibody - RFLP restriction fragment length polymorphism - TCR T-cell receptor Preprint of a lecture to be read at the 22nd Congress of the Gesellschaft für Nephrologie, Heidelberg, September 15–18, 1991 (Editor: Prof. Dr. E. Ritz, Heidelberg)     

New strategies in immunosuppression

This article reviews recent papers relating to immunosuppressives and attempts to categorise the bewildering number of new reagents according to their effects on the immune response. It is apparent that the majority of groups are concentrating on reagents which, like cyclosporin A, are predominantly directed at T cells (42% of the last 200 papers inTransplantation, Transplant International andTransplantation Proceedings). The major change in strategy which is occurring relates to the rapidly increasing use of reagents directed against T cell subsets, especially those directed against the interleukin-2 receptor and CD4-positive T cells. This groups's share of the market has risen from 2% to over 12% within 5 years. New successful monoclonal antibodies include reagents directed against antigen-presenting cells and against molecules directly involved in cell adherence. The use of donor bone marrow or subsets of cells from donor bone marrow as inducers of non-reactivity, especially to solid organ grafts, is certainly one of the most exciting of the non-antibody protocols. It is encouraging that relatively specific immunosuppression can be induced in animals by combinations of specific and non-specific reagents as well as by specific reagents alone. This will facilitate the introduction of specific protocols into the human situation, and this strategy holds out great hope for the future. Unfortunately, one of the most effective ingredients of such combination therapies in animal models (anti-CD4) appears to have its tolerogenic potential abrogated by cyclosporin A and FK-506. One area of immunosuppression which is receiving scant interest relates to antibody (especially non human leucocyte antigen antibody) production, but as the interest in xenotransplantation increases it is anticipated that major new interest will emerge in this area.     

肾移植术后并发泌尿系统肿瘤6例报告并文献复习

 目的　探讨肾移植术后泌尿系统肿瘤的发生情况、临床特点、诊断及治疗。方法　对本院自1991年～ 2 0 0 1年十年间行同种异体肾移植术 10 96例术后泌尿系统肿瘤的发生情况进行回顾性分析 ,并结合复习文献。结果　本组发现泌尿系统肿瘤 6例 ,发生率为 0 .5 5 %。其中肾盂癌 2例 (其中 1例为双侧肾盂癌 ) ,膀胱癌 1例 ,肾盂癌合并膀胱癌 2例 ,输尿管癌 1例。 6例均行手术治疗 ,平均随访11.4个月 ,效果良好。结论　肾移植术后出现血尿 ,除排斥反应外 ,还应注意泌尿系统肿瘤的可能性。     

同种异体原位心脏移植2例报告

目的 总结2例原位心脏移植成功的治疗经验，探讨手术方式及术后围手术期处理。方法 2003年5月和2003年12月先后为2例终末期心肌病患者施行原位心脏移植手术。术后免疫抑制剂应用“环孢素A 强的松 骁患”三联疗法。结果 2例手术均获成功，术后无并发症发生，心功能良好，生活质量好。结论 经典法原位心脏移植操作方便、缝合牢固确实，但存在术后心房偏大的不足；围手术期处理中应重视右心功能不全、肾功能不全的防治和胃肠道营养的应用。     

雷公藤甲素对小鼠淋巴细胞体外活化的抑制作用

目的:研究雷公藤甲素(TRD)对小鼠T淋巴细胞活化标志CD69、CD25及细胞因子IL-2及IFN-γmRNA表达的影响,为阐明其免疫抑制作用提供分子药理学依据.方法:无菌分离小鼠淋巴结细胞,加入不同浓度的雷公藤甲素预先孵育1 h,用多克隆刺激剂刀豆蛋白(ConA)刺激T细胞活化,利用荧光标记的单克隆体双染技术,流式细胞仪检测TRD对小鼠T细胞CD69、CD25表达的影响;采用半定量RT-PCR技术从mRNA水平检测TRD对细胞因子IL-2、IFN-γ mRNA的表达的影响.结果:TRD能抑制T细胞早期活化标志CD69和CD25,同时TRD也能抑制IL-2及IFN-γmRNA的表达.结论:TRD对T细胞早期活化分子及细胞因子表达的抑制作用可能是其发挥免疫抑制作用的机制之一.     

Analysis of immunological enhancement of immunosuppressed chickens by Chinese herbal extracts

Ethnopharmacological relevance

Radix astragali, Radix codonopis, Herba epimedii and Radix glycyrrizae are 4 plants commonly used in Chinese traditional medicine or veterinary medicine to improve immune functions against chronic diseases in humans and animals.

Aim of the study

We compared immunological enhancement by 4 herbal extracts in clinical healthy chickens or immunosuppressed chickens singly and in combination.

Materials and methods

Water extracts of 4 herbs individually and in different combinations were supplemented in drinking water. Hemagglutination inhibition (HI) antibody titers against Newcastle disease virus (NDV) and H5 avian influenza virus (H5-AIV) after vaccination were measured as indicators to evaluate immunological stimulation across groups supplemented with different herbal extracts. The experiments were conducted in both clinically healthy chickens and chickens with immunosuppression induced by reticuloendotheliosis virus (REV) infection.

Results

In clinically healthy chickens HI antibody titers against NDV and H5-AIV after vaccination were not influenced by supplementation with the herbal extracts of Radix astragali, Radix codonopis, Herba epimedii and Radix glycyrrizae in drinking water. In chicks with REV-induced immunosuppression, however, supplementation of some herbal extracts significantly increased HI antibody titers to NDV and H5-AIV when compared to the immunosuppressed control group (P < 0.01), but the titers were still lower than those in chicks not infected by REV. The 4 herbal mixtures produced the best enhancement among various combinations. The components of the herbal extract were water soluble and treatment by ether had no influence on immunological enhancement. The molecular weights of the active components of the herbal extracts were in the range of 10,000–100,000 Da.

Conclusion

Our results show that the herbal extract supplementation in drinking water can induce an immune stimulation response in immunosuppressed chickens.It suggests that chickens with REV infection-induced immunosuppression could be used as an experiment model for determination of immunological enhancement effects of some herbal components.