New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.     

吗替麦考酚酯抑制小鼠TH17细胞的分化和增殖

目的 通过观察吗替麦考酚酯(MMF)对小鼠辅助性T淋巴细胞17(TH 17细胞)分化和增殖的影响,探讨MMF的免疫抑制作用及其机制.方法 采用随机数字表法将小鼠分为MMF组与对照组,每组8只.MMF组小鼠每天给予MMF 40 mg·kg-1·d-1灌胃,对照组小鼠每天给予等体积生理盐水灌胃.3周后取小鼠外周血和脾脏,采用流式细胞术检测小鼠外周血和脾细胞中TH17细胞和CD4+CD25+调节性T淋巴细胞(Treg细胞)的比例,并计算出TH 17细胞与Treg细胞的比值;采用酶联免疫吸附试验法分别检测两组小鼠血清中白细胞介素(IL)-17和IL-23的浓度.结果 MMF组外周血和脾细胞中TH17细胞比例分别为(1.95±0.08)％和(2.42±0.06)％,对照组分别为(3.19±0.07)％和(4.21±0.25)％,两组比较,差异均有统计学意义(P＜0.05).MMF组外周血和脾细胞中TH 17细胞与Treg细胞的比值均显著低于对照组(P＜0.05).MMF组小鼠血清IL-17水平明显低于对照组(P＜0.05),而血清IL-23水平高于对照组(P＜0.05).结论 MMF能够明显抑制小鼠体内TH17细胞的分化与增殖,降低TH 17细胞与Treg细胞的比值,减少IL-17的分泌,有利于诱导免疫耐受.     

Effect of mycophenolate mofetil on CD26 expression in the kidneys of diabetic rats

Objective To investigate the expression of CD26 (dipeptidyl peptidase 4) in the kidney tissues of diabetic rats and the effects of mycophenolate mofetil (MMF) on the renal CD26 expression. Methods Wistar rats were randomly divided into three groups: normal control group (NC group, n=7), diabetic model group (DM group, n=7) and MMF-treated group (MMF group, n=7). Wistar rats were fed with high-sucrose-high-fat diet and injected with streptozotocin into abdominal cavity to induce diabetes. Sixteen weeks later, blood glucose (BG), blood urea nitrogen (BUN), serum creatinine (Scr), renal hypertrophy index (kidney weight/body weight) and 24 hour urinary protein (24Upro) were measured. The number of CD3+/CD4+ T cells in renal tissues were measured through flow cytometry. The expression of CD26 in kidney was examined by using Western blotting and immunohistochemistry. Results Compared with NC group, BG, BUN, Scr, kidney weight/body weight, 24Upro were significantly increased in DM group (P﹤0.05). Except BG and kidney weight/body weight, the above-mentioned parameters were lower in MMF group compared with that in DM group (P﹤0.05). Intrarenal CD3+/CD4+ T cells were significantly up-regulated in DM group compared with that in NC group (P﹤0.01). CD26 in renal tissue was mainly expressed in T lymphocytes of renal interstitium. CD26 expression in DM group was significantly higher than that in NC group, and also higher than that in MMF group (P﹤0.05). In DM group, CD26+ T lymphocytes infiltration of renal interstitium was positively correlated with 24Upro (r2=0.770, P﹤0.05). Conclusions CD26 is related with diabetic nephropathy. MMF maybe inhibit T lymphocytes infiltration to reduce the expression of CD26 in renal interstitium, thus protecting the kidney function.     

Pancreas transplantation: The Wake Forest experience in the new millennium

AIM: To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression.METHODS: A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide.RESULTS: Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a “type 2 diabetes” phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels.CONCLUSION: In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.     

他克莫司联合糖皮质激素治疗儿童IgA肾病的疗效观察

目的 观察他克莫司（TAC）和霉酚酸酯（MMF）分别联合糖皮质激素（GC）治疗儿童原发性IgA肾病（IgAN）的疗效及安全性。方法 回顾性分析2012年1月至2017年12月经肾脏病理证实为原发性IgAN患儿,根据治疗方案不同分为TAC组和MMF组。收集两组患儿治疗前及治疗1、3、6个月时的临床资料,比较研究期间IgAN的缓解情况和不良反应。结果 共纳入43例符合研究标准的患儿,TAC组15例,MMF组28例。治疗1月时两组患儿缓解情况差异无统计学意义（P > 0.05）;治疗3月及6月时TAC组缓解情况优于MMF组（P < 0.05）。治疗1月时TAC组血清白蛋白高于MMF组（P < 0.05）。两组在治疗后各时点的血清白蛋白均高于基线值,差异有统计学意义（P < 0.0083）;两组治疗3月及6月时肾小球滤过率（GFR）均高于基线值,差异有统计学意义（P < 0.0083）。研究期间两组患儿不良反应总发生率差异无统计学意义（P > 0.05）,但TAC组有1例发生真菌感染。结论 TAC联合GC治疗儿童原发性IgAN有良好的减低尿蛋白的作用,近期疗效优于MMF,且安全性良好。     

麦考酚酸酯及其临床应用进展

目的:麦考酚酸酯(MMF)是一种新型的免疫抑制剂.在临床应用中,MMF的使用也越来越广泛,已不仅仅局限于器官移植,还涉及到系统性红斑狼疮(SLE)、自体免疫风湿性疾病的治疗,以及在糖尿病,肺部血管高压的辅助治疗等诸多方面.肠包衣麦考酚酸钠,是一种新的可抵抗胃溶作用的麦考酚酸肠包衣剂型,药物在肠内释放,可以降低胃肠道(GI)不良反应的发生.     

麦考酚酸联合迪银片治疗寻常型银屑病的近期临床疗效观察

目的研究麦考酚酸(MMF)联合迪银片治疗寻常型银屑病的使用方法、近期临床疗效及其副作用。方法46例患者随机分为治疗组和对照组。治疗组23例,MMF1.5 g/d分3次口服,1月后,减为1.0 g 2次/d,共4周,同时服用迪银片5片,3次/d共8周;对照组32例,服用迪银片和火把花根各5片,均3次/d,共8周。结果治疗组基本痊愈14例,显效5例,进步2例,无效2例,有效率91.30%;对照组基本痊愈16例,显效8例,进步2例,无效6例,有效率81.25%。两组疗效差异无显著性(P>0.05)。结论MMF联合迪银片治疗寻常型银屑病疗效与迪银片联合火把花根片相当,有较好的疗效。但因其价格昂贵,可作为二线银屑病治疗药物。     

HPLC法测定人血浆中霉酚酸的浓度及药动学研究

目的:建立以高效液相色谱法测定人血浆中霉酚酸浓度的方法,并对其在人体内的药动学参数进行研究。方法:霉酚酸血浆样品经甲醇沉淀后直接进样测定,其中色谱柱为Symmetry Shield C18,流动相为乙腈-水-三乙胺(40∶60∶0.3),流速为1.0mL·min-1,柱温为30℃,测定波长为218nm,进样量为20μL。结果:霉酚酸检测浓度在0.2~50mg·L-1范围内与峰面积积分值线性关系良好(r=0.9996),定量下限为0.2mg·L-1;平均方法回收率为101.94%,平均提取回收率为87.06%;日内、日间RSD均<6%。另,人体药动学研究表明,霉酚酸在体内存在肠肝循环导致双峰出现,人体过程符合单室开放模型。结论:本方法简便、灵敏、专一、准确、精密,可用于霉酚酸的药动学研究。     

HPLC法测定吗替麦考酚酯有关物质优化条件评定研究

目的建立以高效液相色谱法(HPLC)测定吗替麦考酚酯有关物质的各优化条件。方法采用AgilentC8色谱柱(4.6mm×150mm,5μm)。流动相采用乙腈-磷酸三乙胺缓冲液,用三乙胺调节pH值至3.8考评测试的麦考酚酯有关物质各种优化条件。结果HPLC法测定吗替麦考酚酸,测定波长250nm,线性范围为0.00831~0.0249μg·ml-1,r=0.9996,本方法重复性和精密度良好。结论采用HPLC法测定吗替麦考酚酯有关物质,方法简便,结果准确。     

Infantile systemic lupus erythematosus presenting with pulmonary hemorrhage

Systemic lupus erythematosus in infants born to healthy mothers is a rare entity. We describe a male infant who presented at 1 month of age with pulmonary hemorrhage and glomerulonephritis due to systemic lupus erythematosus, confirmed serologically and histologically. He was managed with a combination of prednisone and intermittent cyclophosphamide, but also received mycophenolate mofetil, with a complete serological and clinical remission at 30-month follow-up. This case underscores the importance of a broad approach to the evaluation of pulmonary hemorrhage and glomerulonephritis in the very young and the need for aggressive immunosuppressive therapy to achieve sustained serological and clinical remission.