Immediate and long-term results of ATG induction therapy for delayed graft function compared to conventional therapy for immediate graft function

The use of polyclonal antibodies for delayed graft function (DGF) was tested in 83 renal allograft recipients. Conventional immunosuppression (CI) was given to 52 patients with immediate graft function (IGF) while 31 patients with DGF received the polyclonal antibody ATG. Administration of OKT3 was restricted to steroid-resistant acute rejections in both groups. The incidence and severity of acute rejections, graft survival rate, CMV infections, and lymphocyte subsets were examined. ATG patients experienced a total of 0.6 acute rejections per patient, whereas CI patients had 0.9 on the average (P < 0.05). Second and third acute rejections occurred less frequently and later in the ATG group than in the CI group (P < 0.01). Steroid-resistant acute rejections occurred in 20 of the CI patients (38 %) but in only 7 of ATG patients (23 %). One-year graft survival in the CI and ATG groups was 98.1 % and 93.2 %, respectively. A decreased CD4 + to CD8 + T-lymphocyte ratio of about 0.5 was still detectable 5 years after the initial ATG administration. Hence, patients with DGF appear to benefit from induction therapy with ATG. Received: 3 March 1998 Received after revision: 20 July 1998 Accepted: 23 September 1998     

A single center's clinical experience with quadruple immunosuppression including ATG or IL2 antibodies and mycophenolate mofetil in simultaneous pancreas–kidney transplants

Acute rejection remains a major problem in simultaneous pancreas–kidney (SPK) transplant and occurs in 60–100% of the cases.
With the introduction of mycophenolate mofetil (MMF) replacing azathioprine (AZA) as a basis immunosuppressant, reduced rates of rejection have been reported. This study investigates the frequency and clinical relevance of allograft rejection in SPK patients receiving anti‐thymocyte globulin (ATG) or Basiliximab® induction therapy and cyclosporine Neoral® (CyA), MMF, steroid basis immunosuppression.
Between December 1996 and October 1999, 21 consecutive patients (15 males, 6 females) received a SPK transplant at our institution with a mean±standard deviation (SD) age of 42±6 yr. Of these, 14 patients were treated with anti‐thymocyte globulin (ATG) Fresenius® (rabbit) 3–5 mg/kg for 6±2 d, cyclosporine Neoral (CyA) (trough levels 350–400 ng/mL), MMF 3 g/d and low dose steroid therapy. Seven SPK patients were treated with Basiliximab (Simulect®, Novartis 20 mg on d 0 and d 4 post‐transplant) instead of ATG. The patients had an average human leucocyte antigen (HLA) mismatch of 3.9/6 and a negative cross match. All patients remained on triple drug therapy. Three patients were switched to tacrolimus instead of Neoral for CyA intolerance. The mean±SD cold ischemia time (CIT) of the organs was 10.1±2.4 h for the pancreas and 10.5±2.6 h for the kidney.
Results: Biopsy‐proven rejection occurred in the kidney of 1 ATG patient (8%), which responded to steroid bolus therapy. One of the patients (14%) with Basiliximab induction developed renal allograft rejection, which was resolved after a 6‐d course of anti‐CD3 mAb (OKT3) treatment. All patients (100%) were free from rejection in the pancreas, as measured by urine amylase levels and glycemic control without the need for exogenous insulin with a mean glycosylated hemoglobin (HBA₁C) of 5.1±0.7% and serum creatinine with a mean of 1.24±0.24 mg/dL in a mean follow‐up period of 17±15 months (median 12, range 2–37).
Conclusion: Triple drug immunosuppression including cyclosporine, MMF and low dose steroids with ATG or interleukin 2 (IL2) receptor antibodies induction therapy appears to be a very suitable immunosuppressive regimen for combined pancreas–kidney transplant (PKT) with a marked reduction in the incidence of rejection.     

Single‐bolus high‐dose ATG for prophylaxis of rejection in renal transplantation ‐ a prospective,randomized study

Abstract Currently, most centers use antithymocyte globulin (ATG) for induction or treatment of acute rejection. In the literature, postponement of introduction of cyclosporin or delay in acute rejection following ATG induction are well documented [1‐4]. In contrast, data are very scant on the reduction of incidence of rejection or improvement of graft survival following ATG prophylaxis [5, 6]. The objective of this study was to compare the efficacy and safety of ATG high‐dose single‐bolus therapy with that of a standard cyclosporine‐based protocol in prophylaxis of acute rejection in renal transplantation in an adult population. Rabbit ATG (Fresenius, Oberursel) was administered intraoperatively (before revascularization) to 19 renal transplant recipients as a single intravenous injection in a dose of 9 mg/kg body weight (high dose, single bolus). Treatment results were compared with those of a control group comprising 19 recipients receiving the same cyclosporin‐Neoral‐based protocol as the study group. In all patients concomitant medication consisted of steroids and azathioprine. The incidence of acute rejection in the high‐dose ATG bolus group was 26%, compared with 58% in controls (P < 0.05). In the ATG treated group no grafts were lost to acute rejection in both high‐and low‐risk recipients, versus compared with a loss of 37% of rejecting grafts in controls. Though the observed difference in 1‐year graft survival between study and control groups (84.2% vs 73.6%) did not reach statistical significance, the same trend was also observed in patients (n = 9 and n = 12 respectively) who, at he time of this report, had completed a 2nd post‐transplantation year. The bolus and control groups had a similar incidence of complications and comparable renal function. We conclude that a single‐bolus high‐ATG protocol is efficient and safe in prophylaxis of renal allograft rejection.     

Moving to tolerance: clinical application of T regulatory cells

Decreasing the incidence of chronic rejection and reducing the need for life-long immunosuppression remain important goals in clinical transplantation. In this article, we will review how regulatory T cells (Treg) came to be recognized as an attractive way to prevent or treat allograft rejection, the ways in which Treg can be manipulated or expanded in vivo, and the potential of in vitro expanded/generated Treg for cellular therapy. We will describe the first regulatory T cell therapies that have been or are in the process of being conducted in the clinic as well as the safety concerns of such therapies and how outcomes may be measured.     

T300A polymorphism of ATG16L1 and susceptibility to inflammatory bowel diseases:A meta-analysis

AIM:To evaluate the association of the autophagy- related 16-like 1 (ATG16L1 ) T300A polymorphism (rs2241880) with predisposition to inflammatory bowel diseases (IBD) by means of meta-analysis.METHODS: Publications addressing the relationship between rs2241880/T300A polymorphism of ATG16L1 and Crohn‘s disease (CD) and ulcerative colitis (UC) were selected from the MEDLINE and EMBASE data-bases. To make direct comparisons between the data collected in these studies, the individual authors were contacted when...     

基于定痫汤干预后癫痫小鼠海马区miRNA-204表达水平的变化及脑电图变化的研究

目的:研究定痫汤干预后癫痫小鼠脑电图的变化、小鼠海马区miRNA-204表达水平的变化以及自噬相关蛋白ATG7、LC3II的表达变化,探讨其可能的作用机制。方法:取50只雄性昆明小鼠,其中40只随机分成模型组、生理盐水组、卡马西平组和定痫汤组,每组10只,另外10只为备用小鼠。首先对各组实验动物进行灌胃给药两周,模型组和生理盐水组均予20 mL·kg^-1·d^-1生理盐水进行灌胃;定痫汤组予7 g·kg^-1·d^-1定痫汤药液进行灌胃;卡马西平组予30 mg·kg^-1·d^-1卡马西平混悬液灌胃。然后,通过盐酸匹罗卡品构建小鼠急性癫痫模型。其次,对各组小鼠进行行为学和脑电图观察。最后,将小鼠断头取脑,采用实时荧光定量PCR技术检测小鼠海马区miRNA-204表达水平的变化;并且通过免疫组化法检测自噬相关蛋白ATG7、LC3II的表达变化。结果:与生理盐水组相比,模型组小鼠癫痫发作的频率多、持续时间长,小鼠脑电图尖波、棘波、棘慢波明显增多,海马区miRNA-204的表达明显下调(P<0.01),自噬相关蛋白ATG7、LC3II的表达明显增多(P<0.01)。与模型组相比,使用定痫汤干预后小鼠癫痫发作频率减少,小鼠脑电图痫性波形减少,小鼠海马区miRNA-204的表达升高(P<0.01),自噬相关蛋白ATG7、LC3II的表达下调(P<0.01)。结论:定痫汤可以减少小鼠癫痫发作的频率,减少小鼠脑电图的痫性波形。其可能是通过上调miRNA-204的表达,抑制自噬相关蛋白ATG7、LC3II的表达,拮抗小鼠海马神经元过度自噬,从而发挥抗癫痫的作用。     

Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation

Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis. Although targeting NLRP3 inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial. By focusing on the flavonoid lonicerin, one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb., here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2 (EZH2) histone methyltransferase. EZH2-mediated modification of H3K27me3 promotes the expression of autophagy-related protein 5, which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation. Mutations of EZH2 residues (His129 and Arg685) indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin. More importantly, in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3–ASC–pro-caspase-1 complex assembly and alleviates colitis, which is compromised by administration of EZH2 overexpression plasmid. Thus, these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.     

肾移植术后应用抗人T细胞免疫球蛋白逆转急性排异反应的观察与护理

目的探讨肾移植术后应用抗人T细胞免疫球蛋白（ATG）逆转急性排异反应的观察和护理。方法总结肾移植术后应用ATG逆转急性排异反应的护理经验。结果本组13例患者血尿素氮及肌酐均恢复正常,尿量增多,血尿消失。结论严密观察应用ATG后的副作用,采取有效的预防措施及精心护理,是移植肾功能恢复的保证。     

The induction of autophagy by γ‐radiation contributes to the radioresistance of glioma stem cells

Malignant gliomas are characterized by a short median survival which is largely impacted by the resistance of these tumors tochemo‐ and radiotherapy. Recent studies suggest that a small subpopulation of cancer stem cells, which are highly resistant to γ‐radiation, has the capacity to repopulate the tumors and contribute to their malignant progression. γ‐radiation activates the process of autophagy and inhibition of this process increases the radiosensitivity of glioma cells; however, the role of autophagy in the resistance of glioma stem cells (GSCs) to radiation has not been yet reported. In this study we examined the induction of autophagy by γ‐radiation in CD133+ GSCs. Irradiation of CD133+ cells induced autophagy within 24–48 hr and slightly decreased the viability of the cells. γ‐radiation induced a larger degree of autophagy in the CD133+ cells as compared with CD133? cells and the CD133+ cells expressed higher levels of the autophagy‐related proteins LC3, ATG5 and ATG12. The autophagy inhibitor bafilomycin A1 and silencing of ATG5 and beclin1 sensitized the CD133+ cells to γ‐radiation and significantly decreased the viability of the irradiated cells and their ability to form neurospheres. Collectively, these results indicate that the induction of autophagy contributes to the radioresistance of these cells and autophagy inhibitors may be employed to increase the sensitivity of CD133+ GSCs to γ‐radiation. © 2009 UICC