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Acute Graft Rejection (acute + graft_rejection)
Selected AbstractsImmunoprophylaxis with Basiliximab Compared with Antithymocyte Globulin in Renal Transplant Patients Receiving MMF-containing Triple TherapyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2002Yvon Lebranchu Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with Thymoglobulin® or basiliximab has significantly reduced the incidence of acute rejection episodes and graft loss following kidney transplantation. This open, randomized, multicenter study investigated the efficacy and tolerability of basiliximab (20 mg day 0, day 4) plus early cyclosporine from day 0 (n = 50) compared with Thymoglobulin® plus delayed cyclosporine (n = 50) in adult kidney transplant patients. In addition, all patients received steroids and mycophenolate mofetil (MMF) at standard doses from day 0. Patient and graft survival rates at 12 months were 98 and 94% in the basiliximab group, respectively, compared with 100 and 96% in the Thymoglobulin® group. The incidences of biopsy-confirmed acute rejection (8.0% in each group) and treatment failure (14% in the basiliximab group vs. 8% in the Thymoglobulin group) were comparable in the two groups. There was a nonsignificant tendency to more dialysis (14 vs. 6%), and fewer cytomegalovirus (CMV) infections (p =,0.005) in the basiliximab group, but the percentage of clinical CMV was not different between the two groups (6 vs. 12%). Both strategies give excellent results, despite the differences in patterns, in nonhyperimmunized patients receiving their first cadaveric renal allograft. [source] The impact of late acute rejection after cadaveric kidney transplantationCLINICAL TRANSPLANTATION, Issue 4 2001JT Joseph Background: Acute graft rejection (AR) following renal transplantation results in reduced graft survival. However, there is uncertainty regarding the definition, aetiology and long-term graft and patient outcome of AR occurring late in the post-transplant period. Aim: To determine if rejection episodes can be classified by time from transplantation by their impact on graft survival into early acute rejection (EAR) and late acute rejection (LAR). Materials and methods: 687 consecutive adult renal transplant recipients who received their first cadaveric renal transplant at a single centre. All received cyclosporine (CyA)-based immunosuppression, from 1984 to 1996, with a median follow-up of 6.9 yr. Details were abstracted from clinical records, with emphasis on age, sex, co-morbid conditions, HLA matching, rejection episodes, patient and graft survival. Analysis: Patients were classified by the presence and time to AR from the date of transplantation. Using those patients who had no AR (NAR) as a baseline, we determined the relative risk of graft failure by time to rejection. The characteristics of patients who had no rejection, EAR and LAR were compared. Results: Compared with NAR, the risk of graft failure was higher for those patients who suffered a rejection episode. A much higher risk of graft failure was seen when the first rejection episode occurred after 90 d. Thus, a period of 90 d was taken to separate EAR and LAR (relative risk of 3.06 and 5.27 compared with NAR as baseline, p<0.001). Seventy-eight patients (11.4%) had LAR, 271 (39.4%) had EAR and 338 (49.2%) had NAR. The mean age for each of these groups differed (LAR 39.6 yr, EAR 40.8 yr compared with NAR 44 yr, p<0.003). The 5-yr graft survival for those who had LAR was 45% and 10-yr survival was 28%. HLA mismatches were more frequent in those with EAR vs. NAR (zero mismatches in HLA-A: 36 vs. 24%, HLA-B: 35 vs. 23% and HLA-DR: 63 vs. 41%, p<0.003). There was no difference in mismatching frequency between NAR and LAR. Conclusions: AR had a deleterious impact on graft survival, particularly if occurring after 90 d. AR episodes should therefore be divided into early and late phases. In view of the very poor graft survival associated with LAR, it is important to gain further insight into the main aetiological factors. Those such as suboptimal CyA blood levels and non-compliance with medication should be further investigated with the aim of developing more effective immunosuppressive regimens in order to reduce the incidence of LAR. [source] Graft rejection mediated by CD4+ T cells via indirect recognition of alloantigen is associated with a dominant Th2 responseEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2005Keri Csencsits Abstract CD4+ T cells that respond to indirectly presented alloantigen have been shown to mediate chronic rejection, however, the role of the indirect pathway in acute rejection has yet to be completely elucidated. To this end, BALB/c or C57BL/6 mice were depleted of CD8+ T cells and transplanted with class II transactivator (CIITA)-deficient cardiac allografts, which cannot directly present class II alloantigens to CD4+ T cells. In this manner, the rejection response by CD4+ cells was forced to rely upon the indirect recognition pathway. When not depleted of CD8+ cells, both BALB/c and C57BL/6 mice rejected CIITA,/, allografts and a polarized Th1 response was observed. In contrast, when BALB/c recipients of CIITA,/, allografts were depleted of CD8+ T cells, the grafts were acutely rejected and a strong Th2 response characterized by eosinophil influx into the graft was observed. Interestingly, CD8-depleted C57BL/6 recipients of CIITA,/, allografts did not acutely reject their transplants and a Th2 response was not mounted. These findings indicate that CD4+ T cells responding to indirectly presented alloantigens mediate graft rejection in a Th2-dominant manner, and provide further evidence for the role of Th2 responses in acute graft rejection. [source] Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010Lihua Zeng WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? , Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. , Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. , Mycophenolic acid exhibits considerable inter- and intra-patient pharmacokinetic variability in adults and paediatric transplant recipients. , The AUC of mycophenolic acid over a 12 h dose interval at steady-state is generally agreed to be the most reliable metric associated with the risk of acute rejection. , Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter- individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. WHAT THIS STUDY ADDS , This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. , Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. , This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration,time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l,1 h associated with optimal outcome. RESULTS A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration,time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h,1, 3.74 l h,1, 7.24 l, 16.8 l, 0.39 h,1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCLUSIONS The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation. [source] IMMUNOCHEMICAL CHARACTERIZATION OF THE FUNCTIONAL CONSTITUENTS OF TRIPTERYGIUM WILFORDII CONTRIBUTING TO ITS ANTI-INFLAMMATORY PROPERTYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1 2008Kwong-Fai Wong SUMMARY 1Tripterygium wilfordii (TW) contains bioactive compounds that possess immunosuppressive properties. These compounds are considered to be potential drugs in the treatment of acute graft rejections. However, their structure,activity relationships remain unknown. 2The aim of the present study was to delineate the molecular moieties of triptolide that could account for its ability to inhibit inflammatory responses. In this context, purified TW active compounds (triptolide and triptonide) and synthetic triptolide derivatives were prepared to investigate the structure,activity relationships of triptolide. To this end, rat splenocytes were treated with increasing concentrations of the compounds and then allogenically stimulated using a mixed lymphocyte reaction to determine their antiproliferative activities. From the results, the IC50 value of each compound was calculated. 3Modification of the ,-hydroxyl group at the C-14 position of the triptolide molecule significantly affected the immunosuppressive activity of T59, as demonstrated by a sevenfold increase of the IC50. Conversely, reduction of the ,-butyrolactone group in T60 and T61 completely abrogated the antiproliferative effect. Alterations in the C-14 ,-hydroxyl and ,-butyrolactone groups also resulted in reduced cytotoxicity. 4The present findings demonstrate that the C-14 ,-hydroxyl and ,-butyrolactone moieties of the triptolide molecule are crucial for its anti-inflammatory properties and cytotoxicity and are responsible for the compound's antiproliferative activity. [source] | |||||||||||||||||||