ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.The prompt and vigorous immune response to xenogenic tissue remains a significant barrier to clinical xenotransplantation. Simultaneous blockade of the CD28 and CD40 costimulatory pathways has been shown to dramatically inhibit the immune response to alloantigen.Methods.In this study, we investigated the ability of simultaneous blockade of the CD28 and CD40 pathways to inhibit the immune response to xenoantigen in the rat-to-mouse and pig-to-mouse models.Results.Simultaneous blockade of the CD28 and CD40 pathways produced marked inhibition of the cellular response to xenoantigen in vivo and produced long-term acceptance of xenogeneic cardiac and skin grafts (rat-to-mouse), and markedly suppressed an evoked antibody response to xenoantigen. In addition, this strategy significantly prolonged the survival of pig skin on recipient mice.Conclusions.Long-term hyporesponsiveness to xenoantigen across both a concordant and discordant species barrier, measured by the stringent criterion of skin grafting, can be achieved using a noncytoablative treatment regimen.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Nonspecific inflammatory damage in the early stages of transplantation is the major cause of primary islet graft nonfunction. Using murine isografts, we attempted to prevent this islet graft damage by treating recipients with pravastatin (Pravacol), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor. Nicotinamide was also tested to determine the synergistic effect of both agents.Methods.Unpurified newborn BALB/c islets, ranging in number from 1800 to 2500, were transplanted into the left renal subcapsular space of a syngeneic adult mouse made diabetic with streptozotocin. Recipient mice were divided into the following four groups, based on treatment protocols: treatment with 40 mg/kg pravastatin (group 1), 500 mg/kg nicotinamide (group 2), 40 mg/kg pravastatin and 500 mg/kg nicotinamide (group 3), and vehicle alone (group 4). Pravastatin and nicotinamide were administered orally every day for 14 days, starting on the day of transplantation (day 0). Nonfasting blood glucose levels, urine glucose levels, and the intravenous glucose tolerance test were used to monitor the diabetic state. The reversal of diabetes was defined by normoglycemia and negative urine glucose maintained for more than 7 days.Results.After islet transplantation, levels of blood and urine glucose were significantly lower in groups 1 and 3, compared with those in group 4.K-values of an intravenous glucose tolerance test performed on day 14 were significantly higher in groups 1 and 3 than those of group 4. Reversal of diabetes had occurred in 63% of mice in group 1 and 67% in group 3, levels that were higher than those in group 2 (17%) and group 4 (0%)(P<0.02, groups 1 and 3 vs. group 4). Histological examination of grafts, biopsied on day 21, revealed well preserved islets with little sign of inflammation in groups 1 and 3, whereas grafts in groups 2 and 4 contained broken, smaller islets surrounded by severe fibrosis and mononuclear cell infiltration.Conclusion.Our results in mice have shown the effectiveness of pravastatin for protecting islets from nonspecific inflammatory damage. Nicotinamide did not show a synergistic effect with pravastatin at the dosage used in this study. These results indicate that pravastatin may be a useful agent for clinical islet transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.A model of total hepatic ischemia is currently not available in mice. Models described in rats using portosystemic shunts to achieve total ischemia have been notoriously difficult. In mice, the problem is compounded further when using this type of technique because of the small size of the animal. A new technique is described combining partial hepatectomy with clamping of the remnant liver.Methods.A partial (30%) hepatectomy is performed with resection of the caudate, right lateral, and quadrate lobes, and papillary process. Vascular microclamps are placed across the pedicles of the median and left lateral lobe at the level of the hilum to achieve total ischemia. Spontaneous portocaval shunts through caudate branches and collateral vessels prevent mesenteric congestion. Animals were studied for survival.Results.The procedure consistently took less than 30 min (25±2 min), and no bleeding of the resected tissue was observed. Evidence for total hepatic ischemia and spontaneous shunts was demonstrated by the use of an intraportal dye. All animals survived 60 min of ischemia, whereas all died after 90 min of ischemia.Conclusion.This is a technically simple and rapid procedure to perform. In the current environment of multiple knockout mice and bioreagents that are available, a model of this type is essential.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.The recently identified autonomous mouse parvovirus designated mouse parvovirus-1 (MPV-1) persists in adult BALB/c mice for at least 9 weeks, infects lymphoid tissues, interferes with the ability of cloned T cells to proliferate, and exhibits immunomodulatory properties. As a consequence of these findings, the present studies were undertaken to characterize further the immunomodulatory effects of MPV-1 on T cell-mediated immune responses in vivo and in vitro.Methods.To evaluate the effect of MPV-1 infection on CD8+T cell-mediated responses, BALB/c-H2dm2mice were infected after transplantation of allogeneic BALB/c skin.Results.MPV-1 potentiated the rejection of allogeneic skin grafts. This potentiation was not a result of virus infecting the cellular or vascular component of the graft as determined by in situ hybridization, but was mediated by T cells. However, the proliferative capacity of alloantigen-reactive lymphocytes from graft-sensitized infected mice was diminished. MPV-1 also induced the rejection of syngeneic skin grafts, and T cells from these infected graft-sensitized mice lysed syngeneic P815 target cells.Conclusions.These results suggest that MPV-1 infection of skin-grafted mice may disrupt normal mechanisms of peripheral tolerance and provide a unique model to study virus-induced autoimmunity.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Graft coronary arteriosclerosis (GCA) is the major limiting factor for long-term survival after heart transplantation. In this study, we investigated the effect ofMultiglycosidorum tripterygii(MT) on GCA and platelet-derived growth factor A (PDGF-A) mRNA expression of transplanted hearts.Methods.Two groups of Lewis rats (n=7/group) underwent heterotopic heart transplantation from Wistar-King donors and were treated with either cyclosporine (CsA;10 mg/kg/day) or MT (30 mg/kg/day). Histological evaluations of rejection and coronary arteriosclerosis, as well as Northern blot analysis on graft PDGF-A mRNA expression were made 60 days after transplantation.Results.Morphometric results indicated no significant difference in rejection between the CsA- and MT-treated groups. However, the extent of GCA in the MT-treated group was significantly less than that seen in the CsA-treated group (P<0.01). The expression of PDGF-A mRNA of cardiac allograft was also significantly suppressed in the MT-treated group when compared with the CsA-treated group (P<0.01).Conclusion.MT is superior to CsA in preventing graft coronary arteriosclerosis, and this efficacy is probably associated with the depressed expression of graft PDGF-A mRNA in the MT-treated group.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Three large-scale clinical trials conducted in North America, Europe, and Australia showed that mycophenolate mofetil (MMF) decreases the incidence of acute renal allograft rejection in the first 6 months after transplant compared with placebo or azathioprine. This study extends the randomized, prospective, double-blind trial of MMF conducted by the Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group.Methods.Patients (n=503) were randomized to receive 100-150 mg of azathioprine(AZA) (n=166), 2 g of MMF (n=173), or 3 h of MMF (n=164) per day, in conjunction with cyclosporine and prednisone from the time of transplantation.Results.During the first 6 months, the incidence of biopsy-proven acute graft rejection (BPR) was reduced by ∼50% in the MMF 2 g (19.7%) and MMF 3 g(15.9%) groups compared with the AZA group (35.5%). The incidence of treatment failure during the first 6 months, including BPR, death, graft loss, and early withdrawal without prior BPR, was significantly decreased: AZA, 50% compared with MMF 2 g, 38.2% (P=0.0287), and MMF 3 g, 34.8% (P=0.0045). At 3 years after transplant, both intent-to-treat and on-study (censoring at 90 days after treatment) analyses of graft and patient survival showed a trend toward advantage for MMF 2 g and 3 g vs. AZA(intent-to-treat: 81.9% and 84.8% vs. 80.2%; on-study: 84.0% and 86.4% vs. 82.7%), although this trend did not reach statistical significance. Rejection was the principal cause of graft loss in all groups: AZA, 9.9%; MMF 2 g, 5.8%; and MMF 3 g, 3.0%. Graft function (intent-to-treat and on-study) was comparable in all three groups at 3 years. Gastrointestinal toxicity, leukopenia, and tissue-invasive cytomegalovirus disease were more common in the MMF 3 g group both during and after the first posttransplant year. Lymphoproliferative disorders were diagnosed in one AZA (0.6%), two MMF 2 g(1.2%), and three MMF 3 g (1.8%) patients. Other (non-lymphoproliferative disorders, noncutaneous) malignancies occurred in six AZA (3.7%), four MMF 2 g(2.3%), and nine MMF 3 g (5.5%) patients. Mortality was comparable in all three groups (AZA, 8.6%; MMF 2 g, 4.7%; MMF 3 g, 9.1%) by 3 years of follow-up.Conclusion.MMF significantly reduced the incidence of rejection in the first 6 months, but there was not a significant improvement in graft survival throughout the 3 years after cadaver kidney transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.A microemulsion formulation of cyclosporine, Neoral, has been developed to overcome the problems associated with the poor and variable absorption of the traditional oil-based oral formulation, Sandimmune. The present study was conducted to compare the safety and tolerability of Neoral versus Sandimmune in maintenance renal transplant recipients over 1 year, and to assess the number of dose adjustments necessary to maintain trough cyclosporine concentrations within the desired therapeutic range.Methods.Patients on Sandimmune were randomized to be converted to Neoral (n=373) or remain on Sandimmune (n=93) for 12 months.Results.The proportion of patients needing dose increases to maintain cyclosporine trough levels within the desired range was significantly higher in the Sandimmune group during the first 3 months of the study, whereas the number of patients needing dose reductions was similar in both groups throughout the study period. There were no differences between the groups in terms of changes in blood pressure, serum creatinine levels, or other laboratory parameters. No significant differences in the incidence of adverse events known to be related to cyclosporine were observed between the treatment groups. More adverse events were causally related to Neoral than to Sandimmune by the investigators. However, overall, there were no clinically relevant differences between the treatment groups in the main safety and tolerability variables.Conclusions.The results of this study in maintenance renal transplant patients suggest that the improved pharmacokinetic characteristics of the microemulsion formulation of cyclosporine, Neoral, may facilitate the clinical management of cyclosporine immunosuppression, compared with the traditional formulation, Sandimmune. Furthermore, there is no evidence that the average improved bioavailability of Neoral has a negative impact on the main safety and tolerability variables, as no significant differences in graft function, the incidence of rejections, and most adverse events were seen.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Posttransplant polycythemia (PTP) affects 6-30% of renal transplant recipients and can result in thromboembolic disease. The pathogenesis of PTP remains unknown and may be multifactorial. Although phlebotomy has previously been the treatment for PTP, drugs such as adenosine receptor antagonists or angiotensin-converting enzyme inhibitors can be used to control PTP.Methods.The authors performed a prospective study of two different drugs to treat PTP: aminophylline and enalapril. Twenty-seven patients with PTP lasting more than 6 months were evaluated. During phase 1, aminophylline was compared with enalapril. The patients sequentially received aminophylline and enalapril during 12-week periods, intercalated by 12-week periods of no drugs. During phase 2, enalapril was administered for 12 weeks.Results.From January 1984 to December 1993, 110 of 333 patients with PTP lasting more than 6 months (33%) developed polycythemia, and 27 patients were included in the present study. In phase 1, aminophylline had no effect on PTP. Enalapril promoted an erythropoiesis inhibition, characterized by a decrease in hematocrit and an increase in iron stores and ferritin levels. After withdrawal of enalapril, the hematocrit increased and the iron stores decreased. In phase 2, there was a progressive reduction in hematocrit after the 4th week of therapy. The lowest hematocrit was observed in the 12th week and then enalapril was stopped, leading to a subsequent rise in hematocrit. Erythropoietin levels and renal function remained constant during all periods of both phases of the study.Conclusion.The use of adenosine antagonists was ineffective to treat PTP in our series. However, treatment with enalapril promoted an erythropoiesis inhibition, demonstrated by a reduction in hematocrit, hemoglobin, red blood cell count, and reticulocyte count, associated with an increase in iron stores. This response occurred independently from erythropoietin levels or hemodynamic graft changes.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Because of the shortage of kidneys available for transplantation, we began in 1985 to harvest kidneys from non-heartbeating (NHB) donors.Methods.We compared the results of a group of 66 kidney recipients from NHB donors(NHB group) with 122 kidney recipients from heartbeating donors (HB group). We analyzed, in the NHB group, the influence of ischemia times in graft survival and we tested the best cut-offs by receiver operating characteristic curves. We also studied, using a univariate and multivariate Cox hazard model, the capacity of different variables to predict graft loss.Results.Patient and graft survival were similar in both groups during the follow-up. The percentage of delayed graft function was the only significant difference between both groups (NHB group 62% vs. HB group 32%;P=0.0001). Delayed graft function, in the NHB group, is influenced by the warm ischemia time, which is directly related to the number of days to achieve a serum creatinine<300 mmol/L (P=0.0001). The best cut-off times in this group were 45 min for warm ischemia time and 22 hr for cold ischemia time. Recipients have a greater likelihood of losing the graft beyond those limits (P=0.017, relative risk: 7.3). The incidence of acute rejection was similar in both groups, and it was the only predictor factor of graft loss in the complete series of patients (P=0.0001), in the NHB group (P=0.007), and in the HB group(P=0.02).Conclusions.Reducing the incidence of acute rejection and shortening ischemia time are conditions needed to guarantee a long graft survival of kidneys from NHB donors.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID