摘要:

Background.Donor-specific tolerance induction remains an attractive objective that generates much research in the field of transplantation. Unfortunately, most of the protocols available involve pregraft conditioning, making these treatments incompatible with clinical applications.Methods.LEW.1A rats were grafted with histoincompatible LEW.1W hearts. On the day of transplantation, recipients were treated with anti-CD40L combined with donor splenocytes. The hearts were evaluated for graft survival; cellular infiltrate and intragraft cytokines were determined using real-time reverse transcriptase-polymerase chain reaction. Tolerance induction was assessed by skin grafting and adoptive transfers.Results.The combination of a single injection of anti-CD40L and donor splenocytes, given on the day of surgery, allowed 40% of cardiac allografts to survive long-term (mean survival time=66.3 day). The cellular composition or the extent of graft infiltrate was not modified but was associated with a massive decrease of proinflammatory cytokines expression within the graft. Long-term survivors accepted donor-matched skin grafts, and leukocytes harvested from these animals transferred tolerance into irradiated freshly grafted recipients.Conclusion.A combination of costimulation blockade and donor cells, given once at the time of transplantation, is sufficient to induce allograft tolerance in rats.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Mitogen-activated protein kinases (MAPKs), including extracellular-responsive kinase (ERK) and p38 MAPK, are activated by stresses associated with hypothermia-rewarming and ischemia-reperfusion. Their activation in heart is associated with beneficial (preconditioning) and adverse effects (apoptosis and impaired contractility). This study determined whether ERK and p38 MAPK activities are altered by hypothermic ischemia and normothermic reperfusion and the consequences of their inhibition on recovery of myocardial function.Methods.Left ventricular work (L·min−1·mm Hg) was assessed during normothermic perfusion (30 min) of isolated rat hearts that were either freshly excised or previously subjected to hypothermic storage (8 hr, 3oC) and rewarming (10 min, 37oC) before normothermic reperfusion (30 min). Phospho-specific immunoblot analysis of p38 MAPK was performed in hearts and various cultured cells.Results.Compared with fresh hearts, hearts subjected to hypothermia and rewarming demonstrated impaired left ventricular work (1.96±0.53, n=12 vs. 8.37±0.46, n=4,P<0.05) during reperfusion. The ERK inhibitor, PD98059 (20 &mgr;M), present during storage and rewarming, caused modest improvement (3.66±0.75, n=9,P<0.05). The p38 MAPK inhibitor, SB202190 (10 &mgr;M), when present during reperfusion, improved recovery (to 6.12±0.75, n=6,P<0.05); it was ineffective if present only during rewarming (1.52±0.88, n=4). In rat2 fibroblasts, hypothermia and rewarming activated p38 MAPK and its downstream kinase MAPK-activated protein kinase 2, but not c-Jun N-terminal kinase/stress-activated protein kinase.Conclusions.Myocardial p38 MAPK and MAPK-activated protein kinase 2 are stimulated by hypothermia, ischemia, and rewarming and are detrimental to recovery of mechanical function of hearts subjected to prolonged hypothermic storage. Inhibition of p38 MAPK may be useful in protocols to improve the recovery of mechanical function of cold-stored hearts.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The standard therapy for short bowel syndrome is total parenteral nutrition, which is expensive and associated with significant morbidity and mortality. New therapeutic approaches for this disorder are needed. We have applied the techniques of tissue engineering to develop a prototype neointestine. We hypothesized that anastomosis of this neointestine to the native bowel would result in regeneration of mucosal morphology and enterocyte dynamics.Methods.Biodegradable polymers seeded with neonatal rat intestinal organoid units were implanted into the omenta of adult rats to form neointestinal cysts. Five weeks after implantation, side-to-side cyst-jejunal anastomoses were fashioned in one cohort of rats. Tissues were harvested from all rats at 5 months after implantation. Native jejunal (J) and non-anastomosed (N-N) and anastomosed (A-N) neointestinal tissues were assessed for morphology, epithelial cell proliferation (5-bromo-2-deoxyuridine immunohistochemistry), apoptotic rates (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay), and SGLT1 in situ hybridization.Results.Mucosal morphology, rates and topography of enterocyte proliferation, and transporter expression in A-N neointestine recapitulated those of native jejunum. Each of these features was rudimentary in N-N neointestine.Conclusions.These results suggest that the tissue-engineered neomucosa can develop structural and dynamic features of the normal jejunum. Anastomosis to the native intestine is an essential step for neomucosal development. Tissue engineering offers promise as a novel approach to the treatment of patients suffering from short bowel syndrome.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described.Methods.In 45 patients with serum creatinine more than 120 &mgr;mol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1–49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus ≤5 ng/mL, cyclosporin A ≤50 ng/mL) in 29 patients (18 patients without [group II] and 11 patients with [group III] previous refractory rejection [rejection after two episodes of treated rejection]).Results.In group I (median interval receiving MMF, 33 months), only one patient (6%) experienced cellular rejection, and serum creatinine normalized in five of eight patients long term. In group II (median follow-up 26.5 months), none of 18 experienced rejection, and serum creatinine normalized in 6 of 10 long term. In group III (median follow-up 34 months), 5 of 11 patients (45%) experienced further rejection, one was not steroid responsive, and serum creatinine normalized in four of eight patients long term. There was no graft loss or death as a result of rejection.Conclusions.Our cohort with prolonged follow-up showed significant improvement in renal function with both MMF monotherapy and in combination with low-dose CNI with minimal rejection (five of six steroid responsive) and no graft loss. MMF substitution is a therapeutic strategy that deserves more extensive use in liver transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and method.Posttransplantation acute pancreatitis (PTAP) is a rare but serious complication after pediatric liver transplantation (LTx). We performed a retrospective review in a large cohort of pediatric liver transplant recipients at a single institution to define the impact of this problem in children.Results.Between January 1986 and December 1999, 634 pediatric LTx were performed. Twenty-six patients developed serious acute pancreatitis. The mean age at transplantation was 7.7 years (9 months to 19 years), and the indications for transplantation were biliary atresia in seven, fulminant hepatic failure in six, chronic rejection in seven, and other etiologies in six patients. PTAP was more likely to occur early after LTx (61% within the first week), was associated with the presence of an infrarenal aortic graft in 14 (54%) of 26 patients, was more likely to occur after retransplantation (11/26 patients), and was associated with blood loss and prolonged surgery in four cases. Acute renal failure occurred in 15 (58%) of 26 patients. Mortality was 42% (11/26); causes of death were sepsis or multiple organ failure in nine and hemorrhage in two patients. Management of PTAP included antibiotics, sphincterotomy, debridement with drainage, hepatic arterial revascularization, and arterial ligation. Of the 14 patients with complicated pancreatitis, 5 were treated conservatively and died. Nine patients had extensive operative interventions and four survived (45%).Conclusions.Several risk factors such as retransplantation, extensive dissection at the time of LTx, and use of infrarenal arterial graft contribute to development of PTAP in children. Early exploration and debridement in patients with complicated pancreatitis may result in a better outcome. Retransplantation in the presence of clinical pancreatitis has a high failure rate.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Infections withStaphylococcus aureusare a significant problem in patients in liver transplant units. An association between prior nasal carriage withS. aureusand subsequent infections has been documented previously in liver transplant recipients and patients with cirrhosis. However, the role of decolonization with mupirocin applied intranasally for the prevention ofS.aureusinfections in these patients has not been determined.Methods.S. aureusnasal carriage was prospectively sought in 70 consecutive liver transplant candidates. Mupirocin two times per day for 5 days was administered to the carriers. Follow-up nasal cultures to document decolonization were performed 5 days after the final application of mupirocin. The primary endpoint was the development ofS. aureusinfections.Results.Thirty-one of 70 patients (44%) were found to be nasal carriers and 27 of 31 nasal carriers (87%) were successfully decolonized. However, 12 of 27 patients (37%) successfully decolonized became recolonized withS. aureus, and an additional nine patients who were initially noncarriers became newly colonized withS. aureusduring the study period. Despite the use of mupirocin, 16 of 70 patients (23%) developed an infection withS. aureus. No isolate was found to be mupirocin resistant.Conclusion.Elimination ofS. aureusnasal carriage by mupirocin did not preventS. aureusinfections in patients in our liver transplant unit.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.In Japan, the new macrolide immunosuppressant, tacrolimus, was approved for the prevention and treatment of allograft rejection in renal transplant recipients in April 1996. This article summarizes efficacy and safety data for tacrolimus gathered since its approval.Method.Data from 1,007 patients who received tacrolimus-based treatment after kidney transplantation at 35 leading Japanese transplant centers between April 1996 and December 2000 were retrospectively analyzed.Results.The renal transplants consisted of 856 living (756 ABO compatible, 100 ABO incompatible) and 151 cadaveric (146 non–heart-beating, 5 brain dead) donor grafts. Mean follow-up duration was 24.4 months. Overall patient and graft survival rates were 98.4% and 94.8% at 1 year, 98.0% and 92.6% at 2 years, and 97.6% and 90.4% at 3 years, respectively. Graft survival rates in living and non–heart-beating donor graft transplantations were 95.9% and 88.8% at 1 year, 94.0% and 85.0% at 2 years, and 92.2% and 80.0% at 3 years, respectively. Graft survival rates in living ABO-compatible donor graft transplantation ranged from 93.4% to 97.5%, and in ABO-incompatible cases, rates were stable at 83.2% throughout the 3-year assessment period. Median serum creatinine levels ranged from 1.30 to 1.37 mg/dL during this time. Percentages of patients receiving antihyperlipidemics, antihypertensives, and insulin were 12.6%, 41.1%, and 6.5% at 1 year, respectively, and remained low at 3 years after transplantation.Conclusion.Three years of tacrolimus therapy demonstrated excellent efficacy and safety in more than 1,000 renal transplant recipients, including recipients of living ABO-incompatible and non–heart-beating donor grafts, with favorable graft function maintained.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Acute rejection is a major complication after renal transplantation and the most important risk factor for chronic rejection. We investigated whether the timing of the last treated acute rejection episode (ARE) influences long-term outcome and compared the risk profiles of early versus late ARE.Methods.A cohort of 654 patients who underwent cadaveric renal transplants (1983–1997) that functioned for more than 6 months was studied. In 384 of 654 transplant recipients, one or more treated AREs were documented; the last ARE occurred in 297 of 384 transplant recipients within 3 months and in 87 of 384 after 3 months. Applying multivariate logistic regression analysis, we compared the predictor variables of the two groups with transplants without AREs.Results.Ten-year graft survival rates censored for causes of graft loss other than chronic rejection were 94%, 86%, and 45% for patients without ARE, with early ARE, and with late ARE, respectively. Delayed graft function, odds ratio (OR) 2.37 (1.55–3.62), and major histocompatibility complex (MHC) class II incompatibility, OR 2.28 (1.62–3.20) per human leukocyte antigen (HLA)-DR mismatch, were independent risk factors for early ARE. In contrast, recipient age, OR 0.75 (0.61–0.93) per 10-year increase, donor age, OR 1.28 (1.07–1.53) per 10-year increase, female donor gender, OR 1.74 (1.03–2.94), and MHC class I incompatibility, OR 1.35 (1.07–1.72) per mismatch of cross reactive groups, were associated with late ARE.Conclusions.Late ARE has a detrimental impact on long-term graft survival and is associated with MHC class I incompatibility, whereas early ARE is correlated with HLA-DR mismatches and has a better prognosis. These data are consistent with the role of direct and indirect allorecognition in the pathophysiology of early and late ARE, respectively.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Genotypes of the renin-angiotensin system have been implicated in essential hypertension and in progression of native kidney diseases, but gene effects on progression in chronic renal allograft dysfunction are unclear.Methods.To examine gene effects on long-term renal allograft function, we conducted a prospective cohort study of 210 nondiabetic renal allograft recipients younger than 36 years of age who underwent transplantation between 1980 and 1993 and were followed up through 1999. All grafts survived more than 1 year and all subjects received cyclosporine-based immunosuppression. DNA was analyzed by polymerase chain reaction for the angiotensin-converting enzyme insertion/deletion and angiotensinogen (AGT) M235T polymorphisms. Linear regression multivariate modeling of the slope of the inverse creatinine-versus-time, survival analyses for time-to-sustained doubling of baseline serum creatinine, time-to-graft loss, and a composite endpoint including patient death were performed.Results.Mean follow-up time was 8.4±3 years. Genotype frequencies for each marker system did not deviate significantly from the Hardy-Weinberg equilibrium. The slope of the inverse creatinine-versus-time for AGT 235T/T and M/T was significantly increased compared with M/M (P<0.0001). The AGT 235T/T genotype was also associated with a shorter time-to-sustained doubling of serum creatinine (P=0.001). When subjects were divided into quartiles based on slope magnitude, the frequency of the AGT 235T/T genotype was overrepresented in the fastest progressing group compared with the slowest (P=0.001). The AGT 235T/T genotype was also associated with shorter time-to-graft loss (P=0.007) and the composite endpoint (P=0.001).Conclusion.The AGT 235 T allele independently influences long-term decline in renal allograft function.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The authors investigated whether antithrombin III (AT-III) could induce unresponsiveness to alloantigens.Methods.CBA mice were given intravenous injection of 50 or 500 U/kg AT-III or control plasma the same day as transplantation of a heart from a C57BL/6 mouse. An adoptive transfer study and mixed leukocyte culture analysis were also performed.Results.Naive CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 9 days). The 50-U/kg dose of AT-III induced a moderate increase in graft survival (MST, 25 days), whereas control mice rejected their graft acutely (MST, 7 days). With the 500-U/kg dose of AT-III, all grafts survived indefinitely (>100 days) and regulatory cells were generated. In vitro, AT-III suppressed proliferation of mixed leukocyte responses and generation of interleukin-2.Conclusion.AT-III can be not only an antithrombotic agent but also a strong immunomodulating agent when used at high dose.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID