摘要:

Background.There is a debate about the relative contribution of immunologic (rejection) and nonimmunologic (limited nephron mass) factors in long-term graft survival.Methods.Using multivariate analysis, we studied the association of the following variables with outcome: delayed graft function (DGF), acute rejection, recipient race (black vs. nonblack), donor age (<50 vs. ≥50), donor race, and donor and recipient gender. Because of the association between DGF and rejection, recipients were grouped as follows: DGF, rejection; DGF, no rejection; no DGF, rejection; no DGF, no rejection. Data were analyzed on 1199 first kidney transplants in adults (752 living donor, 447 cadaver donor) done between January 1, 1985 and December 31, 1996. Two analyses were done: first, all transplants; second, only those with ≥1 year survival. For both, there was no difference in risk factors if death with function was or was not censored.Results.For all cadaver transplant recipients, risk factors were acute rejection, DGF plus rejection, black recipient race, and donor age ≥50. For living donor recipients, only acute rejection was a risk factor. When only 1-year graft survivors were considered, risk factors were the same: for cadaver recipients, risk factors were acute rejection, DGF plus rejection, black recipient race, and donor age ≥50; for living donor recipients the risk factor was rejection.Conclusion.We found immunologic factors (rejection with or without DGF) to be significant in both living donor and cadaver donor transplants. Nonimmunologic factors (donor age, recipient race) were significant only in cadaver donor transplants.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.In organ transplantation, the grafts must be carefully monitored, but it is often difficult to make a quick and accurate diagnosis of unusual changes. Extensive research has failed to identify a useful marker for rejection. We investigated the clinical utility of sialyl LewisX(CD15s) monitoring in 17 renal transplant patients with acute rejection.Methods.The expression of CD15s on peripheral lymphocytes was examined using flow cytometry in renal transplant recipients with rejection (n=17), without rejection (n=23), recipients infected with cytomegalovirus (n=7), recipients with other diseases (n=7), and healthy volunteers (n=18). CD15s expression was compared with histological findings, and was also examined before and after steroid pulse therapy to investigate the effects of steroids on CD15s antigen expression on the surface of the peripheral lymphocytes.Results.CD15s was strongly expressed in all patients with rejection, but was not expressed in any of the patients without rejection or in any healthy volunteers. Histologically, cell infiltration into the rejected graft was moderate or severe in all patients with strong expression of CD15s. In contrast, no or only mild infiltration was observed in patients with weak expression of CD15s. In addition, 14 of 17 patients (14/17, 82%) with strong CD15s expression improved upon administration of steroid pulse therapy, although there was no benefit from steroids in any of the patients with weak expression of CD15s.Conclusions.The CD15s antigen is expressed strongly on the peripheral lymphocytes at the time of rejection. It is interesting that the efficacy of steroid therapy in the patients with elevated creatinine could be predicted by CD15s expression on the peripheral lymphocytes before graft biopsy. There have been only few reports showing the relationship between CD markers and the efficacy of the treatment in patients with elevated creatinine. We report that the detection of CD15s on the peripheral lymphocytes by flow cytometry was an easy, helpful, and noninvasive means for the diagnosis and treatment of patients with elevated creatinine after renal transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Becauseincreasedhepatotoxicity was observed with first line antituberculous agents using four drug standard induction therapy in orthotopic liver transplant patients, we evaluated the efficacy and adverse effects of a novel continuation regimen for the treatment of tuberculosis in orthotopic liver transplant patients at a University Hospital in New York City.Methods.The hospital records of all patients who were referred to Mount Sinai Hospital (n=924) and who underwent orthotopic liver transplant between September 1988 and May 1998 were reviewed. Data were collected from patient records. Nine orthotopic liver transplant patients (0.97%) developed tuberculosis over a 9.5-year period. A total of seven of nine (78%) patients had disseminated tuberculosis including two patients with meningitis. All mycobacterial isolates were sensitive to isoniazid, rifampin, pyrazinamide, and ethambutol. Standard induction therapy with three or four drugs was given for 2 months (mean). Hepatotoxicity related to the standard induction regimen developed in five of six (83.3%) patients. Liver biopsy during induction therapy revealed drug induced hepatitis in five of six (88%) patients and rejection in three of six (50%) patients. Continuation regimens consisted mainly of ethambutol and ofloxacin; mean length of therapy 9 months.Results.Overall mortality was 33.3% (three of nine patients) over a 4.5-year follow-up period. Tuberculosis associated mortality was 22.2%. One patient died before therapy, another died with concomitant bacterial sepsis during induction therapy. Six of seven patients are alive and disease free. One patient died of recurrent hepatitis C and graft failure without evidence of tuberculous infection at death. Another patient retransplanted for chronic rejection, remains disease free at 1 year. The mean follow-up for six patients that completed treatment was 3.75 years (2.5–5.3 years). Six patients are free of tuberculosis.Conclusions.Our experience reveals that orthotopic liver transplant patients have poor tolerance for conventional therapy due to inherent toxicity of these agents and their concomitant bouts of organ rejection. Our nonconventional therapy yielded remarkably good results in that six patients, all with disseminated disease, were well after mean 3.5 years of follow-up. Consideration should be given to this novel follow-up therapy in patients without cavitary pulmonary disease who develop hepatotoxicity during induction.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Thrombocytopenia is a frequent and potentially serious complication in liver transplant recipients. The role of endogenous thrombopoietin level in posttransplant thrombocytopenia, has not been fully defined in liver transplant recipients. Additionally, there is accumulating evidence to suggest that platelets play a important role in antimicrobial host defense.Methods.There were 50 consecutive liver transplant recipients studied. Variables predictive of thrombocytopenia, its impact on infectious morbidity and outcome, and serial thrombopoietin (TPO) serum concentration were assessed.Results.The median pretransplant platelet count was 67×103/cmm. After the liver transplantation, the median nadir platelet count was 33×103/cmm and was reached a mean of 6 days after the transplant. A lower pretransplant platelet count (r=+.068,P=.0001), lower serum albumin before the transplants (r=+0.39,P=.014), longer operation time (r=0.27,P=.05), higher intraoperative packed red cells (r=0.28,P=.049) and fresh frozen plasma transfusions (r=0.42,P=.004), higher bilirubin at Day 7 (r=−.386,P=.005), and higher serum creatinine at Day 7 after the transplants (r=−.031,P=.025) correlated significantly with a lower nadir in platelets after the transplant. Nadir in platelet count was significantly lower in nonsurvivors compared with survivors (16 vs. 36×103/cmm,P=.0001). Forty-three percent (9 of 21) of the patients with nadir platelet counts of ≤30×103/cmm had a major infection within 30 days of the transplant compared with 17% (5 of 29) with nadir platelet counts > 30×103/cmm (P=.04). Fungal infections occurred in 14% of the patients with nadir platelet counts of ≤30×103/cmm versus 0% in those with nadir platelet counts of > 30×103/cmm (P=.06); all patients with fungal infections had nadir platelet counts of ≤30×103/cmm before fungal infection. Nadir in platelet count preceded the first major infection by a median of 7 days. Pretransplant TPO level did not differ between survivors (mean 103 pg/ml) or nonsurvivors (mean 144 pg/ml). After the transplantation, TPO levels increased in both groups. TPO level peaked at Day 7 and subsequently declined in survivors. Nonsurvivors had persistent thrombocytopenia despite a progressive rise in TPO level; TPO level was significantly higher at Day 7 (P=.02), Day 9 (P=.0019), and Day 14 (P=.04) in nonsurvivors compared with survivors.Conclusion.Persistent thrombocytopenia portended a poor outcome in liver transplant recipients and was not related to low TPO levels. Thrombocytopenia preceded infections and identified a subgroup of liver transplant patients susceptible to early major infections; its precise role in fungal infections warrants validation in larger studies.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.We studied the efficacy and tolerability of combined immunosuppressive therapy with cyclosporine A microemulsion (Neoral) plus the macrolide SDZ RAD 40–0 (2-hydroxyethyl) rapamycin (RAD) in a stringent cynomolgus monkey lung graft model in comparison with cyclosporine or SDZ RAD monotherapy.Methods.Thirty-nine cynomolgus monkeys received mixed lymphocyte reaction (MLR) mismatched unilateral lung transplants. Immunosuppressants were administered orally as single daily doses. The observation period was 28 days and follow-up included serial trough blood drug concentrations measured by high performance liquid chromatography/mass spectrometry, blood analyses, chest radiographs, open lung biopsies, as well as tissue drug concentrations and graft histology at necropsy.Results.Graft biopsies in monkeys treated with vehicle (n=4), Neoral (day 1–7: 150 mg/kg/day; day 8–28: 100 mg/kg/day; n=6; mean±SE trough level (MTL): 292±17 ng/ml) or SDZ RAD monotherapy (1.5 mg/kg/day; n=6; MTL: 15±1 ng/ml) showed severe rejection. Coadministration in two transplant monkeys of Neoral (150/100 mg/kg/day) and SDZ RAD (1.5 mg/kg/day) caused their early death. In both animals, SDZ RAD blood levels were more than 5-fold higher than under monotherapy (MTL: 82±18 ng/ml). Simultaneous administration (n=6) of Neoral (150/100 mg/kg/day; MTL: 217±16 ng/ml) and SDZ RAD (0.3 mg/kg/day; MTL: 24±2 ng/ml) improved graft outcome (mild rejection). Side effects included renal failure (n=2) and seizures (n=1). Three monkeys survived to day 28. In this group the MTL for cyclosporin was 143±13 and for RAD 38±3.Staggered treatment completely prevented rejection in four of six grafts. However, five of six monkeys had moderate to severe diarrhea. In a concentration-controlled trial of simultaneously administered Neoral and SDZ RAD in transplant monkeys (target SDZ RAD MTL: 20–40 ng/ml; cyclosporine MTL: 100–200 ng/ml) all six monkeys survived with improved drug tolerability and an average biopsy score of mild rejection.Conclusion.Combination of orally administered SDZ RAD and Neoral showed excellent immunosuppressive efficacy in a stringent lung transplant model. The drug interaction and the narrow therapeutic index of this drug combination required careful dose adjustments to optimize tolerability and efficacy.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Although cyclosporine (CsA) has been a mainstay in liver transplantation immunosuppression the original formulation [Sandimmune (SIM)] has variable absorption, particularly in children. Neoral is a new formulation of CsA that may have improved biovailability that would be advantageous in children. This study was undertaken to assess the pharmacokinetics (PK) and effects on outcome of Neoral versus Sandimmune (SIM) in primary pediatric liver transplant recipients.Methods.Thirty-two patients were randomized to receive Neoral (17 patients) or SIM (15 patients) in the early posttransplant period (days 1–7) in a double-blind fashion. Intravenous CsA was instituted immediately posttransplant followed by Neoral or SIM as soon as the patient was tolerating oral fluids (days 1–7). PK were compared after the first dose (1–7 days), 3 weeks, and 6 and 12 months posttransplant. In addition, side effects, effect of age and food on absorption, and rejection episodes were assessed by intent to treat analysis. Notable characteristics of this study include the use of a central laboratory for all sample analyses and the assessment of renal function using radioisotopic evaluation of glomerular filtration rates.Results.At baseline the two groups were comparable. Neoral resulted in higher peak levels of CsA and total drug exposure with comparable time to peak drug levels at days 1–7 and week 3. This trend was maintained at 6 and 12 months. Time on i.v. CsA was reduced in the Neoral group (8.4 vs. 11.1 days) and the weight adjusted daily dose of SIM required to achieve target trough levels was about 2-fold more than Neoral from day 22 onward. In addition, biopsy proven and treated and steroid-resistant rejection episodes were fewer in the Neoral group (6 vs. 12;P=0.01 and 1 vs. 8:P=0.004, respectively). Side effects were comparable in both treatment groups.Conclusions.Neoral was well tolerated and had greater biovailability than SIM without any increase in the incidence of side effects. In addition fewer episodes of rejection were observed with Neoral versus SIM. We conclude that Neoral is the CsA formulation of choice for use in pediatric liver transplant recipients.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Pentoxifylline (PTX) pretreatment of recipients was shown to protect against liver graft failure from ischemia-reperfusion injury after orthotopic rat liver transplantation. It has also been shown that PTX protects against normothermic ischemia-reperfusion injury to the liver in lobar ischemia model in the rat. Whether PTX can benefit the liver procured from non-heart-beating donors (NHBDs) with up to 9 hr of cold ischemia is unknown.Methods.Donor and recipient rats were pretreated with intraperitoneal PTX (50 mg/kg) 1 hr before cardiac arrest and transplantation, respectively. Grafts were transplanted 0, 30, and 60 min after cardiac arrest with additional 1 and 9 hr of cold ischemia in both PTX-pretreated or untreated (control) groups (10 rats per group). PTX (25 mg/kg/day) was continuously given to the surviving rats for 5 days postoperatively. Recipient survival rates, serum enzyme levels, and histopathological examination of postreperfusion liver biopsies were all analyzed.Results.The survival rates, serum enzyme levels, and postreperfusion histology were significantly improved in groups pretreated with PTX compared to the controls.Conclusion.Donor and recipient PTX pretreatment significantly improves the viability of the liver grafts procured from NHBDs.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Besides alloimmunity to transplanted pancreatic tissue, recurrent autoimmune beta cell destruction is an additional limitation to successful clinical pancreatic allografts in type 1 diabetic patients.Methods.We studied the prevalence of autoantibodies to glutamate decarboxylase (GAD) 65 and tyrosine phosphatase (IA-2) in 68 C-peptide–negative diabetic patients receiving pancreatic allografts. Sera from patients were obtained immediately before grafting. A second blood sample was analyzed at the time of graft failure in patients who returned to hyperglycemia and during the same follow-up period in those who experienced a functional pancreatic allograft. Patients were classified according to clinical outcome into chronic graft failure (group A, n=20), acute graft failure and/or arterial thrombosis (n=7), or functional pancreatic graft (group C, n=41). Sera from patients were screened for the presence of specific autoantibodies using an islet cell autoantibody assay, a combi-GAD and IA-2 test, and individual GAD and IA-2 assays.Results.Patients from group A had significantly higher combi-test values than patients from group C (13±16 vs. 4.5±12 units,P<0.02) and higher anti-GAD65 antibody (Ab) levels (0.19±0.3 vs. 0.04±0.13 units,P<0.01) immediately before grafting. After graft failure in group A, both anti-GAD65 and anti-IA-2 Ab levels increased from baseline, but only the increase in anti-IA-2 Ab levels reached statistical significance (0.28±0.12 vs. 15±34,P=0.03). When compared with group C, patients from group A had higher anti-GAD65 Abs (0.29±0.35 vs. 0.05±0.16,P<0.001) after graft failure. Interestingly, the number of double-Ab–positive patients rose from 5% to 35% in group A, whereas it remained at 5% in group C. In pancreatic transplants with bladder drainage, the presence of anti-GAD65 and/or anti-IA2 Abs was not associated with a reduction in urinary amylase levels. This suggests that a loss of endocrine function was not associated with exocrine failure in patients from group A.Conclusions.We can conclude from the present study that peripheral autoimmune markers are useful in diabetic patients receiving pancreatic allografts.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Anti-CD3&egr; F(ab′)2are nonmitogenic for naive T cells but can induce apoptosis of antigen-activated T cells in vitro and in vivo. We studied the mechanisms by which nonmitogenic anti-CD3&egr; F(ab′)2antibodies induce T cell death.Methods.OVA-responsive T cell lines were generated by immunization in vivo and restimulation in vitro. Fas or Fas ligand (FasL) expression was tested by surface staining with specific mAbs. The apoptotic DNA and cell cycle phase were tested by staining DNA with propidium iodide. Interferon-&ggr; was measured by ELISA, whereas interleukin (IL)-2 and IL-4 were detected by bioassays.Results.Restimulation with anti-CD3&egr; F(ab′)2induced apoptosis of antigen-activated wild-type T cells, but not Fas or FasL-defective T cells. Anti-CD3&egr; F(ab′)2induced death of cells expressing high levels of Fas and FasL, and preferentially deleted T helper (Th)1 cells but spared Th2 cells. Soluble anti-CD3&egr; F(ab′)2did not regulate Fas or induce FasL expression, indicating that the ability of anti-CD3&egr; F(ab′)2to induce T cell apoptosis depends on a distinct mechanism. T cells in S/G2 were found relatively resistant to Fas-mediated apoptosis, but anti-CD3&egr; F(ab′)2rendered those T cells exquisitely sensitive to Fas-mediated apoptosis.Conclusions.Anti-CD3&egr; F(ab′)2induces apoptosis of cycling CD4+T cells through activation of the Fas/FasL pathway. Anti-CD3&egr; F(ab′)2does not regulate Fas or FasL expression but induces susceptibility to Fas-mediated apoptosis of cycling T cells. Anti-CD3&egr; F(ab′)2can induce death of polarized Th1 cells, but not Th2 cells, thus potentially skewing the repertoire of antigen-activated T cells toward the Th2 phenotype. These features predict that nonmitogenic anti-CD3&egr; F(ab′)2-like antibodies can be useful to prevent or reverse pathogenic immune responses mediated by Th1 cells.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Background.Pigs are being used as an alternative source of tissues for humans and we are interested in the xenotransplantation of fetal pig islet-like cell clusters (ICC) into type 1 diabetic patients.Interleukin- (IL) 10 is a Th2 cytokine with immunosuppressive properties that down-regulate the cell-mediated response. In this study, we evaluated the effects of recombinant human IL-10 on human anti-pig xenogeneic cellular response in mixed lymphocyte culture (MLC) and in mixed islet lymphocyte culture (MILC).Methods.Human peripheral blood mononuclear cells as responder cells were cultured in one-way MLC with pig and human peripheral blood mononuclear cells as stimulant cells in xeno and allo-MLC, respectively, and also with fetal pig ICCs in MILC. IL-10 was added at the time of culture.Results.The addition of IL-10 significantly inhibited the xeno-MLC (human anti-pig) in a dose-dependent manner, the percentage inhibition being 36, 60, and 73% at 1, 10, and 50 ng/ml, respectively. Inhibition in xeno-MLC was significantly lower than that of the allo-MLC (human anti-human) at all concentrations used, the percentage inhibition of the latter being 58, 84, and 92% at 1, 10, and 50 ng/ml, respectively. Further, the addition of IL-10 also significantly inhibited the proliferation of human peripheral blood mononuclear cells when they were cocultured with fetal pig ICCs, the inhibition being 59, 72, and 80% at 1, 10, and 50 ng/ml, respectively. IL-10 was not toxic to ICCs as determined by3H-thymidine incorporation over 5 days culture. Preincubation of IL-10 with the pig stimulant cells or the human responder cells did not confer additional benefit in the inhibition of xeno-MLC. IL-10 needs to be present at the start or at an early stage (within 4 hr) in the xeno-MLC because if the addition of IL-10 was delayed by 4 hr, the effect was lost. Next, the production of cytokines was examined in MLC and MILC. In xeno-MLC, levels (pg/ml) of tumor necrosis factor-&agr; (TNF-&agr;) (163±17), interferon-&ggr; (IFN-&ggr;) (278±60), IL-5 (24±10), IL-6 (2959±923), and IL-10 (17±2) were produced in greater amounts than autologous controls (P<0.05). The levels of TNF-&agr;, IFN-&ggr;, IL-6, and IL-10 but not IL-5 were significantly (P<0.05) lower in xeno-MLC than those produced in allo-MLC. All of these cytokines were also produced in MILC when human peripheral blood mononuclear cells (PBMC) were cocultured with ICCs, levels (pg/ml) being TNF-&agr; (308±47), IFN-&ggr; (93±17), IL-5 (6.2±3), IL-6 (5649±421), and IL-10 (122±18). No detectable levels of IL-2 and IL-4 were produced in the MLC and in MILC. Addition of IL-10 significantly inhibited the production of TNF-&agr;, IFN-&ggr;, IL-5, and IL-6 by 76, 96, 100, and 93%, respectively, in xeno-MLC. Addition of IL-10 also significantly (P<0.05) inhibited the production of TNF-&agr;, IFN-&ggr;, IL-5, and IL-6 by 88, 91, 100, and 96%, respectively, in MILC. Exogenous addition of IL-2 was partially able to reverse the effect of IL-10 although addition of TNF-&agr; had no effect on xeno and allo-MLC. Synergism was seen between IL-10 and cyclosporine in the inhibition of xeno and allo-MLC.Conclusion.Taken together, the results demonstrated that IL-10 has an immunomodulatory role to play in the inhibition of cellular immune responses associated with the xenotransplantation of fetal pig ICCs.

ISSN:0041-1337    

出版商:OVID    

年代:2000

数据来源: OVID