ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Cell encapsulation holds promise for the chronic delivery of recombinant proteins such as erythropoietin. Encapsulated xenogeneic mouse C2C12myoblasts display long-term survival in the central nervous system whereas they do not in the subcutaneous tissue, suggesting that encapsulation only partially prevents affector and effector mechanisms of the host immune response. Transient immunosuppression with FK506 at the time of subcutaneous implantation leads, however, to their long-term survival. The nature of this acceptance was further investigated in this report.Methods.Fischer rats were rendered unresponsive to encapsulated murine C2C12myoblasts secreting mouse erythropoietin by either a 1- or 4-week initial treatment of FK506. To examine the extent of xenograft acceptance, animal were challenged with a second implant 9 weeks after the initial implantation.Results.Challenging animals treated only 1 week with FK506 led to rejection of both primary and secondary implants. Animals administered FK506 for 4 weeks accepted both implants over the period investigated. However, these animals rejected unencapsulated xenogeneic cells injected at a later time, highlighting the requirement of the polymer membrane for immune protection. Developed unresponsiveness to encapsulated xenogeneic myoblasts lasted over extended periods (at least 7 months), in the absence of both immunosuppression and stimulating xenoantigens.Conclusions.These findings reveal that host acceptance of encapsulated but not unencapsulated xenogeneic myoblasts can be developed in the subcutaneous tissue after transient FK506 immunosuppression. This may have direct clinical relevance as it enables capsules to be replaced without additional immunosuppression, facilitating long-term cell-based therapies.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Chemical preconditioning was defined as the induction of resistance to massive disruption of energy metabolism through prior chemical suppression of oxidative phosphorylation, by which phenomena similar to those resulting from increased ischemic tolerance as a result of ischemic preconditioning can be induced. It could be induced by the inhibitor of either mitochondrial complex I or II. We investigated whether or not chemical preconditioning by 3-nitropropionate (an inhibitor of the mitochondrial complex II) can suppress ischemia-reperfusion injury in cardiac-arrested lungs, which will be the major problem in lung transplants donated from non-heart-beating cadavers.Methods and Results.In an isolated rat lung perfusion model with fresh rat blood as perfusate, administration of 3-nitropropionate (20 mg/kg) immediately before the induction of cardiac arrest attenuated pulmonary dysfunction during reperfusion after 1 hr postmortem warm ischemia and 1 hr cold preservation. 3-Nitropropionate administration reduced the mitochondrial respiratory functions (state 3 and state 4 respiration, and the respiratory control ratio) before cardiac arrest and kept them at a lower level of activity than when decreased by ischemia alone. 3-Nitropropionate administration also reduced the ATP levels immediately after drug administration. However, 3-nitropropionate did not significantly reduce lipid peroxidation in the lung tissue and mitochondria.Conclusions.These results demonstrated that chemical preconditioning by 3-nitropropionate administration immediately before cardiac arrest suppressed succinate-related oxidation during postmortem warm ischemia and reduced ischemia-reperfusion injury in cardiac arrested rat lungs.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.To date, over 40 in utero transplants have been performed in humans; the only successes were documented in the treatment of severe combined immunodeficiency syndromes. Hemoglobinopathies and metabolic disorders are candidate diseases for this approach; however, when applied clinically, the results have been discouraging. To address the role of the fetal immune system in the outcome of in utero transplantation, we have developed a murine model of in utero transplantation in immunologically intact murine recipients and have studied chimerism and tolerance/immunity to allogeneic donor cells through the lives of the animals.Methods.We have performed experiments in which purified murine sca-1+/lin-cells and c-kit+/lin-cells of C57BL/6 (H2b) mice were injected into Balb/c (H2d) fetal recipients at early gestational ages. Chimerism was tested by highly sensitive semiquantitative polymerase chain reaction assay and tolerance/immunity to donor cells was studied by in vivo (skin grafts, responses to postnatal boosts) and in vitro (mixed lymphocyte culture, cytotoxicity, and cytokine release) assays.Results.One hundred percent (10/10) of mice transplanted with c-kit+cells and 44% (4/9) of mice transplanted with sca+cells showed circulating donor cells within the first 6 months of life (P=0.031). Mice in the sca+group rejected donor skin grafts at a mean time of 9.1±0.2 days, whereas mice in the c-kit+group rejected donor skin grafts at a mean time of 15.1±0.7 days (P=0.001). The difference between the transplanted groups and non-transplanted controls was also significant (P<0.05). All mice transplanted with sca+/lin-cells showed greater response to donor cells than to third-party cells at all effector to target ratios (P=0.002). Differences in response to donor alloantigen between sca+and c-kit+groups were significant (P=0.003). Cytokine quantification demonstrated higher TH1 than TH2 cytokine release in all groups, and the response to donor cells was higher in the sca+compared with c-kit+mice (P =0.031).Conclusion.These results demonstrate a low level of chimerism and tolerance in mice transplanted in utero with sca+/lin-and c-kit+/lin-cells. The possibility of active in utero immunization to donor cells is supported by accelerated skin graft rejection in mice transplanted with sca+cells and enhanced in vitro immune responses in mice with persistent microchimerism.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.The importance of HLA mismatch in determining long-term outcome in lung transplantation remains largely uncertain.Methods.A retrospective analysis of 102 consecutive primary lung transplants was performed to identify risk factors for poor long-term outcome after lung transplantation defined as graft survival and bronchiolitis obliterans syndrome (BOS) stage I and II. Variables included were patient characteristics (age, sex, prior diagnosis), the number of HLA mismatches between donor and recipient, cold ischemic time, cytomegalovirus serologic concordance, number of acute rejections, and time to first rejection. Variables carrying significance in a univariate analysis were subjected to a proportional hazard regression analysis.Results.In the multivariate analysis, an increased number of acute rejections correlated positively with decreased graft survival (risk ratio [RR]=1.25; 95% confidence interval [CI], 1.05–1.5;P=0.011), development of BOS stage I (RR=1.36/episode; 95% CI, 1.16–1.58;P<0.001), and BOS stage II (RR=1.42/episode; 95% CI, 1.2–1.67;P<0.001). An increased time to rejection correlated positively with reduced graft survival (RR=1.03/day; 95% CI, 1.01–1.06;P=0.02), and BOS stage I and II (both RR=1.04/day; 95% CI, 1.01–1.07;P<0.005). Compared with 2 HLA-DR mismatches, 0 or 1 mismatch was associated with improved graft survival (RR=0.43; 95% CI, 0.19–0.98;P=0.045) and protected against development of BOS stage I (RR=0.47; 95% CI, 0.23–0.98;P=0.044) and BOS stage II (RR=0.35; 95% CI, 0.15–0.83;P=0.017).Conclusions.HLA-DR mismatching appears to be a risk factor for the development of BOS and graft loss. Improved outcome after lung transplantation might be achieved with prospective matching for HLA-DR. Alternatively, the amount and type of immunosuppressive drugs may be guided by the degree of HLA-DR (mis)matching.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Chimerism analysis is essential in understanding the etiology of graft failure occurring after allogeneic stem cell transplantation. The detection of marrow and/or blood host cells suggests graft rejection, relapse of the underlying disease, or a state of stable mixed chimerism. However, complete donor chimerism may be observed in some cases. Our objective was to characterize, by a sensitive process of chimerism analysis, six cases of graft failure occurring after transplant.Methods.Six cases of secondary graft failure, in which previous analysis had shown complete donor chimerism by standard polymerase chain reaction amplification of variable number of tandem repeats, were studied. In order to detect a minority population of recipient cells, we increased the sensitivity of the process by using fluorescent polymerase chain reaction and analyzing the origin of T, B, and natural killer lymphocytes at the time of graft failure.Results.The complete donor origin of mononuclear cells and lymphocytic populations was confirmed with this method in five of six patients. In the remaining patient, diagnosis of graft failure was clarified by the detection of a previously undetected mixed chimerism, compatible with graft rejection. In the other five patients, graft rejection was thereby excluded and graft failure could be related to viral infection or to graft-versus-host disease.Conclusion.Our sensitive process of fluorescent lineage-specific chimerism analysis may help in distinguishing between graft rejection and other mechanisms of graft failure, which is essential for deciding appropriate therapy.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The aim of this retrospective study was to determine whether nephron mass may exert a direct, independent effect on immunological tolerance. To this end, data corresponding to patients transplanted with en block pediatric kidneys (EBPK) (n=48) were compared with those of renal transplants with a low risk of hyperfiltration (LRH) comprised of recipients of a kidney from young donors (age 5–40 years) (n=173), and transplants with a high risk of hyperfiltration (HRH) comprised of patients who had received a graft from an elderly donor (older than 55 years) (n=91). All the patients had been subjected to the same immunosuppressive treatment. The median follow-up period was 54 months (6–127 months). The EBPK group showed lowest serum creatinine and highest creatinine clearance levels at each follow-up time. The rate of proteinuria >500 mg/day was 5.7% in EBPK, 7.4% in LRH, and 27.3% in HRH (P=0.000). The incidence of acute corticoresistant rejection was minor in EBPK (7.0% in EBPK, 21.3% in LRH, and 23.3% in HRH;P=0.04). Logistic regression analysis showed that the type of transplant was predictive of acute corticoresistant rejection [RR 5.33 (95% confidence interval (CI) 1.15–24.62) for HRH and RR 4.75 (95%CI 1.06–21.27) for LRH,P=0.03]. Multivariate analyses for graft failure due to chronic rejection and for graft failure due to acute rejection according to Cox’s regression analysis demonstrated that HRH transplant was a significant predictive variable of both types of failure [4.08 (95%CI 1.27–13.04) for graft loss due to chronic rejection and 8.69 (95%CI 1.69–44.67) for graft loss due to acute rejection]. The present stratification of data according to nephronal mass would appear to indicate that the greater the mass, the lower the incidence of both acute and chronic rejection. This finding lends support to the hypothesis that a large mass of transplanted tissue relative to recipient mass may dampen the immune response.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Lamivudine has been reported to be able to stabilize liver enzyme and hepatitis B virus (HBV) replication with recurrent hepatitis that has been regarded as a frequent and major risk factor for hepatic dysfunction and chronic liver disease in renal transplant recipients. Because large number of hepatitis antigenemia patients among renal transplant patients experience recurrent hepatic dysfunction with HBV recurrence and permanent histological deterioration, preemptive or primary prophylactic use of lamivudine before transplantation may be more beneficial than a trial for the treatment of advanced hepatic dysfunction.Methods.We conducted a double arm study to compare the efficacy of lamivudine between the preemptive (HBV DNA positive) or prophylactic (HBV DNA negative) trial for the maintenance of stable liver function (n=10) and the trial for the salvage of advanced hepatic dysfunction developed after renal transplantation (n=6) in hepatitis B viremia carrier renal transplant recipients.Results.Hepatic dysfunction with recurrent HBV antigenemia developed in 11 of 36 (30.6%) hepatitis antigenemia patients with a mean duration of 8.4 months (range 5–19.4 months). In six patients treated with lamivudine after hepatic dysfunction from recurrent hepatitis B viremia, serum AST and ALT level normalized within 1 month and HBV-DNA disappeared in all cases. HBV-DNA, however, reappeared in three (50%) without any discontinuation of lamivudine. Liver biopsy revealed recurrent chronic active hepatitis with severe activity of fibrosis in four cases, cholestatic fibrosing hepatitis in one, and permanent cirrhotic change in one. In seven patients who had preemptive lamivudine treatment at 9, 6, 2, 2, 1, 0, 0 month before the transplantation, HBV-DNA had converted to negative with a mean follow up of 1.2 months (range 1–2 month) in all case. Three patients who had prophylactic trials with lamivudine have all remained HBV-DNA negative. The recurrence rate of HBV viremia in the preemptive or prophylactic lamivudine treated group is 10.0% (1/10), which is significantly lower than that (42.3%, 11/25) in the nonlamivudine-treated group. The re-recurrence rate of HBV viremia was significantly higher (3/6, 50.0%) in the reactive lamivudine treated group than in prophylactic or preemptive group (1/10, 10%).Conclusion.Although lamivudine treatment after hepatic dysfunction can be a sound conventional treatment modality, this preliminary study may suggest that preemptive or prophylactic trial of lamivudine before hepatic dysfunction might be a more effective strategy for prevention of permanent histological deterioration and recurrence of hepatitis B viremia.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Human cytomegalovirus (CMV) is a significant cause of morbidity and mortality among transplant recipients. Monitoring transplant recipients by CMV IgM serology has been questioned by several studies due to the reported insensitivity of serologic tests relative to antigen detection methods.Methods.In this retrospective study, we have evaluated the performance of the new recombinant antigen-based Abbott AxSYM CMV IgM assay and compared it with CMV culture technique in a cohort of 40 liver transplant recipients who did not receive antiviral prophylaxis.Results.The sensitivity, specificity, and positive and negative predictive values for detection of CMV disease by the AxSYM CMV IgM assay were 90.0%, 60.0%, 69.2%, and 85.7%, respectively, and by culture the values were 100%, 55.0%, 69.0%, and 100%, respectively. Detection of CMV IgM occurred before or at the time of CMV disease in only R+ recipients.Conclusion.Although this assay is a sensitive test for CMV-specific IgM, detection of CMV IgM preceded detection of virus by culture in patients only when the liver transplant recipient was CMV immune before transplantation (R+).

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Introduction.The importance of HLA matching for renal transplantation outcomes has been appreciated for several decades. It has been hypothesized that as pharmacologic immunosuppression becomes stronger and more specific, the impact of HLA matching may be vanishing. Mycophenolate Mofetil (MMF) has been demonstrated to both decrease acute rejection and improve three-year graft survival. It is possible that with new immunosuppressive regimens containing MMF the relative effect of HLA matching may be altered. To determine the relative impact of HLA matching in patients on MMF we undertook an analysis of the United States Renal Transplant Data Registry (USRDS).Methods.All primary, solitary renal transplants registered at the USRDS between January 1995 and June 1997, on initial immunosuppression that included either MMF or AZA were followed until June 1998. Primary study end points were graft and patient survival. Kaplan-Meier analysis was performed to compare AZA vs. MMF treated patients by HLA mismatch. Cox proportional hazard models were used to investigate the interaction between HLA mismatch and AZA versus MMF therapy on the study endpoints. All multivariate analyses were corrected for 13 potential confounding pretransplant variables including intention to treat immunosuppression.Results.A total of 19,675 patients were analyzed (8,459 on MMF and 11,216 on AZA). Overall three year graft survival was higher in the MMF group when compared to the AZA group (87% vs. 84% respectivelyP<0.001). For both AZA and MMF three-year graft survival improved with fewer HLA donor-recipient mis-matches. Comparing zero antigen mismatches to six antigen mismatches, the relative improvement was comparable for both patients on AZA (92.4% vs. 80.6%) and MMF (95.2% vs. 82.9%). By Cox proportional hazard model the relative risk for graft loss decreased significantly in both the AZA and MMF treated patients with increased HLA matching.Conclusion.The use of MMF does not obviate the benefits of HLA matching, while HLA matching does not minimize the benefits of MMF on long term graft survival. Our study would suggest that HLA matching and MMF therapy are additive factors in decreasing the risk for renal allograft loss.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID