摘要:

The pig-to-primate model is increasingly being utilized as the final preclinical means of assessing therapeutic strategies aimed at allowing discordant xenotransplantation. We review here the world experience of both pig-to-human and pig-to-nonhuman primate organ transplantation. Eight whole organ transplants using discordant mammalian donors have been carried out in human recipients; only one patient was reported (in 1923) to have survived for longer than 72 hr. Therapeutic approaches in the experimental laboratory setting have included pharmacologic immunosuppression, antibody and/or complement depletion or inhibition, the use of pig organs transgenic for human complement regulatory proteins, and conditioning regimens aimed at inducing a state of tolerance or specific immunologic hyporesponsiveness. The greatest success to date has been obtained with methods that inhibit complement-mediated injury, either by the administration of cobra venom factor or soluble complement receptor I to the recipient (with organ survival up to 6 weeks) or by the use of donor organs transgenic for human decay-accelerating factor (with organ survival up to 2 months). The future of xenotransplantation may lie in the judicious combination of current approaches.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.We have shown previously that heightened expression of the cytotoxic lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated.Methods.We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis.Results.Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values.Conclusion.Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as noninvasive method of monitoring for renal allograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Experiments were designed to determine expression of type II (iNOS) and type III (ecNOS) nitric oxide synthase in lung parenchyma and systemic endothelial cells with rejection and/or infection of single lung allografts.Methods.After single lung allotransplantation, dogs were maintained on standard triple immunosuppressive therapy for 5 days and then placed into one of three groups. Group I (n=4) was maintained on immunosuppresants, group II (n=7) immunosuppression was withdrawn to allow acute rejection of the allograft, and group III (n=6) infection was induced by bronchoscopic inoculation ofEscherichia coli.Results.At postoperative days 7-9, no histological evidence of rejection or infection was observed in transplanted lungs of group I. In lungs of group II, rejection ranged from mild to severe; in lungs of group III, infection was severe. Some animals had both rejection and infection (n=8) and were studied separately. Plasma levels of nitric oxide increased comparably with rejection and/or infection compared to preoperative values. Expression of mRNA for ecNOS decreased significantly in lung parenchyma but not in aortic endothelial cells from dogs of groups II and III. However, expression of mRNA for iNOS increased with both rejection and/or infection in both lung parenchyma and aortic endothelial cells.Conclusions.iNOS is induced locally within the graft and systemically in aortic endothelial cells with rejection and/or infection of lung allografts. Plasma levels of nitric oxide are elevated with both rejection and infection and may not be useful in the differential diagnosis of these processes after lung transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.The injury resulting from cold preservation/reperfusion primarily affects sinusoidal endothelial cells, while hepatocytes are thought to be less vulnerable; morphological changes and increased cytokine release suggest that Kupffer cells are activated. We evaluated the extent of functional damage to the different cell types in the liver after cold preservation and transplantation. Additionally, we analyzed in vivo the patterns of functional recovery of all three cell types over the first week after transplantation in Lewis rats.Methods.We evaluated the in vivo uptake of hyaluronic acid, indocyanine green, and radio-labeled sulphur colloid to assess the function of sinusoidal endothelial cells, hepatocytes, and Kupffer cells, respectively. Measurements were performed immediately after transplantation using syngeneic grafts preserved in University of Wisconsin solution for different periods. Functional recovery was monitored in animals receiving grafts preserved for 24 hr over the first postoperative week.Results.We found that hepatocyte were less affected compared with the profoundly damaged endothelial cells. The phagocytic ability of Kupffer cells was, however, also seriously compromised, which suggests a selective down-regulation. Functional recovery occurs in a differential manner during the first postoperative week starting with hepatocytes followed by sinusoidal endothelial cells. Phagocytic function further deteriorates after transplantation before showing improvement.Conclusions.In viable liver grafts, all cell types recover from preservation/reperfusion injury by the end of the first week after transplantation. The differential time courses of the recovery suggest that successful sinusoidal endothelial cell recovery may depend upon prior hepatocytes regeneration and may involve a paracrine interaction, via cytokines and growth factors.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Nitric oxide (NO) seems to play an important role in modulating tissue injury during reperfusion of the liver. In this study, we have evaluated and compared the effects of FK409 (FK), a potent spontaneous NO releaser, and L-arginine in ischemia-referfusion injury of the rat liver.Methods.Male Sprague-Dawley rats underwent 90 min of hepatic ischemia followed by reperfusion. FK or L-arginine was used (intravenously) in two different doses for each drug (group I, 3.2 mg/kg FK; group II, 1.6 mg/kg FK; group IV, 100 mg/kg L-arginine; and group V, 300 mg/kg L-arginine). Saline was used in control animals (group III). Hepatic enzyme status, microcirculation, serum nitrite (NO2-) and nitrate (NO3-) and tissue injury score were evaluated at predetermined times.Results.Serum NO2-/NO3-was elevated immediately by FK treatment dose-dependently but not by L-arginine. However, L-arginine caused late (6-24 hr) elevation of the NO metabolites dose-dependently. The elevation of serum aspartate aminotransferase and alanine aminotransferase was suppressed and hepatic microcirculation was improved in the FK-treated groups dose-dependently. l-Arginine also improved the microcirculation, but hepatic enzymes at 24 hr of reperfusion were significantly higher in group V than in the control group. These findings were well reflected by the extent of tissue injury in respective groups.Conclusion.FK treatment in the immediate reperfusion period improves hepatic microcirculation and confers a significant protective effect on hepatic ischemia-reperfusion injury in the rat.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Previous studies showed that a combination of posttransplant total lymphoid irradiation (TLI), rabbit antithymocyte globulin (ATG), and a single donor blood transfusion induced tolerance to ACI heart allografts in Lewis rats. All three modalities were required to achieve tolerance. The objective of the current study was to determine the subset(s) of cells in the donor blood that facilitated long-term allograft survival.Methods.Lewis hosts received TLI, ATG, and donor cell infusion after heart transplantation. Graft survival, mixed leukocyte reaction (MLR), and intragraft cytokine mRNA were studied.Results.The intravenous injection of 25×106ACI peripheral blood mononuclear cells (PBMC) significantly prolonged graft survival as compared with that of Lewis hosts given TLI and ATG alone. Injection of highly enriched blood T cells or splenic B cells adjusted for the number contained in 25×106PBMC failed to induce significant graft prolongation. Unexpectedly, depletion of monocytes (CD11b+cells) from PBMC resulted in the loss of graft prolongation activity. Enriched populations of monocytes obtained by plastic adherence were more efficient in prolonging graft survival than PBMC on a per cell basis. Hosts with long-term grafts (> 100-day survival) showed evidence of immune deviation, because the MLR to ACI stimulator cells was vigorous, but secretion of interferon-γ in the MLR was markedly reduced. In situ hybridization studies of long-term grafts showed markedly reduced levels of interferon-γ mRNA as compared with rejecting grafts.Conclusion.Infusion of donor monocytes facilitated graft prolongation via immune deviation.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Mycophenolate mofetil (MMF) is a new immunosuppressive agent that is gaining widespread use in solid organ transplantation recipients. A comprehensive assessment of infectious complications after its use after liver transplantation has never been assessed.Methods.Bacterial, fungal, and viral infections occurring after transplantation were compared for a cohort of consecutive liver transplant recipients who received MMF (because of suspected tacrolimus-related nephrotoxicity or neurotoxicity) and a cohort who did not receive the drug. All patients received a tacrolimus-based primary immunosuppressive protocol.Results.Biopsy-proven acute rejection episodes within the first 6 months after transplant occurred in 6% of MMF-treated patients but in 30% of those who did not receive MMF (P=0.07). No significant differences were found in occurrence of cytomegalovirus infection or disease,Pneumocystis carinii, Aspergillus, or other fungal infection and hepatitis C virus recurrence between MMF-treated and untreated patients. Bacterial infections were more common in MMF-treated patients, but this cohort had a prolonged intensive care unit stay compared with patients who did not receive MMF. None of the MMF-treated patients with bacterial infection had leukopenia.Conclusions.MMF use does not appear to be associated with an significantly increased risk of infection occurring after liver transplantation and is associated with fewer episodes of acute rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Little is known about the value of intraoperative hepatic artery (HA) flow measurement on the development of HA complications in orthotopic liver transplantation (OLT). We undertook this study to see whether assessing HA flow at the OLT helps predict posttransplant HA complications (HA thrombosis or stenosis).Methods.Four hundred and eleven consecutive OLT in 367 adult patients who received grafts between November 1992 and August 1995 were reviewed. Of these, 259 grafts in 255 patients with at least 1 year of follow-up and with complete data were studied. HA flow, portal vein flow, percentage of cardiac index going to HA (HA/CI), HA flow per 100 g of liver tissue, mean arterial pressure, central venous pressure, and CI were analyzed. Preservation injury was assessed by posttransplant alanine aminotransferase and aspartate aminotransferase levels.Results.Thirty-four patients with 35 grafts developed HA thrombosis or stenosis during a median follow-up time of 29 months. HA complications occurring within the first 100 days of OLT were classified as early complications. HA flow at the time of surgery and percentage of CI going to the liver were found to be significant variables in early HA complications. Hepatic hemodynamics were not different in the late HA complication group compared to the control. Systemic hemodynamics and posttransplant alanine aminotransferase and aspartate aminotransferase levels were similar in all three groups. Logistic regression analysis showed that patients with HA flows less than 400 ml/min were more than 5 times as likely to develop HA complications (risk ratio 5.1).Conclusions.HA flow measurement should be obtained at the time of OLT and may help to predict early but not late posttransplant HA complications. Patients with HA flows less than 400 ml/min or HA/CI values of less than 7% may carry a higher risk for HA stenosis or thrombosis and may need close surveillance to detect such problems.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Gender is not a selection criterion for orthotopic liver transplantation (OLT), and reports in adults have shown a less favorable outcome for male recipients of female organs; the only pediatric study did not support this finding. The aim of the present study was to assess the impact of donor and recipient gender on graft and patient survival rates after pediatric OLT.Methods.We have reviewed retrospectively 137 children (male=63; median age: 3.4 years; range: 14 days to 15 years) undergoing primary OLT from January 1991 to June 1996. These children were divided into donor-recipient gender match (M; n=64) and nonmatch (NM; n=73) groups and then classified into female to female (FF; n=30), female to male (FM; n=29), male to female (MF; n=44), and male to male (MM; n=34) subgroups.Results.The M group had better graft and patient survival rates at both 1- and 5-year follow-up compared with the NM group (P<0.01). Graft and patient survival rates were different among gender subgroups (P<0.04). Graft and patient survival rates in the FM group were poorer than in the MM subgroup at both 1 and 5 years (P<0.03,P<0.01). The FM group had a higher incidence of early complications than the MM (P<0.01) group, with 50% and 33% of graft losses, respectively, related to the complications. To minimize the influence of hormonal factors, we have analyzed separately the patients younger than 12 and 10 years who had similar findings.Conclusion.Graft and patient survival rates after pediatric OLT are worse in gender mismatch groups, particularly for male recipients of female organs. Early complications play a role in the decreased survival rates.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Pediatric liver transplant recipients have traditionally been grouped according to age. Age-based classification schemes are useful in identifying clinical problems in selected age groups and also for developing solutions to these problems. Although infants in the first 3 months of life have not traditionally been considered a distinct age group, several features of these infants may distinguish them from other pediatric liver transplant recipients.Methods.The experience with liver transplantation in infants during the first 3 months of life in three large pediatric liver transplant programs (University of Chicago, Stanford University, and UCLA) was analyzed in order to characterize this group.Results.A total of 23 liver transplants were performed at these three centers in children younger than 3 months of age. This group of patients comprised approximately 37% of the U.S. experience between 1988 and 1994 according to United Network for Organ Sharing statistics. Age distribution at the time of transplantation included the following: <1 month, 28%; 1-2 months, 35%; and 2-3 months, 36%. Median age at the time of transplantation was 37 days (range, 7-90 days), and mean age was 57±30 days. Mean weight at the time of transplantation was 3.8±1.0 kg. Etiology of liver disease included idiopathic hepatitis, 52%; iron storage disease, 17%; and other causes, 31%. Types of liver allografts used included cadaveric, 85% (reduced size, 60%, and full-size, 25%); living donor, 15%; ABO-identical, 65%; and ABO-compatible, 35%. Actuarial patient and graft survival rates were 60% and 60% at 1 year and 60% and 42% at 2 years, respectively. Median follow-up was 1.5 years. Rejection occurred in 42% of patients, with a median time to first rejection of 13 days. Of these patients, 28% required steroids only and 14% required OKT3. Three patients (14%) were retransplanted at a median time to retransplantation of 1.6 years. Vascular thrombosis occurred in three patients (14%).Conclusions.Liver transplantation performed in infants younger than 3 months of age (1) provides acceptable short- and long-term patient and graft survival, (2) is associated with significant rates of rejection, and (3) is not associated with excessive rates of vascular thrombosis. The etiology of end-stage liver disease occurring in the first 3 months of life is distinct from that in other pediatric liver transplant recipient age groups. These infants should be referred promptly for liver transplantation as reasonable survival can be expected.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID