摘要:

Background.Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirrhosis (RPBC) is a histologic diagnosis. Clinical data is unreliable in predicting or diagnosing recurrence. RPBC appears to have a changing clinical presentation in recent years.Materials and Methods.The diagnosis of RPBC after liver transplantation was made histologically. Data were obtained from our prospectively maintained liver-transplant database and evaluated statistically.Results.Between 1985 and 1999, 1,835 liver transplants were performed, 169 for PBC. One hundred fifty-six patients were evaluated (one patient received retransplantation, and 13 were excluded). Seventeen (10.9%) experienced recurrence. Median posttransplantation follow-up time was 72.1 months. Median time to recurrence was 49.6 months. Median follow-up time after recurrence was 11.5 months. Neither acute rejection episodes (P=0.34) nor OKT3 use (P=0.36) before diagnosis of recurrence was significant. The combination of cyclosporine, azathioprine, and prednisolone demonstrated recurrence in 6 of 71 (8.4%). Six of 49 (12.2%) patients treated with cyclosporine with or without mycophenolate mofetil and prednisolone experienced recurrence. Six of 36 (16.7%) patients treated with tacrolimus and prednisolone with or without mycophenolate mofetil experienced recurrence. Patients treated with cyclosporine had numerically fewer recurrences than those treated with tacrolimus (P=0.11).Conclusions.Patients with RPBC demonstrated prolonged survival. Clinical factors did not aid in predicting RPBC. The clinical course of RPBC appears to be different than in the earlier years of liver transplantation. Immunosuppression may play a role. The use and type of antimetabolite drugs had no affect on recurrence. RPBC demonstrated a different clinical course with tacrolimus treatment (shorter time to recurrence) and increased incidence when compared with cyclosporine treatment. Controlled randomized studies are necessary to determine differences between tacrolimus and cyclosporine treatment, if any.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Our aim was to study time-dependent modifications in the characteristics of renal transplants in Spain during the 1990s and risk factors associated with death-censored graft failure after the first year.Methods.A total of 3,365 adult patients who underwent transplantation in 1990, 1994, and 1998 with a functioning graft after the first year were included.Results.Ten-year patient and graft survival rates were 82% and 70%. Major modifications between 1990 and 1998 were increases in donor age (32±15 to 43±18 years,P<0.0001) and number of HLA mismatches (2.8±1.2 to 3.2±1.2,P<0.0001). Acute rejection decreased from 39% to 25% (P<0.0001), and the prevalence recipients with hepatitis C virus decreased from 29% to 10% (P<0.0001). The use of lipid-lowering agents during the first year increased from 6% to 41% (P<0.0001). Projected renal allograft half-life estimate was 15.4 (range, 14.1–16.8) years in 1990 and 17.7 (range, 14.0–21.4) in 1998 (P=0.007). Independent variables associated with graft survival were as follows: recipient age, last panel-reactive antibodies, acute rejection, hepatitis C virus antibodies in the recipient, triglycerides, serum creatinine and proteinuria at 3 months, and the increase of serum creatinine and proteinuria between the 3rd and 12th month. The use of statins during the first year was associated with a decreased risk for graft loss.Conclusion.Despite worsening of surrogate parameters of renal quality and poorer HLA matching, graft survival improved during the 1990s in Spain.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Sirolimus (SRL) seems to impair renal recovery from ischemic injury in animal models and delayed graft function after clinical renal transplantation. This study determined the impact of SRL on renal recovery after ischemia-reperfusion injury in a rat kidney transplant model.Methods.Syngeneic kidneys were preserved in University of Wisconsin solution before transplantation into bilaterally nephrectomized rats. Recipients received vehicle or SRL targeting for whole-blood trough levels of 10 to 20 ng/mL as measured by high-performance liquid chromatography. Renal function was assessed by animal survival or daily serum creatinine. Tissue samples were collected for histologic examination.Results.Median SRL whole-blood concentrations were 16.6±1.6 ng/mL on postoperative day (POD) 1 and 12.0±0.9 ng/mL on POD 3. Transplantation of kidneys after 39 hr of cold storage resulted in 30% survival in the SRL-treated group compared with 100% survival in the control group (P=0.002). Transplantation of kidneys after 24 hr of cold storage resulted in no survival differences, but there were significant differences in renal function. Daily serum creatinine (PODs 1–4) was higher in the SRL-treated group compared with the control group (P<0.05 at all time points). Grafts from SRL-treated animals showed more severe tubular necrosis compared with control animals.Conclusions.When given at therapeutic immunosuppressive doses, SRL compromises renal function after ischemia-reperfusion injury in a rat kidney transplant model. The antiproliferative effect of SRL may translate into impairment of tubular repair and regeneration necessary for recovery after such injury.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Prolonged cold storage of organs for transplantation may lead to inflammatory damage upon reperfusion. The aim of this study was to investigate whether organs from living donors experience less damage upon reperfusion than those retrieved from cadaver donors, where cold ischemia times are significantly longer.MethodS.Biopsies were obtained from cadaveric (n=23) and living-related donor (LRD) (n=10) liver transplants before and 2 hours after reperfusion. Cryosections were stained with antibodies against neutrophils, platelets, activated platelets, and endothelium.Results.LRD liver allografts showed minimal changes postreperfusion. In contrast, after reperfusion of cadaver allografts, neutrophil infiltration was detected in 22% and increased expression of von Willebrand factor (vWF), CD41, and P-selectin in 48%, 30%, and 13% of allografts, respectively. In cadaver allografts with deposition of activated platelets expressing either P-selectin or vWF, the cold ischemia time was significantly longer (885±123 min vs. 608±214 min,P=0.04; 776.8±171 min vs. 559.3±216 min,P=0.01, respectively). Increases in neutrophils and platelets after reperfusion were not significantly associated with clinical events posttransplant. However, in cadaver transplants that experienced early acute rejection, the mean cold ischemia time was significantly longer than in allografts with no rejection (732±174 min vs. 480±221 min,P=0.006).Conclusions.This study demonstrates that in the clinical situation, cold ischemia causes platelet deposition and neutrophil infiltration after reperfusion of cadaveric liver allografts. These early inflammatory events may contribute to make the graft more susceptible to acute rejection.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Despite its reduced benefit for a single recipient, the transplantation of two single-lung allografts as opposed to one bilateral lung transplant has the indisputable advantage of maximizing the number of patients that benefit from a single donor.Methods.In the period 1997 to 1999, 90 paired single-lung transplants (SLTx) from 45 donors were performed in 16 lung centers in Eurotransplant, with a complete follow-up of 1 year.Results.No significant differences between left- and right-lung allograft recipients were observed regarding age, sex, primary disease, number of human leukocyte antigen mismatches, cold ischemic time, and donor-to-recipient cytomegalovirus match. Early posttransplant outcome, as assessed by oxygenation index at 12, 24, and 48 hr, also did not differ significantly, and there were no differences in time to extubation and time spent in the intensive care unit. In the first month, six left- and three right-lung allograft recipients died. Bronchiolitis obliterans syndrome developed in 5 of 39 left-lung and 10 of 42 right-lung allograft recipients. If the retrieval team was different from the transplanting team, a significantly worse 1-year posttransplant survival rate was seen in patients who underwent left SLTx compared with those who underwent right SLTx (62% vs. 92%, respectively;P=0.04).Conclusions.More fatal posttransplant complications occur in patients undergoing left SLTx compared with right SLTx. A less optimistic assessment of the left lung by the not-implanting retrieval team is warranted.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Activation of immature dendritic cells (DC) in the presence of the glucocorticoid hormone dexamethasone (DEX) results in alternatively matured DC that present antigen in the absence of a proper co-stimulatory context. This maturation process is irreversible, making these cells an attractive potential tool for the induction of antigen-specific T-cell tolerance in vivo. The authors explored the possibility of using these DC for the induction of transplantation tolerance in a fully allogeneic setting in mice.Methods.Immature dendritic cells (D1, an immature splenic DC line derived from B6 mice) were pretreated with DEX for 24 hr, after which lipopolysaccharide or nothing was added to the culture for another 48 hr. These cells were analyzed for their in vitro and in vivo stimulating or tolerizing capacities.Results.In line with their phenotype, including decreased interleukin (IL)-12 production, in vitro co-culture of alternatively matured D1 (B6 origin; H-2b) with completely allogeneic T cells of BALB/c origin led to a significant decrease in the alloreactive T-cell response. A single injection of 1×106alternatively matured H-2bDC into BALB/c mice induced a different alloimmune response compared with mature DC. The responding T cells showed a lower proliferation rate and a lower interferon-&ggr; production, whereas a significantly higher proportion of the cells produced IL-10 as measured ex vivo by enzyme-linked immunospot assay. Furthermore, injection with alternatively matured DC, followed by transplantation of fully mismatched skin grafts (C57BL/6), led to a significantly prolonged survival compared with that of mature DC-pretreated mice or untreated mice. The immunomodulatory effect was antigen specific, as third-party reactive alloresponses were not affected.Conclusions.The authors’ data constitute the first direct demonstration that DC alternatively matured in the presence of glucocorticoid hormones can be exploited for the specific suppression of the alloreactive Th1 response, resulting in a delayed skin graft rejection in a complete major histocompatibility complex-incompatible strain combination.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.CD56+human natural killer (NK) cells are the principal anti-pig cytotoxic effectors in vitro. Expression of certain human leukocyte antigen (HLA) class I molecules in porcine cells can inhibit NK cell-mediated natural cytotoxicity in serum-free medium, but had not been shown to inhibit antibody-dependent cellular cytotoxicity (ADCC) by CD16+NK cells in the presence of human xenoreactive immunoglobulin G. Moreover, expression of HLA molecules might amplify the previously weak CD8+cytotoxic T-lymphocyte (CTL) response against porcine cells.Methods.A novel porcine B-lymphoblastoid cell line (13271) was stably transfected withHLA-Cw*0304gene constructs encoding wild-type (wt) Cw3 or genetically modified Cw3 unable to interact with CD8 (Cw3-D227K). The Cw3 transfectants were used in limiting dilution assays to estimate the CTL precursor frequency in CD56-depleted human peripheral blood mononuclear cells (PBMC) obtained from eight unrelated donors. The 13271 transfectants were also used as targets for clonal and polyclonal NK cells in the presence and absence of human serum, to measure inhibition of ADCC.Results.Expression of Cw3-wt in 13271 cells significantly increased the human CTL response compared with the empty-vector control transfectant, whereas no significant increase resulted from expression of CD8-interaction mutant Cw3-D227K molecules. The Cw3-D227K mutant was indistinguishable from Cw3-wt in its ability to inhibit both natural cytotoxicity and ADCC mediated by human NK clones that have the appropriate CD158b inhibitory receptor.Conclusions.Transgenic expression of HLA molecules in pig cells will likely amplify the CD8+CTL response against the xenograft. Disruption of HLA-CD8 interaction could minimize this amplification without compromising NK-cell inhibition.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The recent success of islet transplantation using the Edmonton protocol involved the use of sirolimus, tacrolimus, and daclizumab for immunosuppression. Islets were infused into the portal circulation after transhepatic access. This protocol provided a unique opportunity to measure sirolimus and tacrolimus levels from the portal vein and compare them to systemic venous levels. A total of 11 portal venous samples with a corresponding peripheral venous sample were obtained from patients undergoing a first or second islet infusion and medication levels were obtained on both types of specimens. The portal-to-systemic drug level ratio ranged from 0.95 to 2.71 for sirolimus and 1.0 to 3.12 for tacrolimus. Given the potential toxicity of these agents to islets, the findings in this study may have implications for designing the next generation of immunosuppressive protocols for islet transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Hepatocellular carcinomas (HCC) that originate de novo in liver transplants without preceding HCC in the explanted organ have only rarely been reported. Because recent data demonstrated a mixed hepatocellular chimerism caused by the integration of host-derived stem cells, a study was conducted on the origin of tumor cells in de novo HCC.Methods.From two cases of de novo HCC arising in liver transplants after hepatitis B reinfection, tumor cells and nonneoplastic liver cells from the patient’s own liver and donor liver were isolated by laser microdissection and highly polymorphic short tandem DNA repeats (STR) were investigated.Results.Isolated tumor cells revealed donor-specific STR genotypes that could clearly be discriminated from the genotype of the host.Conclusions.Hepatitis B virus-associated de novo HCC in liver transplants is of donor but not host origin. The new technique described here can also discriminate between true recurrence of the original tumor and new recipient tumors.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

FK778 blocks the dihydro-orotate dehydrogenase, necessary for pyrimidine synthesis, and mycophenolate mofetil (MMF) inhibits the inosine monophosphate dehydrogenase, a crucial enzyme for purine biosynthesis. Beneficial immunosuppressive effects have been suggested for the combination of both drugs. The Brown Norway-Lewis rat heterotopic heart transplantation model was used. FK778 (5 and 20 mg/kg/day), MMF (10 and 40 mg/kg/day), or a combination of both drugs for 10 days was used for prevention of acute graft rejection. Grafts of untreated animals were rejected after 6.2±0.4 days. Low-dose FK778 and low-dose MMF administration did not result in a significantly prolonged graft survival (6.7±0.8 and 8.7±1.4 days;P=not significant). Grafts of rats treated with high-dose FK778 or high-dose MMF survived significantly longer (17.0±2.8 and 20.7±3.8 days;P<0.01). Concomitant use of low-dose FK778 with low-dose MMF produced synergistic interactions (mean survival time 12.3±2.9 days;P<0.01; combination index=0.85). High-dose drug combination (mean survival time 24.0±1.4 days) showed antagonistic drug interaction (combination index=1.55) with increased toxic side effects.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID