ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.Results of clinical liver transplantation have shown that rejection and loss of human liver allografts occurs despite immunosuppression. Because genetic disparity and liver immunogenicity remain a matter of controversy, we reexamined the fate of outbred liver allografts without immunosuppression and used partially inbred miniature swine, in which the genetics of major histocompatibility complex (MHC) antigens have been characterized and can be controlled.Methods.Orthotopic liver transplantation was performed between pairs of outbred domestic farm pigs and between pairs of inbred miniature swine with genetically defined major histocompatibility (SLA) loci. A passive splenic and vena caval to jugular vein shunt with systemic heparinization prevented hypotension during the anhepatic phase. Immunological responses were monitored by mixed lymphocyte culture (MLC), CML, skin graft rejection, liver biopsies, and serial serum chemistries.Results.Median survival of technically successful liver allografts between pairs of outbred pigs (n=20) was 38 days and between partially inbred swine matched at the SLA locus (n=17) was 79 days. MLC responsiveness did not correlate with the development of rejection. Five of 20 (25%) outbred pigs and 6 of 17 (35%) MHC matched inbred miniature swine survived more than 100 days. In the long-term survivors, donor, but not third party, MHC matched skin graft survival times were prolonged. In contrast, all SLA-mismatched inbred recipients (n=26) died rapidly from massive liver rejection, with a median survival time of 9 days. In these rejecting animals, the marked MLC responsiveness to donor lymphocytes evident pretransplant diminished rapidly after transplantation, but an undiminished PHA responsiveness and a blunted third party MLC response persisted.ConclusionThe length of survival and the degree and incidence of rejection were similar in outbred pigs and in SLA-matched inbred miniature pigs, indicating that the outbred animals were, therefore, probably closely related and shared relevant genes. However, survival was significantly shortened and liver allograft rejection was accelerated in SLA-mismatched inbred swine. These results indicate that major histocompatibility differences play an important role in the rejection of liver allografts, as is true for other vascularized grafts in the unimmunosuppressed recipient. The development of liver allograft rejection across non-MHC differences is variable and, when present, appears to be a chronic process.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.HuOKT3γ1(Ala-Ala) is a genetically-engineered derivative of the parental murine OKT3 monoclonal antibody, in which the six complementarity-determining regions have been grafted within a human IgG1 mAb, and whose CH2 region has been altered by site-directed mutagenesis to alter FcR-binding activity, thereby eliminating T cell activation properties. This report describes the results of a phase I trial of huOKT3γ1(Ala-Ala) treatment of acute renal allograft rejection.Methods.Acute renal allograft rejection in kidney and kidney-pancreas transplant recipients was treated with huOKT3γ1(Ala-Ala). huOKT3γ1(Ala-Ala) dosing consisted of daily 5- or 10-mg doses adjusted initially to achieve target levels of 1000 ng/ml.Results.A total of seven patients, five kidney transplant and two kidney-pancreas transplant recipients, were treated with the monoclonal antibody for first rejection episodes. Corticosteroids (500 mg i.v. Solumedrol) were given 2 hr before the first huOKT3γ1(Ala-Ala) dose only. Banff classification of treated rejections were the following: grade I, 1 patient, grade IIA, 1 patient, grade IIB, 4 patients, and grade III, 1 patient. Median time from transplant to rejection was 15 days, and median follow up 12 months (range 10-17 months). HuOKT3γ1(Ala-Ala) therapy was given for 10.1±2.5 days, and mean total dose was 76±27 mg. Rejection was reversed in five of seven patients, and recurrent rejection was observed in one patient. Serum creatinine values peaked on day 1 of huOKT3γ1(Ala-Ala) therapy, and thereafter demonstrated a progressive decline. Rejection reversal (return of creatinine to baseline) occurred at a median of 4 days and a mean of 4.1±2 days. Renal allograft biopsies obtained during huOKT3γ1(Ala-Ala) therapy provided evidence of rapid rejection reversal. Patient and graft survival were both 100%. First dose reactions were minimal, and anti-OKT3 antibodies were not detected. Elevations in serum IL-10, but not IL-2 levels were observed after the first huOKT3γ1(Ala-Ala) dose. Marked reductions in circulating CD2+, CD4+, and CD8+T cells were observed after the first huOKT3γ1(Ala-Ala) dose, followed by a slow progressive return of cell counts toward pretreatment values. Pharmacokinetic analysis revealed a half-life of 142±32 hr.Conclusions.HuOKT3γ1(Ala-Ala) possesses the ability to reverse vigorous rejection episodes in kidney and kidney-pancreas transplant recipients, and in comparison to murine OKT3, possesses minimal first dose reactions and does not seem to induce antibodies that bind the OKT3 idiotype. These results support the conduct of additional clinical trials with the huOKT3γ1(Ala-Ala) antibody.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.The first administration of CD3 monoclonal antibodies, such as anti-human CD3 (OKT3), induces a massive release of several cytokines, including tumor necrosis factor alpha (TNF-α), interferon (IFN)-γ, interleukin (IL)-2, IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor.Methods.Cytokine levels in patient's sera were measured by specific ELISA. In vitro cultures were performed using OKT3-stimulated peripheral blood mononuclear cells and/or whole blood from patients and normal controls.Results.Here we describe that OKT3 administration to human renal allograft recipients also leads to a significant release of IL-10. Contrasting with most OKT3-induced cytokines, such as TNF-α whose release is transient, IL-10 levels show a more progressive increase, they peak only by 4-8 hr after the first OKT3 injection and persist longer. Thus, significant IL-10 levels are still detectable at the time of the second and the third OKT3 injection. Administration of corticosteroids, 1 hr before the first OKT3 injection, significantly reduced both TNF-α and IL-10 release. Experiments were performed to evaluate the source(s) of IL-10 and its (their) influence on the initial T-cell activation. When stimulated in culture with soluble OKT3, the production of IL-10 was dependent on the cooperation between T lymphocytes and monocytes. It is important that, as assessed through the use of a specific neutralizing antibody, the endogenous IL-10 produced in the co-culture system exerted a negative feed-back on the release of the other pro-inflammatory CD3-induced cytokines, which was reproducible.Conclusion.These results are supportive of a major role of IL-10 in the down-modulation of the OKT3-triggered T-cell activation cascade.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.Graft loss due to rejection is uncommon after human histocompatibility leukocyte antigen-identical living related donor (LRD) transplantation, resulting in an excellent long-term graft survival. Data on the impact of recurrence of the original disease on graft survival after LRD transplantation are scarce.Methods.We have studied the influence of recurrent glomerulonephritis in adult recipients of a human histocompatibility leukocyte antigen-identical LRD graft transplanted in our center in the period from 1968 to 1996. To that end, the data of 33 patients with proven or suspected primary glomerulonephritis and 27 patients with nonglomerular diseases were analyzed.Results.The patient survival was similar in both groups at 5, 10, and 20 years. The functional graft survival, i.e., graft survival after censoring for death, was, however, significantly worse for patients with glomerulonephritis as underlying disease (P<0.01). At 5 years graft survival was 100% vs. 88%, at 10 years 100% vs. 70%, and at 20 years 100% vs. 63%, respectively. Thus none of the patients with nonglomerular diseases lost a graft, whereas eight grafts were lost in the group of patients with glomerulonephritis. The main cause of graft loss in this patient group was recurrent glomerulonephritis (n=5), whereas chronic vascular rejection caused graft loss in two patients and occlusion of a transplant artery was the cause in one. A clinically significant proteinuria was detected in six more patients in the glomerulonephritis group: a recurrent glomerulonephritis was diagnosed in four patients and in two patients there was no biopsy. The cumulative incidence of recurrence was as high as 45% at 12 years after transplantation.Conclusion.Recipients of a human histocompatibility leukocyte antigen-identical LRD kidney have a good prognosis with respect to graft survival. After censoring for death, recurrent glomerulonephritis is the main cause of graft failure in these patients and the impact of recurrent disease on graft survival will become even more prominent with longer follow-up.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.We sought to compare the immunoreactive potential of human cord blood (CB) versus normal adult bone marrow (BM) versus mobilized blood (peripheral blood stem cells; PBSC) from cancer patients.Methods.Forty mice were randomized to receive a range of doses of T cell-replete cell preparations from one of the above three cell sources. Twenty-eight control mice underwent transplantation with T cell-depleted cells. Mice were observed for 60 days for the development of fatal xenogeneic graft-versus-host disease-like syndrome (GVHDLS).Results.For the mice that had received T cell-replete grafts of CB or BM or PBSC, the duration of GVHDLS-free survival of the chimeras was inversely proportional to the number of T cells transplanted. After adjustment for the number of T cells transplanted, the relative hazard of developing fatal GVHDLS was 62-fold higher for PBSC and 210-fold higher for BM as compared with CB. Flow cytometric and histologic analyses of selected chimeras that died of GVHDLS showed extensive proliferation of human T cells in multiple organs. In contrast, mice that survived to day 60 were engrafted with human myeloid and B lymphoid cells.Conclusions.The immunoreactive potential, as measured by this in vivo assay, differed among clinical grafts: BM > PBSC > CB.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Introduction.Short-term and long-term results of renal transplantation have improved over the past 15 years. However, there has been no change in the prevalence of recurrent and de novo diseases. A retrospective study was initiated through the Renal Allograft Disease Registry, to evaluate the prevalence and impact of recurrent and de novo diseases after transplantation.Materials and Methods.From October 1987 to December 1996, a total of 4913 renal transplants were performed on adults at the Medical College of Wisconsin, University of Cincinnati, University of California at San Francisco, University of Louisville, University of Washington, Seattle, and Washington University School of Medicine. The patients were followed for a minimum of 1 year. A total of 167 (3.4%) cases of recurrent and de novo disease were diagnosed by renal biopsy. These patients were compared with other patients who did not have recurrent and de novo disease (n=4746). There were more men (67.7% vs. 59.8%,P<0.035) and a higher number of re-transplants (17% vs. 11.5%,P<0.005) in the recurrent and de novo disease group. There was no difference in the rate of recurrent and de novo disease according to the transplant type (living related donor vs. cadaver,P=NS). Other demographic findings were not significantly different. Common forms of glomerulonephritis seen were focal segmental glomerulosclerosis (FSGS), 57; immunoglobulin A nephritis, 22; membranoproliferative glomerulonephritis (GN), 18; and membranous nephropathy, 16. Other diagnoses include: diabetic nephropathy, 19; immune complex GN, 12; crescentic GN (vasculitis), 6; hemolytic uremic syndrome-thrombotic thrombocytopenic purpura (HUS/TTP), 8; systemic lupus erythematosus, 3; Anti-glomerular basement membrane disease, 2; oxalosis, 2; and miscellaneous, 2.The diagnosis of recurrent and de novo disease was made after a mean period of 678 days after the transplant. During the follow-up period, there were significantly more graft failures in the recurrent disease group, 55% vs. 25%,P<0.001. The actuarial 1-, 2-, 3-, 4, and 5-year kidney survival rates for patients with recurrent and de novo disease was 86.5%, 78.5%, 65%, 47.7%, and 39.8%. The corresponding survival rates for patients without recurrent and de novo disease were 85.2%, 81.2%, 76.5%, 72%, and 67.6%, respectively (Log-rank test,P<0.0001). The median kidney survival rate for patients with and without recurrent and de novo disease was 1360 vs. 3382 days (P<0.0001). Multivariate analysis using the Cox proportional hazard model for graft failure was performed to identify various risk factors. Cadaveric transplants, prolonged cold ischemia time, elevated panel reactive antibody, and recurrent disease were identified as risk factors for allograft failure. The relative risk (95% confidence interval) for graft failure because of recurrent and de novo disease was 1.9 (1.57-2.40),P<0.0001. The relative risk for graft failure because of posttransplant FSGS was 2.25 (1.6-3.1),P<0.0001, for membranoproliferative glomerulonephritis was 2.37 (1.3-4.2),P<0.003, and for HUS/TTP was 5.36 (2.2-12.9),P<0.0002. There was higher graft failure (64.9%) and shorter half-life (1244 days) in patients with recurrent FSGS.Conclusion.In conclusion, recurrent and de novo disease are associated with poorer long-term survival, and the relative risk of allograft loss is double. Significant impact on graft survival was seen with recurrent and de novo FSGS, membranoproliferative glomerulonephritis, and HUS/TTP.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.We sought to determine whether diagnoses established through the Banff schema for evaluation of renal allograft pathology have implications for clinical management, compared with diagnoses established using descriptive terminology.Methods.All patients included in this study had mild to severe allograft rejection diagnosed, and, as part of a therapeutic protocol, they received OKT3 as primary anti-rejection therapy. We conducted a retrospective review of their renal allograft biopsy specimens and reclassified them, using the Banff schema, without knowledge of clinical information, laboratory data, or previous biopsy interpretation. Although there is no strict correspondence between descriptive diagnostic terminology and the criteria used in the Banff schema, for the purpose of comparisons, the following approximation was used: mild and mild to moderate rejection=Banff borderline and Banff grade 1, moderate and moderate to severe rejection=Banff grades 2A and 2B, and severe rejection=Banff grade 3. The diagnosis was considered concordant when the diagnosis by descriptive terminology and Banff grading were within the adopted approximation.Results.Of 96 biopsies specimens with mild to severe allograft rejection, 10 were insufficient for diagnosis, and three had changes of chronic allograft rejection. Of the remaining 83 biopsy specimens, 34 (41%) were concordant in interpretation of rejection grades, whereas 49 (59%) were discrepant. The greatest degree of concordance was in grades 2A (66.7%, 18 of 27) and 2B (64.7% 11 of 17), and the lowest was in the borderline category (11.8%, 2 of 17). The greatest degree of discrepancy was in normal and grade 3 (100%, 3 of 3 and 2 of 2, respectively), and the lowest was in grade 2A (33.3%, 9 of 27). Although primary anti-rejection therapy with OKT3 resulted in a high reversal rate of rejection (98%), there were 5 deaths, 12 graft loses, six episodes of serious infections, and three malignancies in this group of patients during a mean follow-up period of approximately 38 months.Conclusions.Because patients with borderline changes and grades 1 and 2A rejection may be treated differently from patients with higher grades (2B and 3), the use of the Banff schema may allow for better adjustment of immunosuppressive therapy in response to specific grades of acute allograft rejection and may result in decreased complications of immunosuppressive therapy.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective.The objective of this study was to describe the complications specifically related to orthotopic liver transplantation (OLT) with preservation of the inferior vena cava and to their therapeutic management. This preservation technique has considerably influenced the surgical phases of liver transplantation, increasing hepatectomy time and modifying the number of vascular anastomoses.Methods.Our retrospective multicentric study, based on data from 1361 adult patients that had undergone orthotopic liver transplantation with preservation of the inferior vena cava in France between 1991 and 1997, analyzed the concomitant surgical complications. Type of cavo-caval anastomosis performed (piggyback, end-to-side, or side-to-side), use of a temporary portacaval anastomosis, technique-related complications, and mortality, were investigated.Results.Cavo-caval anastomosis was side-to-side in 50.6% of cases (n=689), piggyback in 42.7% (n=582), and end-to-side in 6.6% (n=90). In total, 882 temporary portacaval anastomosis were carried out. Fifty-five patients presented with one or more complications related to the preservation of the inferior vena cava technique; i.e., overall morbidity was 4.1% (55/1361). Overall mortality was 0.7% (10/1361). Mortality rate for patients who presented with surgical complication was 18%. A total of 64 complications were recorded: 57 (89%) were in the perioperative or immediate postoperative period and 7 (11%) were postoperative.Conclusions.These retrospective, descriptive results show significant advantages in favor of side-to-side anastomosis in terms of vascular complications. Certain factors should be evaluated specifically at pretransplant assessment to prevent certain serious complications; principally, these are anatomic factors of the recipient (inferior vena cava included in segment I, anatomic abnormalities of the inferior vena cava) and graft size. Depending on these factors, surgeons must be able to adapt the orthotopic liver transplantation, either before or during orthotopic liver transplantation, preferring the standard technique.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.The present study analyzes pretransplantation variables associated with long-term liver allograft survival in 278 children who underwent transplantation under primary tacrolimus (FK506) therapy at a single center between October 1989 and October 1996.Methods.The influence of 17 pretransplantation variables on long-term liver allograft outcome was analyzed. Donor variables included age, weight, gender, and cold ischemia time. Recipient variables included age, weight, gender, original liver disease, pretransplantation waiting time, previous abdominal surgery, United Network of Organ Sharing (UNOS) status, ABO blood group, bilirubin level, prothrombin time, ammonia level, creatinine level, and reduced-size/split liver grafts.Results.Overall actuarial graft survival was 79.9% at 1 year, 79.1% at 2 years, and 78.3% at 3, 4, and 5 years. Retransplantation rate was 10.8%. Pretransplantation variables with a significant adverse effect on graft survival by univariate analysis were donor age ≤1 year (P<0.004), donor weight ≤10 kg (P<0.003), UNOS status I and II (P<0.007), ABO type O, B, and AB (P<0.03), and reduced-size/split liver grafts (P<0.02). Pretransplantation variables significant by multivariate analysis and therefore independent predictors of inferior graft outcome were donor weight ≤10 kg (relative risk [RR] 2.91, confidence interval [CI] 1.53-5.51); reduced-size/split liver grafts (RR 2.53, CI 1.30-5.64); and UNOS status I (RR 2.22, CI 1.11-4.43).Conclusions.Pediatric liver transplant recipients receiving primary tacrolimus therapy have long-term graft survival rates approaching 80%. UNOS status, donor weight, and the use of reduced-size/split liver grafts are the most important factors affecting survival.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID