摘要:

T cell tolerance to self-antigens is established through the recognition by immature T cells of dominant self-peptides presented in association with self-MHC molecules in the developing thymus (negative selection). The self-peptide Dd61-80 is dominant in syngeneic BALB/c mice (H2d). T cell tolerance to Dd61-80 in this mouse strain resulted in the absence of T cell proliferation following in vivo priming with Dd61-80 peptide. Here, we show that transplantation of BALB/c mice with allogeneic B10.A (H2a) splenocytes led to an autoimmune T cell response toward the dominant self-peptide Dd61-80. No T cell responses to Dd61-80 peptide were observed after transplantation of C57BL/6 (H2b) splenocytes into BALB/c recipients. In addition, we provide evidence indicating that the breakdown of tolerance to Dd61-80 self-peptide resulted from the presentation of the donor crossreactive peptide Kk61-80 at the surface of recipient antigen-presenting cells. Taken together, our results suggest that following allotransplantation, T cell responses to donor antigens could spread to crossreactive determinants on self-proteins, thus perpetuating and amplifying the rejection process and presumably initiating tissue-specific autoimmune disorders.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Small vessel thrombosis is a prominent feature in kidneys undergoing vascular rejection. Type 1 and type 2 plasminogen activator inhibitors (PAI-1 and PAI-2, respectively) are known to mediate thrombosis. To examine the potential role of PAI-1 and PAI-2 in the mediation of vascular injury, the relationship and the time course of gene expression of PAI-1 and PAI-2 with the thrombotic changes in renal grafts were investigated in an unmodified rejection model in rats. Orthotopic renal transplantation was performed from Lewis to dark agouti (DA) rats and from DA to DA isografts; untreated normal rat kidneys were used as controls. The rats were killed on days 1-9 posttransplantation (n=18 in each allograft and isograft group). The grafts were analyzed by histopathology, in situ mRNA hybridization and Northern blot methods. The results show that PAI-1 mRNA was first detected at day 4, when the thrombotic changes in the grafts were first seen, and that this relationship persisted during the time course observed to day 9. There was no detectable PAI-1 mRNA in the control groups and no PAI-2 in either group. In situ hybridization showed that PAI-1 positive cells were predominantly located in the cortical interstitium, consistent with the distribution of interstitial microthrombi. These results provide experimental evidence that the thrombotic changes in rejecting allografts are associated with the up-regulation of PAI-1 in the donor tissue, whereas PAI-2, from our results, does not seem to influence these changes. The data are consistent with a role for PAI-1 in the pathogenesis of vascular rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The significance of poor medullary reperfusion in the etiology of acute tubular necrosis during renal transplantation is poorly understood. Our objective was to determine the kinetics of renal hemoglobin oxygenation using near-infrared spectroscopy during renal transplantation, to provide a framework against which the timing of mitochondrial dysfunction could be considered. New Zealand White rabbit kidneys were flushed with hypertonic citrate solution (0-2°C) and autografted immediately (group 1) or stored at 0-2°C for 72 hours before autografting (group 2). Changes in oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) were monitored by near-infrared spectroscopy for 3 hours of reperfusion. Intrarenal perfusion was evaluated separately by barium sulfate angiography. Reperfusion resulted in rapid increases in HbO2within 1 minute in both groups. Group 1 HbO2fell sharply to a minimum at 3 minutes but recovered by 20 minutes; group 2 changes were similar, but there was no recovery (P<0.05 by 10 minutes). Hb increased rapidly in both groups upon reperfusion but in group 2 was significantly greater after 10 minutes (P<0.05). Total hemoglobin levels were similar in both groups. Renal hemoglobin saturation was 69% at 1 minute in both groups; there was no significant change in group 1 but a profound desaturation in group 2 to 25% at 10 minute (P<0.005) and no recovery thereafter. Barium sulfate distribution was normal in all group 1 kidneys; cortical distribution was normal in all group 2 kidneys, but medullary perfusion was poor for the first 60 minutes. Renal hemoglobin oxygenation kinetics as determined here do not correlate with the timing of mitochondrial dysfunction previously reported (Thorniley et al.,Kidney International, 1994; 45: 1489). We conclude that secondary ischemia during reflow is not the only mechanism leading to acute tubular necrosis.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The effect of pancreatic transplantation on noninsulin-dependent diabetes mellitus (NIDDM) had not been evaluated in animal models. We assessed its impact by the insulin-glucose clamp study in experimental diabetic rats.NIDDM was induced in Lewis female rats by streptozocin at the age of 5 days (n5-STZ). To determine its effect on insulin sensitivity, we measured the glucose turnover rate and performed euglycemic hyperinsulinemic clamp studies, evaluating hepatic glucose production (HGP) and glucose uptake. This assessment was conducted on 5 groups of 6 female Lewis rats: 2 groups n5-STZ tested at the age of 10 and 14 weeks, respectively; 2 normal age-matched groups; and a fifth group (n5-STZ) transplanted at 10 weeks of age and tested at 14 weeks. Heterotopic pancreaticoduodenal transplantation was performed, using an end-to-side anastomosis between the donor celiac artery and portal vein to the recipient infrarenal aorta and vena cava, respectively. Pancreatic drainage was achieved by an end-to-side duodenojejunostomy.At 10 weeks of age, diabetic n5-STZ rats showed decreased body weight, hyperglycemia, moderate insulinopenia, a significantly higher basal HGP as compared with normal controls (28.5±10 vs. 10.7±4 mg/kg/minute,P<0.05), and ineffective suppression of the HGP by the insulin infusion.Glycemia, body weight, and basal HGP were normalized in the transplanted group and were statistically similar to age-matched normal controls. HGP was totally suppressed by the insulin infusion. However, the blood insulin level remained significantly higher than in the normal groups (P<0.05).We conclude that n5-STZ is a reliable model of NIDDM and that pancreatic transplantation, without immunosuppressive drugs in this isogenic line, corrects all tested parameters of glucose homeostasis and improves insulin sensitivity.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Hepatitis C viral recurrence after orthotopic liver transplantation is almost universal. Hepatitis C-induced graft failure may occur, but the clinical and histologic profiles are not well defined. The aim of this study was to describe the pattern of early graft failure in patients with recurrent hepatitis C after liver transplantation. Thirty patients with hepatitis C underwent liver transplantation from October 1989 through September 1994. Four patients were excluded because of death (2 patients), graft failure unrelated to hepatitis C (1 patient), and lost to follow-up (1 patient). Hepatitis C recurred in 24 of the 26 remaining patients. In 4 patients with hepatitis C virus recurrence and cholestasis, graft failure developed at 5.25, 11.0, 11.0, and 18.5 months. The medical records and liver biopsies were reviewed.In all 4 patients, a histologic pattern characterized by centrilobular ballooning degeneration developed and progressed to involve more than two-thirds of the lobules. Moderate to severe cholestasis and bridging fibrosis were present in all grafts at explant. Two patients had portal inflammation on 3-month biopsies consistent with viral hepatitis. All patients had mild macrovesicular steatosis, but only 1 patient had significant lymphoid aggregates. No patient had evidence of hepatic artery thrombosis. One patient had potential drug-induced cholestasis. One patient had 3 episodes of rejection that were not believed to contribute to graft loss. All 4 patients developed clinical features of hepatic failure and were retransplanted. Two patients had early recurrence of graft failure.We conclude that a pattern of progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis occurs in some patients with hepatitis C with early graft failure, similar to fibrosing cholestatic hepatitis seen in some transplant patients with recurrent hepatitis B.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A review of 550 consecutively transplanted liver grafts stored in University of Wisconsin solution (UW) was performed during a 4-year period to ascertain whether graft function was impaired by flushing the aorta with Eurocollins (EC) rather than UW during the harvesting. The outcome of 255 liver grafts flushed with UW in both the aorta and portal vein (group UW/UW) was compared with 295 liver grafts flushed with EC through the aorta and UW through the portal vein (group EC/UW). Liver grafts in both groups were flushed with 1 L of UW during the back table procedure and subsequently stored in UW at 4°C before transport. Donor and recipient characteristics, cold and warm ischemia times, and methods of transplantation were similar in both groups, except that the recipient prothrombin time (PT) before liver transplantation (LT) was lower in the UW/UW group. There was no significant difference between the groups with peak transaminases aspartate aminotransferase (AST) and alanine aminotransferase, maximum value of serum bilirubin within 10 days following LT, incidence of primary nonfunction, need for retransplantation, and patient and graft survival at 1 month. Results were improved, however, in the EC/UW group in regard to PT after LT, operative bleeding and proportion of grafts with histologic lesions at the reperfusion biopsy (P<0.001). These better results in the EC/UW group were confirmed when grafts transplanted in urgent situations were excluded from analysis and by multivariate analysis assessing the effects of pretransplant PT and AST values of the recipients combined with the method of liver cooling with each of the aforementioned criteria. In conclusion, the method of using EC for the aortic flush during liver procurement reduces the amount of UW solution by 50% with improved graft function. This method seems justified in that it is less expensive while affording improved graft function.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Univariate and multivariate analyses have been performed on donor and recipient variables to determine possible effects on the outcome of 516 primary cadaveric renal transplants performed in our single center from 1989 until 1993.The overall actuarial patient survival at 1 year and 5 years was 94.4% and 87.4%, respectively; the 1 year and 5 year graft survival rates were 88.3% and 77.8%, respectively. A total of 95 grafts were lost; death with function (35%) and chronic rejection (22%) were the major causes. Three variables (HLA-DR mismatch, delayed graft function, and prolonged cold ischemia time) had a significant detrimental effect on both short- and long-term graft survival. Zero HLA-DR mismatched grafts showed significantly enhanced survival over those with 1 HLA-DR mismatch both at 1 year (92.8% vs. 84.5%) and at 5 years (88.3% vs. 73.9%) only if cold ischemia time was less than 26 hours (P=0.0009). Occurrence of delayed graft function significantly lowered graft survival at both 1 year and 5 years (P=0.002), and the incidence was significantly associated with prolonged cold ischemia time (P<0.0001).HLA-A or HLA-B matching, percentage panel reactive antibodies (PRA), and anastomosis time showed no independent effect on long-term survival. The small number of 2 HLA-DR mismatched grafts (n=6) precluded separate analysis of this group. Acute rejection accounted for 12% of losses but had no statistically significant effect on graft survival, even though an increased frequency of rejection episodes was significantly associated with HLA-DR mismatch (P<0.0001).These results would suggest that significant survival benefits may be achieved by prospective HLA matching if cold ischemia times are limited. The efficiency of organ sharing must be improved to make optimal use of a limited resource.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A long-term retrospective follow-up study was performed to evaluate the risk of skin cancer in 1098 renal transplant recipients in Queensland, Australia. In a subgroup, we also assessed the influence of immunosuppressive therapy on the risk of developing skin cancer: cyclosporine alone or in combination with prednisolone; azathioprine alone or in combination with prednisolone; or the combination of cyclosporine and azathioprine with or without prednisolone.The cumulative incidence of developing skin cancer, calculated by life table analysis, increased progressively from 7% after 1 year of immunosuppression to 45% after 11 years and to 70% after 20 years of immunosuppression.Multivariate analysis in a subgroup comparing the risk of developing skin cancer in patients on either long-term cyclosporine or azathioprine (each with or without prednisolone) and in patients on the combination of cyclosporine and azathioprine (with or without prednisolone) showed no differences between the groups. We conclude that it is likely that the increased risk of skin cancer associated with immunosuppression is independent of the agent(s) used and is a result of the immunosuppression per se.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In a 6-month open label, randomized, multicenter trial, we compared the efficacy and safety of mycophenolate mofetil (MMF) with high dose intravenous steroids (IVS) for the treatment of refractory, acute cellular rejection in recipients of first or second cadaveric or living-donor renal allografts. A total of 150 patients were enrolled and randomized in a 1-to-1 ratio to receive oral MMF 1.5 g twice daily (n=77) or i.v. methylprednisolone 5 mg/kg for 5 days (n=73), tapered over the subsequent 5 days to 20 mg/day or the baseline dose of steroid given on the day before the diagnosis of rejection. Patients in both groups generally received cyclosporine and maintenance doses of corticosteroids throughout the study period. The IVS group (but not the MMF group) was generally maintained on azathioprine. The primary efficacy variable was graft and patient survival at 6 months. Graft loss and death were reduced by 45% in the MMF treatment group; 19 patients (26.0%) in the IVS group experienced graft loss or died, compared with 11 patients (14.3%) in the MMF group (P=0.081, sequential probability ratio test analysis). In the IVS group, 64.4% of patients experienced either subsequent biopsy proven rejection, presumptive rejection (presumed rejection clinically diagnosed but not biopsy proven and treated with a full course of immunosuppressive therapy), or treatment failure (premature termination for any reason, including death, graft loss, or an adverse event) compared with 39.0% in the MMF group (P=0.001, Cochran-Mantel-Haenszel [CMH] general association test). One or more full courses of immunosuppressive treatment for subsequent rejection episodes were administered to 35.6% of patients in the IVS group and 24.7% of patients in the MMF group. The number of patients who received full courses of corticosteroids for subsequent episodes of rejection was equal in the 2 groups, but the number of patients who received full courses of antilymphocyte therapy was more than twice as great in the IVS group (n=18) compared with the MMF group (n=8). Adverse events were reported in 74.6% of patients who received IVS and in 93.5% of patients who received MMF. A cerebral lymphoma developed in 1 patient in each group, and a lymphoproliferative disorder developed in 2 patients in the MMF group; in 1 of these patients, the lymphoproliferative disorder was subsequently determined to be present before study entry. Opportunistic infections occurred in 35% of patients in each treatment group. The incidence of cytomegalovirus (CMV) viremia/syndrome was comparable between groups, but tissue-invasive CMV was reported for 7 patients (9.1%) who received MMF, compared with 1 patient (1.4%) who received IVS. At 12 months postenrollment, the cumulative proportions of patients who died or lost their grafts were 31.5% in the IV steroid arm versus 18.2% for the MMF arm (P=0.042, CMH general association test, not adjusted for sequential monitoring). Thus, graft loss and death were reduced by 42% in the MMF treatment group. In summary, MMF is a clinically promising immunosuppressant and was effective for the treatment of refractory acute rejection with continuing administration for prophylaxis of subsequent rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We studied 822 kidney transplant recipients followed 1-9 years to determine the dynamics of their entering and leaving the work force. Multivariate analysis revealed that not being diabetic and that being employed pretransplant were associated with a higher rate of posttransplant employment. Some recipients in all pretransplant employment categories, including those receiving disability benefits pretransplant, returned to full-time work posttransplant. The most rapid return to work was in those who had been working full-time or attending school pretransplant. After returning to work, a higher percentage of diabetic recipients stopped working; of those who stopped working, 50% received disability benefits. In contrast, nondiabetic recipients who stopped working full-time were more likely to be retired or working part-time; only 22% received disability benefits.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID