摘要:

The effect of intrathymic (IT) injection of donor splenocytes and a short course of rapamycin (Rapa) treatment on rat to mouse skin xenograft survival was investigated. ACI rat skin xenografts were transplanted to (C57BL/6×A)Fl mice treated with rabbit anti-mouse lymphocyte serum (ALS) on days −1, +2, and +4 relative to skin grafting on day 0. Fifty million donor-type splenocytes were injected intrathymically on day 7 after transplantation. Rapa was given intraperitoneally every other day from day 0 to day 12 at a dose of 3.0 mg/kg. Prolonged skin xenograft survival was observed in ALS- and Rapa-treated recipients (no IT injection) with a median survival time of 47 days. However, skin graft survival was markedly more prolonged in the group treated with ALS, Rapa, and IT injection of donor-type splenocytes with a median survival time of 100 days. Cyclosporine combined with IT injection of donor splenocytes did not have a beneficial effect on skin xenograft survival in ALS-treated recipients. An increased presence of donor-type cells was observed in the thymus of the ALS- and Rapatreated recipients for 7 days after IT injection of donor splenocytes. In conclusion, a short course of Rapa markedly augments rat skin xenograft survival in ALS-treated mice injected intrathymically with donortype splenocytes.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

We examined the cytokine profiles associated with tolerance and rejection using the mouse model of neonatal tolerance. BALB/c mice primed with CAF1splenocytes during the neonatal stage showed increased A/J skin graft survival of >60 days and failed to develop anti-A/J cytotoxic responses, but rejected third-party C57BL/6 grafts. Lymph node cells that drained A/J grafts on neonatal-primed mice produced allospecific immune cytokine responses characterized by high IL-4 and low IFN-γ levels. In contrast, lymph node cells that drained either rejected third-party grafts or rejected A/J grafts placed on adult controls produced less IL-4 and more IFN-γ. Tolerogen-specific immune responses from neonatal-primed mice made up to 100 times higher IL-4 to IFN-γ ratios than did controls. Alloantigen priming during the immediate neonatal stage induced constitutive expression of IL-4 mRNA in the spleen without IFN-g mRNA, whereas alloantigen stimulation during adulthood induced the opposite pattern. IL-4 production from neonatal primed mice was confined to the CD4 population. The altered cytokine profile of enhanced IL-4/IFN-γ in neonatal primed mice persisted for up to 12 weeks after priming in in vitro secondary MLR assays, which suggests that the initial timing of antigen stimulation critically influenced CD4 maturation. The results support a model of immunoredirection as a mechanism of tolerance and provide rationale for examining the therapeutic use of cytokines in transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The effects of warm ischemia were investigated in obese Zucker rats with severe hepatic steatosis in order to develop a nontransplant fatty liver ischemia model. Obese (Ob) and lean (Ln) Zucker rats were subjected to in vivo partial hepatic warm ischemia of 45 or 90 min. Injury was assessed by serum alanine aminotransferase, animal survival, and liver histology. Liver lipids were quantified in control animals. After 90-min ischemia and 2-hr reperfusion, liver malondialdehyde was measured and neutrophils in 12 microscopic fields were counted after esterase staining.After 45 and 90 min of ischemia, Ob animals had significantly higher alanine aminotransferase at 1-hr and 24-hr reperfusion, compared with Ln animals (P<0.01). After 90 min of ischemia, none of the Ln and 8/9 Ob animals died within 48 hr (P<0.01). Histologically, Ob animals had more hepatocyte necrosis than did Ln animals. Hepatic neutral and phospholipid content (mg/g) in Ob versus Ln animals was 45.2±2.6 versus 8.2±0.7 (P<0.01) and 36.2±1.9 versus 27±2.2 (P<0.05), respectively. After reperfusion, liver malondialdehyde content increased significantly in Ob animals (8.5±0.4 vs. 12.3±0.8 pM/mg protein;P<0.05), but not in Ln animals. Neutrophils, scant in control livers, increased significantly (P<0.01) after ischemia/RP, but it increased to a similar degree in Ob and Ln animals.Obese Zucker rats with hepatic steatosis are more susceptible to warm ischemia/reperfusion injury than lean animals, and lipid peroxidation may be an important contributory mechanism. Further studies in this model might help to investigate the human problem.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The present study was designed to investigate the effectiveness of staurosporine and 2,3-butanedione monoxime (BDM) in preserving cardiac function of long-term hypothermic-stored hearts. Rat isolated hearts were perfused very slowly at 4°C for 16 hr with a storage buffer solution containing staurosporine and BDM. Heart functions were then examined during 2 hr of normothermic reperfusion. Isovolumetric left ventricular-developed pressure (LVDP), its differential, heart rate, and coronary flow were measured in 5 groups of hearts: controls (fresh unstored hearts), stored drug-free hearts, stored staurosporine-treated hearts, stored BDM-treated hearts, and stored BDM+staurosporine-treated hearts. Hearts that had been perfused with staurosporine or BDM during hypothermic storage attained LVDP values that were 37% or 70%, respectively, of that shown by the control group. Hearts perfused without any drug in the storage buffer attained an LVDP value that was 20% of the control value. Heart rates of stored and then normothermically reperfused hearts were lower than, but not significantly different from, values in the control group. Coronary flow values in all stored hearts were significantly lower than the control values. Thus, BDM, and to a lesser extent staurosporine, applied during prolonged hypothermic storage improved cardiac function during normothermic reperfusion.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

This study aimed to clarify the difference in the effects of sodium acetate and sodium lactate administration on hepatic energy metabolism during hepatic warm ischemia and reperfusion. In the first experiment, Ringer's acetate (AR) or Ringer's lactate (LR) solutions were administered intravenously during 20 min of hepatic inflow occlusion in rabbits. Blood gas analyses and measurements of blood pressure, pyruvate, lactate, and ketone body concentrations in arterial blood were performed until 30 min of reperfusion. Hepatic tissue adenine nucleotide concentrations were determined at the end of the experiment. With AR administration, the plasma pyruvate level and the ratio of pyruvate to lactate were significantly elevated during reperfusion. Hepatic energy charge at 30 min of reperfusion improved significantly (P<0.001) with AR compared with LR administration. Plasma ketone body concentrations decreased markedly with LR administration, but were maintained with AR administration. In the second experiment, intravenous administration of AR or LR, hepatic ischemia, and reperfusion were similarly performed in rabbits. Ketone body concentrations were determined in arterial and vena cava blood at 0 min, 20 min of inflow occlusion, and 30 min of reperfusion. With AR administration, a large arteriovenous difference in ketone body concentrations was observed, indicating utilization in the peripheral tissues. With LR administration, no arteriovenous difference was observed. Availability of energy substrate in peripheral tissues by administration of AR is thought to decrease the metabolic load to the liver and to improve hepatic energy status during reperfusion.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

This study was designed to investigate the possible involvement of the thromboxane A2 (TXA2)-TXA2 receptor (TXA2R) system of the hepatic sinusoid in cold preservation/reperfusion injury in liver grafts. Rat livers were preserved in cold University of Wisconsin solution for either 6 or 24 hr. The number of TXA2Rs in sinusoidal endothelial cells isolated from 0-, 6-, and 24-hr preserved liver specimens was 22.50 ±1.80 × 103/cell, 12.66±1.00 × 103/cell, and 4.17±0.65 × 103/cell, respectively. Kd and Bmax at 0 hr, 6 hr, and 24 hr of preservation were 8.54±1.26 nM and 37.34±3.01 fmol/106cells, 7.08±1.14 nM and 12.66+1.00 fmol/106cells, and 1.91±0.10 nM and 3.88±0.59 fmol/106 cells, respectively. The administration of OKY-046 (inhibitor of TXA2 synthesis) to the University of Wisconsin solution suppressed this reduction in TXA2R number. Furthermore, the concentration of TXA2 in hepatic sinusoid was decreased by OKY-046. In a reperfusion experiment, liver tissue preserved for 24 hr exhibited a higher reperfusion pressure, and effluent levels of both aspartate aminotransferase and lactate dehydrogenase were markedly elevated. The addition of OKY-046 to the preservation solution, however, prevented the rise in reperfusion pressure almost completely and the increase in effluent enzyme levels.This study showed that the TXA2Rs in sinusoidal endothelial cells were internalized through binding with TXA2 during cold preservation, causing activation of the TXA2-TXA2R system. This activation apparently induces an increase in reperfusion pressure, possibly due to sinusoidal contraction, resulting in microcirculatory disturbances. Thus, the TXA2-TXA2R system in the hepatic sinusoid may be one of the major mechanisms of cold preservation/reperfusion injury in the liver graft.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The impact of delayed graft function on outcome after cadaver renal transplantation has been controversial, but most authors fail to control their analyses for the presence or absence of rejection. We studied 457 adult recipients of primary cadaver allografts at a single institution during the cyclosporine era. All patients received sequential immunosuppression. The incidence of delayed graft function (defined as dialysis being required during the first week after transplant) was 23%. There was a significant association between delayed graft function and cold ischemia time >24 hr (P=0.0001) and between delayed graft function and the occurrence of at least one biopsy-proven rejection episode (P=0.004).Actuarial graft survival was not significantly different when comparing delayed graft function versus no delayed graft function for patients without rejection (P=0.2). However, it was significantly worse for patients with both delayed graft function and rejection versus those with delayed graft function but no rejection (P=0.005), as well as for grafts preserved >24 hr versus ≤24 hr (P=0.007). By multivariate analysis, delayed graft function per se was not a significant risk factor for decreased graft survival for patients without rejection (P=0.42). In contrast, rejection significantly decreased graft survival for grafts with immediate function (relative risk=2.3,P=0.0002), particularly in combination with delayed graft function (relative risk=4.2,P<0.0001). While cold ischemia time >24 hr was also a significant risk factor (relative risk=1.9,P=0.02), other variables (preservation mode, 0 HLA Ag mismatch, age at transplantation, gender, diabetic status, and panel-reactive antibody at transplantation) had no impact on graft survival.Patient survival was significantly affected by the combination of delayed graft function and rejection (relative risk=3.1,P< 0.0001), age at transplantation>50 years (relative risk=2.6,P=0.0001), and diabetes (relative risk=1.8,P=0.006). Further studies are necessary to elucidate the mechanisms linking delayed graft function and rejection, which, in combination, lead to poor allograft outcome.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

In order to determine whether the donor-specific T cell allorepertoire evaluated in patients before transplantation can be predictive for kidney graft survival, a study has been set up in which the number and activation state of donor-specific T lymphocytes before transplantation were correlated to transplant survival time. Limiting dilution analysis assays were carried out to determine precursor frequencies of both T helper and cytotoxic T lymphocytes. The activation state of these cells was studied by evaluating the inhibitory capacity of cyclosporine on helper and cytotoxic T cells and/or a monoclonal antibody directed against CD8 on cytotoxic T cells. This study shows that neither a significant difference in the number nor activation state of donor-directed helper and cytotoxic T cells before transplantation could be detected when patients who acutely rejected their grafts were compared with patients who still had a wellfunctioning kidney graft after more than 10 years. Moreover, no significant differences in the donorspecific T cell repertoire were found when patients who had been subject to multiple rejection episodes were compared with patients who experienced few complications after transplantation. Therefore, we conclude that in individuals who have not been sensitized to HLA antigens of the donor, the donor-specific peripheral T cell allorepertoire prior to transplantation is not predictive of kidney graft survival.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The current organ shortage has made utilization of organs from less-than-ideal donors more common. Although several transplant centers use kidneys from non-heart-beating donors (NHBDs), there has been reluctance to extend the use of these donors to extrarenal organs. Of the 130 donors referred to our organ procurement organization between January 1993 and May 1994, 16 (12.3%) were NHBDs. Organ retrieval from 10 of these resulted in extrarenal donation, 5 resulted in renal donation only, and 1 resulted in no retrieval as a result of prolonged warm ischemia (> 2 hr). A total of 39 organs were transplanted from these NHBDs. A rapid en bloc retrieval technique was used for extrarenal NHBDs. The mean warm ischemic time was 15.4 min; preservation times were similar for both NHBDs and heart-beating donors. After liver transplantation (n=5), one episode of primary nonfunction that was technical in origin required retransplantation. Following simultaneous pancreas-kidney transplantation (n=6), all patients were insulin independent and free of graft pancreatitis; one patient required hemodialysis (16.7%). After isolated renal transplantation (n=21), 3 patients (14.3%) required hemodialysis. Three of 4 liver recipients are alive after a mean follow-up period of 12.7 months; all simultaneous pancreas-kidney and renal transplant recipients are alive after a mean follow-up period of 8.4 and 8.3 months, respectively. Three liver allografts, 5 pancreas and kidney allografts, and 19 renal allografts are functioning. The lung allograft was lost to rejection 81 days after transplantation; however, the recipient is alive 3 months after retransplantation. Our results demonstrate that in controlled situations, extrarenal organs can be utilized from NHBDs and can be expected to function similarly to organs retrieved from heart-beating donors. We increased the number of transplanted organs by 8.6% using NHBDs for both renal and extrarenal donation. Continued application of these techniques will likely further increase the number of organs retrieved for transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Kidney transplant recipients are exposed to multiple factors that lead to osteoporosis after kidney transplantation. Recent short-term longitudinal studies revealed a strong decline of bone mineral density (BMD) within 1 year after transplantation. The longterm course of BMD after transplantation is still unknown. Therefore, we performed a cross-sectional study to determine BMD in 190 renal graft recipients (mean age 44 years, range 20–71 years) by dual-energy x-ray absorptiometry at various time intervals up to 20 years after transplantation (range 0–237 months).Mean BMD of graft recipients was lower than BMD values of an age- and sex-matched European reference collective at every time of measurement after renal transplantation (P<0.01). Lowest mean BMD values were measured 12–24 months after transplantation. No loss of BMD occurred after the second posttransplant year beyond the normal age- and sex-dependent decline of BMD. Mean daily prednisone dosage was significantly higher within the first 2 posttransplant years compared with the later posttransplant period (13.1±6.2 vs. 6.7±3.4 mg/day). Other drugs or metabolic causes, including daily dosage of CsA, AZA, parathormone level, and graft function, did not show additional important differences before and after the second posttransplant year.Interpreting the results of a cross-sectional study in light of a time-dependent process, we suggest that the preexisting low BMD of kidney transplant recipients at the time of transplantation is further strongly reduced within the initial 2 posttransplant years, probably due mainly to the effect of prednisone therapy. After that time, when prednisone dosage is below a threshold of 7.5 mg/day, only a moderate, normal loss of BMD is apparent, even in patients up to 20 years after transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID