ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.We have recently established a new method for bone marrow transplantation (BMT) in mice: bone marrow cells are directly injected into the intra-bone marrow (IBM) cavity. IBM-BMT induces persistent donor-specific tolerance and enhances the rapid recovery or reconstitution of the hematolymphoid system of donor origin without any signs of graft-versus-host disease (GVHD) or graft failure. Furthermore, the prior injection of fludarabine can reduce the irradiation dose to the sublethal level (4.5 Gy×2). Therefore, we hypothesize that IBM-BMT plus fludarabine is applicable to allogeneic leg transplantation in rats.Methods.Brown Norway (BN; RT1An) rats were injected intravenously with 50 mg/kg of fludarabine phosphate, followed by sublethal fractionated irradiation (4.5 Gy×2) 1 day before IBM-BMT. The hind limbs from Fischer 344 (F344; RT1Al) rats were transplanted on day 0, and bone marrow cells (3×107cells/50 &mgr;L) obtained from the donor F344 rats were injected into the bone marrow cavity of the left tibias of the recipient BN rats.Results.The hematolymphoid cells in the recipient BN rats were completely reconstituted by the cells of the donor F344 rats. The limbs transplanted from the donor F344 rats were accepted for >1 year without any clinical signs of rejection (10 of 10). The lymphocytes of the BN rats showed tolerance to both donor-type and recipient-type major histocompatibility complex determinants in mixed lymphocyte reaction, but showed a significant response to the third-party major histocompatibility complex determinants.Conclusions.Using a combination of the injection of fludarabine, low-dose irradiation, and IBM-BMT, we have succeeded in allogeneic limb transplantation without using any immunosuppressants after the operation. This strategy would be applicable to the transplantation of other vascularized organs in humans.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation “simultaneously.”Methods.Group 1 included controls in which naïve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI→WF) chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100×106ACI T-cell–depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy.Results.The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (>80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity.Conclusions.This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Allograft rejection is still a main cause of graft failure in high-risk keratoplasty. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of tumor cells without significant toxicity and inhibit autoimmune disease. Therefore, we attempted to determine the roles of TRAIL in graft survival.Methods.Thirty-two BALB/C mice were recipients of corneal grafts from C57BL/6 mice. The 32 eyes were equally divided into four groups receiving graft without incubation with viral preparations, graft immersed in Dulbecco’s minimum essential medium containing soluble human death receptor 5 (sDR5) before transplantation, graft carrying the recombinant adenovirus with TRAIL gene (Ad-TRAIL), and graft carrying the recombinant adenovirus with green fluorescent protein (Ad-GFP), respectively. Pathologic and immunohistochemical examinations were performed, and apoptotic cells were detected.Results.High levels of TRAIL expression were detected in the Ad-TRAIL group, which lasted more than 2 weeks. The mean graft survival time was 17.7, 12.3, 22.0, and 17.4 days for control group, sDR5 group, Ad-TRAIL group, and Ad-GFP group, respectively. The degrees of inflammation in tissue sections taken from all groups after the onset of rejection were similar. There were more apoptotic cells in the graft of the Ad-TRAIL group than in other groups.Conclusion.TRAIL appears to play an important role in corneal-allograft rejection and may be used to prolong the survival of allografts.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Clinically, an increasing number of older recipients are listed for transplantation. We examined recipient age-associated alterations of the immune response and their effects on graft function.Methods.Three- and 18-month-old Lewis (LEW) rats received kidneys from 3- and 18-month-old Fischer 344 (F344) rats (1.5 mg/kg/d cyclosporine A for 10 days; n=6/group) and were observed for 180 days. In additional groups, double kidney transplantations were performed to determine the impact of nephron mass and recipient age on graft outcome.Results.All young recipients but only 66% of old recipients survived the observation period. Increasing recipient age resulted in a significant decrease in renal allograft function (P<0.001), more advanced morphologic evidence of chronic allograft damage (P<0.001), and greater cellular infiltration (P<0.05) and major histocompatibility complex expression (P<0.01) within grafts. Additional in vitro studies examined age-related changes in the cellular immune response by enzyme-linked immunosorbent assay, fluorescence-activated cell sorter analysis, and alloreactive enzyme-linked immunospot: splenocytes from old LEW rats produced significantly more interleukin (IL)-2 (P<0.0001), IL-4 (P<0.05), interferon (IFN)-&ggr; (P<0.0001), and tumor necrosis factor-&agr; (P<0.05). IFN-&ggr;–producing memory-type T cells were significantly elevated in older rats (P<0.0001). Moreover, they revealed significantly more alloreactive T cells directed against F344 (146±64.2 and 512±277/106T cells;P<0.05). Double renal allografts from young donors into old recipients confirmed an independent effect of recipient age on the acceleration of chronic graft deterioration.Conclusions.The enhanced cellular immune responsiveness in elderly recipients was associated with advanced chronic graft injury. Clinically, older recipients may need a modified immunosuppression.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Recent observations have demonstrated the importance of host cells in neointima formation after transplantation. Because little is known regarding the dynamics of host-derived cells in the graft media, we investigated this question in a mouse carotid artery transplantation model.Methods.C57BL/6 carotid arteries were orthotopically transplanted into BALB/c mice ubiquitously expressing enhanced green fluorescent protein. Grafts were harvested at 1, 2, 4, and 8 weeks after transplantation for histologic examination. No immunosuppression was used.Results.Immunostaining and semiquantitative analysis of cross sections showed that donor medial smooth muscle cells decreased over time in the graft media, whereas green fluorescent protein-positive/smooth muscle &agr;-actin-positive cells (i.e., cells of host origin) increased over time. Interestingly, host cells were located only in the inner media and the neointima at 2 weeks and thereafter also in the outer media, indicating that the host-derived cells entered the media from the luminal side rather than from the adventitia. In longitudinal sections, there were no differences in the accumulation of donor- and host-derived cells between the end and middle regions of the graft media at 8 weeks.Conclusions.After transplantation, medial cells were replaced by &agr;-actin–expressing host cells that were probably derived from circulating precursor cells. Our observations differ from the traditional view of a major contribution of donor medial smooth muscle cells to the neointima formation. Thus, circulating progenitor cells may be important for graft vessel disease.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Patients with end-stage renal disease on dialysis have among the highest cardiovascular event rates documented. Abnormal nitric oxide (NO)-dependent endothelial reactivity and increased arterial stiffness are commonly described in hemodialysis (HD) patients. Measures of aortic stiffness—aortic pulse wave velocity (PWV) and augmentation index (AGI)—have been shown to be powerful predictors of survival on hemodialysis. It is not known how these parameters interfere with successful renal transplantation.Methods.PWV and aortic AGI (difference between the first and second systolic peak on the aortic pressure waveform divided by the pulse wave height) were determined from contour analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCor device in 41 HD patients (20 men; age, 41.8 years) and in a control group of 20 patients with essential hypertension (HTA) (10 men; age, 43.6 years). Twenty of the HD patients (10 men; age, 39.7 years) received live-related renal transplants (RTx) and were restudied (3 months after RTx, normal serum creatinine). NO-dependent and NO-independent vascular reactivity were assessed by changes in AGI after challenges with inhaled salbutamol (SAL) and sublingual nitroglycerin (NTG), respectively.Results.AGI values were significantly lower in RTx patients compared with subjects on hemodialysis (15.9±13.9% vs. 27.9±11.9%,P<0.05), but similar to essential HTA controls (16.5±17%). Serial AGI measurements showed that successful renal transplantation is associated with a decrease in AGI in all cases, from a mean of 25.1±7.8% while on dialysis to 15.9±7.0% 3 months after transplantation (P<0.0001). The responsiveness to both endothelium-dependent stimuli (inhaled SAL) and endothelium-independent stimuli (sublingual NTG) was greater in transplant patients than in hemodialysis patients (SAL-induced decrease in AGI −82.3±65.7% vs. 45±72.3%,P<0.01; and NTG-induced decrease in AGI 197±108 vs. −129.0±215.5%,P<0.01). PWV values in dialysis patients (7.19±1.88 m/sec) were significantly higher than those measured in essential HTA patients (6.34±1.32 m/sec,P<0.05) with normal renal function (despite similar blood pressure levels). PWV after RTx was 6.59±1.62 m/sec, significantly different from pretransplantation (dialysis) values (P<0.05 for comparison) but similar to the control group of essential HTA patients.Conclusions.Renal transplantation is associated with marked improvements in vascular structure and function to a profile comparable to essential HTA patients.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The authors reviewed their long-term experience with pediatric renal transplantation into a dysfunctional lower urinary tract to evaluate the results of contemporary lower urinary tract evaluation and management on graft survival and function.Methods.Between 1990 and 1996, 21 renal transplants were performed in 20 children with dysfunctional lower urinary tracts and 61 transplants were performed in 61 patients with normal lower urinary tracts. The minimum follow-up was 36 months (mean, 62.0±19.6 months). The cause of lower urinary tract dysfunction included posterior urethral valves (n=13), prune belly syndrome (n=4), meningomyelocele (n=2), and urogenital sinus abnormality (n=1). Urodynamics were performed on all children with dysfunctional lower urinary tracts. Using these perioperative assessments, lower tract management strategies were devised, including timed voiding alone (n=6), clean intermittent catheterization (n=8), bladder augmentation (n=4), and supravesical urinary diversion (n=2).Results.Overall 5-year actuarial patient and graft survival rates were 100% versus 95% (P=not significant [NS]) and 83% versus 69% in the dysfunctional and normal urinary tract groups (P=NS), respectively. Mean serum creatinine levels in dysfunctional and normal urinary tract patients with functioning grafts at 3 years were 1.3±0.5 and 1.3±0.7 mg/dL, respectively (P=NS). However, 35% of patients with a dysfunctional lower urinary tract experienced urologic complications.Conclusions.Pediatric renal transplantation into a dysfunctional lower urinary tract yields outcomes comparable to transplantation into the normal lower urinary tract. Because of the high urologic complication rates, careful surveillance of lower urinary tract function by urodynamic evaluation is essential to optimize these outcomes.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID