摘要:

BK virus is a human polyomavirus associated with a range of clinical presentations from asymptomatic viruria with pyuria to ureteral ulceration with ureteral stenosis in renal transplant patients or hemorrhagic cystitis in bone marrow transplant recipients. Infection of renal allografts has been associated with diminished graft function in some individuals. Fortunately, however, the majority of patients with BK virus infections are asymptomatic. The type, duration, and intensity of immunosuppression are major contributors to susceptibility to the activation of BK virus infection. Histopathology is required for the demonstration of renal parenchymal involvement; urine cytology and viral polymerase chain reaction methods are useful adjunctive diagnostic tools. Current, treatment of immunosuppressed patients with polyomavirus viruria is largely supportive and directed toward minimizing immunosuppression. Improved diagnostic tools and antiviral therapies are needed for polyomavirus infections.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Cardiac and renal allo- and xenografts can become naturally resistant to vascular rejection. Understanding this process of “accommodation” would enhance our understanding of vascular inflammatory responses and have implications for immune manipulation and tolerance induction. A feature of these grafts is infiltration by leukocytes secreting a Th-2 pattern of cytokines.Methods.HLA-DR-1-transfected, immortalized porcine endothelial cells (IPEC) were incubated with polyclonal human immunoglobulin G (IgG) for 6 days before incubation with purified human CD4+T cells.Results.IgG-incubated IPEC stimulated a normal proliferative response from alloreactive T cells. However, interferon (IFN)-&ggr; levels were significantly reduced, whereas interleukin (IL)-5 and IL-10 were maintained at levels equivalent to those stimulated by control IPEC. Cognate interaction between T cells and IPEC was not required for this effect, because IgG-incubated, MHC-class II-negative IPEC caused reduced IFN-&ggr; secretion during a response to human Epstein-Barr virus-transformed B cells. Experiments with the nitric oxide (NO) donor, (z)-1-2-[2-Aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1, 2-diolate (DETA-NO), and the NO synthase inhibitor, NG-monomethyl-L-arginine.monoacetate (L-NMMA), showed that NO released by the IgG-incubated IPEC was actively involved in the development of this phenotype.Conclusions.These data suggest a novel, IgG-mediated, NO-dependent mechanism by which endothelial cells (EC) influence T cell responsiveness and that the Th-2 cytokine skewing seen in “accommodated” grafts may be a secondary phenomenon, resulting from the T-EC interactions.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Recent studies from our laboratory have demonstrated that in vivo contractile function of rejecting mouse heterotopic abdominal heart allografts 5 days after transplantation is depressed to 40% of that of syngenic controls, and that this depression of function is prevented by the nitric oxide synthase (NOS) inhibitorNG-monomethyl-l-arginine. However, the mechanisms of altered myocyte function caused by nitric oxide production in this setting are not established.Methods.We measured intracellular calcium concentration ([Ca2+]I) transients (fluo-3, confocal microscopy), fractional shortening (video motion), and L-type Ca2+currents (whole-cell patch clamp) 5 days after transplantation in ventricular myocytes freshly isolated from syngenic (Balb/C into Balb/C) and allogenic (Balb/C into C3H) transplants.Results.L-type Ca2+currents, [Ca2+]itransient amplitudes, and fractional shortening did not differ between nonrejecting, syngenic and rejecting, allogenic transplants. Catecholamine responsiveness as analyzed by the change in the peak [Ca2+]itransient induced by 100 nM isoproterenol was also similar. Superfusion with l-arginine, an NOS substrate, caused decreased shortening with no change in [Ca2+]itransients in allogenic myocytes, but had no effect in syngenic myocytes.Conclusions.Depressed contractile function of rejecting allogenic heart transplants in vivo appears to be caused in part by an NOS-dependent decrease in myofilament Ca2+sensitivity.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Highly disparate xenogeneic pig skin graft tolerance and efficient repopulation of mouse CD4+T cells are achieved in thymectomized (ATX) B6 mice that receive T cell and natural killer (NK) cell depletion by injection of a mixture of monoclonal antibodies (mAbs) (GK1.5, 2.43, 30-H12, and PK136) on days −6, −1, +7, and +14 and 3 Gy total body irradiation (TBI) followed by implantation of fetal pig thymus/liver (FP THY/LIV) grafts on day 0. The requirements for each treatment in this model to achieve pig skin graft tolerance have not previously been defined. Therefore, we performed a series of experiments to address the role of each treatment in achieving maximal skin graft tolerance.Methods.Peripheral mouse CD4+T-cell repopulation and pig skin graft survival were followed in this pig-to-mouse model in which recipient B6 mice were treated with modified regimens that omitted thymectomy, 3 Gy TBI, anti-Thy1.2, and anti-NK1.1 mAbs, injection of a mixture of mAbs on day +14, or coimplantation of FP LIV, respectively.Results.Prolongation but not permanent survival of donor MHC-matched pig skin grafts was observed in euthymic B6 mice that received T and NK cell depletion, 3 Gy TBI, and 7 Gy thymic irradiation and FP THY/LIV in the mediastinum, suggesting that full xenogeneic tolerance was not achieved in euthymic mice. However, after grafting FP THY alone to ATX B6 mice treated either with the “standard” regimen, or with a conditioning regimen that omitted all components of the conditioning regimen except treatment with anti-CD4 and anti-CD8 mAbs, efficient peripheral repopulation of mouse CD4+T cells and long-term donor MHC-matched pig skin graft acceptance were observed.Conclusions.Highly disparate xenogeneic pig skin graft tolerance can be achieved by grafting FP THY alone in anti-CD4 and anti-CD8 mAb-treated ATX B6 mice, but not in euthymic B6 mice. Additional treatment of ATX recipient mice with anti-Thy1.2 and NK1.1 mAbs and 3 Gy TBI is not essential for donor pig skin graft tolerance induction.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Human lung transplantation carries a poor prognosis because of chronic rejection in the form of obliterative bronchiolitis syndrome (OBS). Using the mouse model of heterotopic tracheal transplantation, we examined the role of costimulation in the allograft rejection that characterizes obstructive airway disease (OAD).Methods.C57BL/6 or BALB/c tracheae were implanted into wild-type control, CD28−/−, &mgr;MT (B-cell deficient), or CD40L−/−recipient mice. Grafts were explanted from 7 to 42 days posttransplantation and evaluated.Results.Thickening of the basement membrane and a decrease in patent luminal area were first noted at 2 weeks in wild-type allogeneic trachea recipients and to a slightly lesser degree in CD28−/−recipients. In contrast, CD40L−/−recipient mice showed no evidence of cellular infiltrates or fibrosis in transplanted tracheae. To determine whether CD40L interacted with host or donor CD40, CD40-deficient tracheae were transplanted into CD40L+/+, CD40+/+wild-type mice. Wild-type mice rejected CD40−/−tracheae. Tracheae were transplanted into B-cell-deficient mice to determine the role of B-cell CD40 in chronic pulmonary allograft rejection. The OAD reaction was identical in wild-type and B-cell-deficient mice.Conclusions.Development of OAD in the mouse trachea transplant model is primarily dependent on CD40L and is relatively CD28 independent. The ability of mice to reject CD40−/−tracheae demonstrated that host, not donor, CD40 is required for rejection. Furthermore, the ability of B-cell-deficient mice to reject allogeneic tracheae demonstrated that B-cell CD40-mediated responses are not required for the development of OAD.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Much discussion has been focused on the use of steatotic livers for transplantation due to the prevalence of steatosis in the potential donor liver pool(1). The aim of this study was to investigate the possibility that the microcirculation of steatotic liver is more sensitive to the ischemia-reperfusion (IR) injury than normal liver.Methods.The left liver lobe of obese (n=9) and lean Zucker rats (n=9) were subjected to 40 min of warm ischemia followed by 60 min of reperfusion. Fluorescent probes rhodamine 123 (Rh123), bisbenzimide (Bis), and rhodamine 6G (Rh6G) were administered for the identification by intravital fluorescence microscopy (IVFM) of mitochondrial membrane potential, hepatocyte nuclei and leukocytes, respectively before hepatic ischemia and at 15, 30, 45, and 60 min after reperfusion. Blood samples were obtained before and after 60 min of reperfusion. Liver tissue was taken at the end of experiment for histological analysis.Results.The liver of the obese rats showed prominent macro- and microvesicular fatty changes (MAFC and MIFC) and hepatocyte swelling. Under IVFM, the obese animals had significantly wider hepatic cords (23.1±0.8 &mgr;m) than the lean ones (15.9±0.5 &mgr;m) (P<0.01), whereas no significant difference in sinusoidal diameters was noted. The number of functional sinusoids significantly decreased after 30 min of reperfusion in both groups but no significant change was noted in the nucleus count throughout the experiment. Rh123 fluorescence intensity dropped significantly in the obese group after 60 min of reperfusion but not in the lean rats. Leukocyte adherence showed a significant rise after reperfusion in both groups. Plasma AST and ALT levels were 40- and 24-fold higher respectively for the obese animals after IR compared with their preischemic values, whereas the corresponding increase were 4.2- and 3.4-fold for the lean animals, respectively.Conclusions.Our results indicate that the liver of the obese Zucker rat is steatotic and presents with an abnormal microcirculation manifested by a reduced sinusoidal density. IR led to significantly greater hepatic injury in the steatotic than in the normal liver. This injury was accompanied by a significant reduction in the functional sinusoidal density and mitochondrial membrane potential as assessed by Rh123-associated fluorescence in the steatotic liver. In conclusion, the increased sensitivity of the steatotic liver to IR injury would appear to involve both alterations in blood flow in the microcirculation and to cellular changes.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Eighty percent of donor organs come from donors who have suffered brain trauma (brain-dead donors). This unphysiological state alters the hemodynamic and hormonal status of the organ donor. This can cause organ injury, which has been suggested to alter the immunological or inflammatory status of the organ after transplantation, and may lead to increased sensitivity of the organ to preservation/transplantation injury. In this study we asked the question: does brain death cause injury to the liver that decreases successful liver preservation?Methods.The rat liver transplant model was used to compare survival in rats receiving a liver from a brain-dead donor versus a non-brain-dead donor. Brain death was induced by inflation of a cranially placed balloon catheter. The rats were maintained normotensive with fluid infusion for 6 hr. The livers were flushed with University of Wisconsin (UW) solution and immediately transplanted or cold stored for 20 hr before transplantation.Results.Recipient survival with immediately transplanted livers or those stored for 20 hr was 100% with livers from non-brain-dead donors. However, survival decreased when livers were procured from brain-dead donors. Survival was 75% (6/8) when storage time was 0 hr and 20% (2/10) when the liver was cold stored for 20 hr before transplantation.Conclusion.This study shows that brain death induces alterations in the donor liver that make it more sensitive to preservation/reperfusion injury than livers from donors without brain death. The mechanism of injury to the liver caused by brain death is not known. Because most livers used clinically for transplantation come from brain-dead donors, it is possible that poor function of these livers is due to the intrinsic condition of the donor organ, more than the quality of the preservation. Methods to treat the brain-dead donor to improve the quality of the liver may be needed to allow better preservation of the organ and to give better outcome after liver transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

We report an experience with 71 simultaneous kidney-pancreas transplant (SKPT) recipients receiving daclizumab induction in combination with tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. The mean follow-up time was 5.9±2.5 (SD) months (range 0.5–11 months). The study population included 47 males (65%) and 24 females (35%) with a mean age of 40±8 years. The mean pretransplant duration of diabetes and dialysis were 25±8 and 1.5±0.9 years (34 hemodialysis, 16 peritoneal dialysis), respectively. Mean HLA match was 1.2±1.5, with one patient receiving a second transplant. The mean cold ischemic times for the kidney and the pancreas were 15±5 and 16±4 hr, respectively. Six-month patient, kidney, and pancreas graft survival and rejection rates were 97, 96, 93, and 35%, respectively. There were two deaths, one due to fungal infection and the other due to a cardiac event. There were three kidney graft losses, two immunological, and one death with function. Of the five pancreas graft losses, two were due to infection, one immunological, one thrombosis, and one death with function. The patient population was then stratified according to the number of daclizumab doses: 4–5 doses (n=45) or 1–3 doses (n=26). There were no differences in patient and kidney graft survival rates, 98 vs. 96%, and 92 vs. 92%, respectively. However, there was a trend toward improved pancreas graft survival in the group receiving 4–5 doses (96%) compared with 1–3 doses (85%),P=0.07. Although more patients receiving 1–3 doses had rejection (54%) than patients receiving 4–5 doses (24%), there was no dose response relationship between the total number of doses or the adjusted total mg/kg dose and time to rejection. All patients with functioning grafts have good renal and pancreas allograft function at 6 and 12 months. The overall incidence of major infection was 27% and there were no differences in the incidence of infection between the two groups. No major adverse events were attributed to daclizumab use. In conclusion, excellent short-term outcomes were noted in this retrospective, multicenter survey of initial experience with daclizumab induction in combination with TAC, MMF, and steroids in SKPT recipients. Optimal dosing strategies for SKPT recipients remain to be determined.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID