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Biomedical subjects

E von Willebrand

Publications and source records attributed to E von Willebrand.

At least 19 recordsLinked to original sources
PubMed2006

Effects of cis-9,trans-11 CLA in rats at intake levels reported for breast-fed infants.

CLA intake in exclusively breast-fed infants is close to levels found to have physiological effects in animals. However, in the majority of studies mixtures of CLA isomers have been used and the independent effects of the major CLA isomer in human milk, cis-9,trans-11 CLA, at the intake level in exclusively breast-fed infants have hardly been studied. We therefore studied the effects of cis-9,trans-11 CLA on plasma lipids and glucose, immune function, and bone metabolism in growing rats. Thirty male Sprague-Dawley rats (n = 10/group) were fed either 20 mg/kg/d cis-9,trans-11 CLA and 20 mg/kg/d sunflower oil (CLA20), 40 mg/kg/d cis-9,trans-11 CLA (CLA40), or 40 mg/kg/d sunflower oil (placebo) for 8 wk. No significant differences between groups were found in plasma lipids, glucose, insulin, C-reactive protein, or lipid peroxidation. Liver fat content was lowest in the CLA20 group. In vitro interleukin 2 (IL-2) production increased, and tumor necrosis factor alpha, IL-1beta, prostaglandin E2, and leukotriene B4 production decreased in the CLA20 group. No differences between groups were detected in IL-4, IL-6, or interferon gamma production, plasma osteocalcin, insulin-like growth factor, or urinary deoxypyridinoline crosslinks. Plasma tartrate-resistant acid phosphatase 5b activity was significantly increased in the CLA40 group. The results indicate anti-inflammatory effects and enhanced T-cell function for the CLA20 group. No adverse effects were seen in the CLA20 group, whereas indications of increased bone resorption rate were observed in the CLA40 group.

Animals↗
PubMed2006

Sirolimus attenuates chronic allograft nephropathy in an experimental rat kidney transplantation model.

Chronic allograft nephropathy (CAN) is the primary reason for late allograft loss in kidney transplantation. The use of calcineurin inhibitors is suggested to be a risk factor for the development of CAN. Thus, calcineurin-inhibitor-free immunosuppressive protocols are needed to improve long-term graft outcome. Sirolimus affects the immune response by interfering with postreceptor interleukin-2 signaling. Safety profile of sirolimus is different from that of calcineurin inhibitors. We investigated the long-term effects of sirolimus on kidney allografts and fibrogenic growth factor expression and compared it to cyclosporine A. Kidney transplantations were performed from DA to WF rats and syngenic controls were done between DA rats. Allograft recipients were immunosuppressed daily with sirolimus 2 p.o. or CsA 1.5 mg/kg s.c. In addition, sirolimus-treated animals were treated with cyclosporine 1.5 mg/kg s.c. for the first 7 days after transplantation. Serum creatinine levels were measured once a week. Grafts were harvested 90 days after transplantation for histology and immunohistochemistry. Histological changes were scored according to the chronic allograft damage index (CADI). No signs of CAN were seen in syngenic grafts, CADI 0.8 +/- 0.2 (mean +/- SEM). In cyclosporine-treated allografts moderate to intense chronic changes were seen; CADI 10.3 +/- 0.6. Sirolimus significantly ameliorated the development of CAN compared to cyclosporine, CADI 3.0 +/- 0.5 (P < .05). Creatinine values of sirolimus-treated allografts were lower compared to the cyclosporine-treated allografts and were nearly similar to the syngenic grafts. Our results demonstrate that sirolimus attenuates the development of CAN and restores kidney function. Based on our findings, sirolimus improves the long-term kidney graft outcome.

Animals↗
PubMed2006

The effect of FK778 on acute rat renal allograft rejection and expression of platelet-derived growth factor and transforming growth factor-beta.

BACKGROUND: Acute rejection is the single most important risk factor for the development of subsequent chronic allograft nephropathy (CAN). Both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are major mitogens mediating mesenchymal cell proliferation and epithelial to mesenchymal cell transition. Early posttransplant induction of these growth factors may start molecular mechanisms leading to CAN. A new promising immunosuppressive drug, FK778, is an analogue of the active metabolite of leflunamide, which inhibits de novo pyrimidine biosynthesis. Herein we investigated the effect of FK778 on acute rejection and on the expression of PDGF and TGF-beta both alone and in combination with cyclosporine (CsA) or tacrolimus (Tac). METHODS: Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth (WF) rats with syngeneic controls between DA rats. No immunosuppression was given to syngeneic grafts. Allografts were immunosuppressed with FK778 alone or in combination with CsA or Tac. Grafts were harvested on day 5 for histology and immunohistochemistry (PDGF-A, -B, PDGFR-alpha, -beta, TGF-beta1, and TGF-betaR1). RESULTS: FK778 ameliorated the inflammatory response and reduced PDGF and TGF-beta expression in a dose-dependent manner. It also showed synergy with calcineurin inhibitors, an effect that was stronger with Tac than with CsA. CONCLUSIONS: Our results indicated that FK778 decreased PDGF and TGF-beta expression early in acute rejection, suggesting it to be a promising therapy for CAN.

Alkynes↗
PubMed2006

Vascular endothelial growth factor (VEGF) ligand and receptor induction in rat renal allograft rejection.

BACKGROUND: Acute rejection is the single most important risk factor for the subsequent development of chronic allograft nephropathy (CAN), which is still the primary reason for late allograft loss in kidney transplantation. Vascular endothelial growth factor (VEGF) is a proangiogenic factor that has an important role in the development and maintenance of physiological endothelium. While its role has been characterized in the pathology of diabetic nephropathy and preeclampsia, its role in the development of acute and chronic allograft rejection remains unclear. METHODS: Kidney transplantations were performed from DA to WF rats and syngeneic control transplantations were performed between DA rats. Normal kidneys were used as controls to evaluate physiological VEGF and VEGFR-1 expression. Allografted rats were immunosuppressed with cyclosporine (CsA) (1.5 mg/kg/d subcutaneously); and no immunosuppression was given to syngeneic grafts. Grafts were harvested at 5 and 90 days after transplantation for histology and immunohistochemistry (VEGF, VEGFR-1). RESULTS: In normal kidneys VEGF ligand and receptor expression was almost nonexistent. Only mild glomerular, arterial, and tubular VEGF expression was seen. In syngeneic grafts, no histological signs of acute or chronic rejection were seen, whereas characteristics of both acute and chronic rejection were seen in CsA-treated allografts. Altough VEGF expression was increased in syngenic grafts when compared to controls it still remained mild in both the early and the late posttransplant period. In CsA-treated allografts moderate VEGF expression was seen already 5 days after transplantation; the expression increased at 90 days after transplantation. The same pattern was also discovered for VEGFR-1 expression although the difference was not as remarkable after 5 days. CONCLUSIONS: Our results demonstrated that VEGF ligand and receptor expression was increased in both acute and chronic rejection. Our data suggested that VEGF may have an important role in the pathology of chronic rejection. Based on our findings VEGF inhibition could be a potential intervention to prevent CAN in clinical kidney transplantation.

Acute Disease↗
PubMed2006

The effect of leflunomide analogue FK778 on development of chronic rat renal allograft rejection and transforming growth factor-BETA expression.

BACKGROUND: Chronic allograft nephropathy (CAN) remains the primary reason for late allograft loss in kidney transplantation. Transforming growth factor beta (TGF-beta) is a major mitogen mediating mesenchymal cell proliferation and epithelial to mesenchymal cell transition in CAN. FK778, an analogue of an active metabolite of leflunomide, is a promising immunosuppressive drug that inhibits de novo pyrimidine biosynthesis. Herein we investigated the effect of FK778 on development of chronic rejection and TGF-beta expression in combination with calcineurin inhibitors cyclosporine (CsA) and tacrolimus (Tac). METHODS: Kidney transplantations were performed from DA to WF rats and syngeneic control transplantations between DA rats. Allografts were immunosupressed alone with CsA (1.5 mg/kg/d subcutaneously) or Tac (1.5 mg/kg/d orally) or with combinations of FK778 (10 mg/kg/d orally) and CsA or Tac. No immunosuppression was given to syngeneic grafts. Grafts were harvested 90 days after transplantation for histology and immunohistochemistry (TGF-beta, TGF-betaR1). The chronic changes in allografts were scored according to the Chronic Allograft Damage Index (CADI). RESULTS: No histological signs of chronic rejection were seen in syngeneic grafts. According to CADI, moderate chronic changes were seen in grafts treated only with CsA or Tac. In both groups the changes typically associated with CAN were significantly ameliorated with FK778. CsA-treated grafts showed intense posttransplant expression of TGF-beta and TGF-betaR1 after 90 days. In grafts treated with Tac monotherapy this expression was substantially lower. FK778 markedly reduced the expression of TGF-beta and TGF-betaR1 when combined with calcineurin inhibitors and lesser expression was demonstrated with the combination of FK778 and Tac. CONCLUSIONS: Our results demonstrated that FK778 is a potent immunosuppressive drug having synergistic effects with calcineurin inhibitors. When combined with CsA or Tac, it decreased posttransplant TGF-beta ligand and receptor expression. Our data also showed that FK778 prevented chronic changes typically associated with CAN. Taken together our results suggested that FK778 could be a promising therapy for CAN in clinical kidney transplantation.

Alkynes↗
PubMed2005

Human polyoma virus in kidney transplants: SV40 T-antigen demonstration in the urine.

We wanted to develop an immunostaining method of urine cytopreparations to detect polyoma virus infection by using fresh urine samples and staining with the monoclonal SV40 antibody and to compare the findings to the demonstration of decoy cells in the urine or to kidney histology. Routine urine samples from pediatric kidney transplant patients were collected either early after transplantation or later, cytocentrifuged, and immunostained with SV40-T-antibody. The number of SV40-T-antigen-positive epithelial cells was counted in the cytopreparations and compared to the findings in routine urine cytology and transplant histology. Immunostaining of urine cytology with SV40-T-ab demonstrated clearly that the infected epithelial cells and the rate of infection could be estimated by semiquantitative counting. There was strong correlation between the findings in the urine and in the biopsies, but in the urine preparations the number of infected cells was much higher than in the biopsies. The high number of SV40-positive cells in the urine also correlated to the severity of clinical infection and to the state of transplant. Immunostaining of urine cytology with SV40-T-antibody seems to be useful in the diagnosis and follow-up of polyoma virus reactivation disease in transplant patients, especially in children with renal transplants.

Antigens, Polyomavirus Transforming↗
PubMed2001

Early induction of platelet-derived growth factor ligands and receptors in acute rat renal allograft rejection.

BACKGROUND: Acute rejection is the single most important risk factor for the development of subsequent chronic rejection. Platelet-derived growth factor (PDGF) is a major mitogen that mediates mesenchymal cell proliferation in chronic rejection. Therefore, we investigated whether PDGF ligands and receptors are induced during acute renal allograft rejection in rat. METHODS: Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth (WF) rats, and syngenic controls were performed from DA to DA rats. Allografts were immunosuppressed with cyclosporine (CsA) 1.5 mg/kg/d subcutaneously or left untreated. Grafts were harvested at 1, 3, 5, and 7 days for histology and immunohistochemistry. RESULTS: In syngenic grafts, no histological signs of acute rejection were seen and the expression of PDGF ligands and receptors remained almost nonexistent. In nontreated allografts, intense rejection resulted in graft necrosis in 7 days. Acute rejection was associated with the induction of all PDGF ligands and receptors (P<0.05 compared to syngenic controls). The expression of PDGF ligands and receptors was located mainly to graft-infiltrating macrophages but also to capillary endothelium and arteriolar smooth muscle cells. CsA significantly ameliorated acute rejection but failed to inhibit the induction of PDGF and its receptors in CsA-treated allografts. CONCLUSIONS: Our results demonstrate that PDGF ligands and receptors are induced during acute rejection. PDGF may be induced directly as a reparative response to graft injury in acute rejection or indirectly by various inflammatory mediators released by graft-infiltrating inflammatory cells. This study indicates that PDGF ligands and receptors are already induced in acute rejection, which suggests a link between acute rejection and the subsequent development of chronic rejection.

Acute Disease↗
PubMed2001

Soluble intercellular adhesion molecule-1 (sICAM-1) after kidney transplantation: the origin and role of urinary sICAM-1?

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) binds to leukocyte adhesion receptors LFA-1 and MAC-1, and mediates leukocyte adhesion to target structures. During acute rejection there is increased expression of ICAM-1 in vascular and tubulointestial cells, and consequently accumulation of inflammatory leukocytes. Soluble ICAM-1 (sICAM-1) is released from ICAM-1 expressing cells and excreted into the surrounding fluid. Increased serum sICAM-1 levels are found in patients with acute rejections of various allografts, and high urinary levels in steroid resistant acute kidney allograft rejection. METHODS: Urinary excretion of sICAM-1 was measured by EIA in 136 kidney allograft recipients during the first 1-6 post transplant weeks: 30 patients developed acute rejection, and 106 patients had stable graft function. The molecular weight, binding to hyaluronan, and the origin of urinary sICAM-1 were studied. RESULTS: We show that urinary sICAM-1 circulates as a monomer with a molecular weight between 50 and 100 kD. It binds to immobilized, but not to circulating hyaluronan. About one week after transplantation the mean sICAM-1/creatinine ratio (306 ng/mmol) in transplanted patients was higher than in the healthy controls (167 ng/mmol, P<0.01), and remained basically unchanged during the follow-up in patients with stable graft function, whereas it increased in patients developing rejection, being about 2.5-fold above the initial level a few days before rejection (P<0.01). Urinary sICAM-1 did not correlate with the urinary albumin, whereas in patients developing rejection it correlated with urinary IL-2R (r=0.5146, P<0.001), a marker of lymphocyte activation. In the urinary sediment of rejecting patients ICAM-1 was demonstrated in the tubular epithelial cells, and in the macrophages. CONCLUSIONS: Increased urinary excretion of sICAM-1 was demonstrated in kidney transplanted patients a few days before acute rejection. It seems to originate from activated macrophages and/or from the tubular epithelial cells. The fact that urinary sICAM-1 is not bound to hyaluronan or to leukocytes suggests that it is not able to compete with membrane-bound ICAM-1 for these bindings, but may do so for the binding of activated macrophages.

Albuminuria↗
PubMed2001

Fine-needle aspiration biopsy allows early detection of acute rejection in children after renal transplantation.

UNLABELLED: analysis detected rejections often before clinical signs. Half of the patients had increased serum creatinine concentration and 38% had fever at the time of rejection diagnosis. Both signs were present in only 19% of the episodes. A decrease in urine output (>20%) was seen in a third of the episodes. The rejections responded well to oral methylprednisolone (3 mg/kg/day), and lymphoglobulins were needed in only 12% of the episodes. More than 90% of the rejections were completely reversible and no transplant was lost because of acute rejection. CONCLUSION: The results indicate that FNAB is a safe and sensitive method for the diagnosis and follow-up of acute cellular rejection in pediatric recipients of different ages.

Adolescent↗
PubMed1998

Adhesion molecules and urinary tumor necrosis factor-alpha in idiopathic membranous glomerulonephritis.

Adhesion molecules are required in several physiological processes, but their altered function/expression is associated with the pathogenesis of inflammatory diseases. In the present study on idiopathic membranous glomerulonephritis (MGN) the expression of adhesion molecules (ICAM-1, VCAM-1, PECAM-1, E-selectin, LFA-1, Mac-1) was analyzed in different cellular compartments of the kidney using an indirect immunoperoxidase technique and monoclonal antibodies. Relationships between the expression of these molecules and the clinical and morphological activity of the disease and the urinary excretion of tumor necrosis factor alpha (TNF-alpha) were studied in 20 patients. The results were compared with the findings in ten normal kidneys and urinary TNF-alpha in 17 healthy subjects. The expression of adhesion molecules in glomeruli and tubules was unchanged apart from a diminished expression of VCAM-1 (P = 0.014) in glomerular parietal epithelial cells and PECAM-1 in glomerular endothelial cells (P < 0.01). Interstitial peritubular capillaries expressed significantly (P = 0.009) more E-selectin compared with the controls. The interstitial compartment had a highly increased number of cells expressing ICAM-1 in MGN (32.4 +/- 4.6 cells/high power field) compared with the controls (9.4 +/- 1.2; P < 0.001). Also, cells expressing VCAM-1 (10.2 +/- 1.6 vs. 2.8 +/- 1.9; P = 0.005). PECAM-1 (25.9 +/- 5.3 vs. 7.4 +/- 2.1; P = 0.006), and LFA-1 (20.4 +/- 3.6 vs. 8.3 +/- 1.5; P = 0.041) were increased in the interstitium. Proteinuria correlated particularly with the expression of E-selectin in peritubular capillaries (r = 0.63, P = 0.004). The number of LFA-1 expressing inflammatory cells in the interstitium correlated with peritubular capillary E-selectin (r = 0.8, P < 0.001) and interstitial ICAM-1 (r = 0.61, P = 0.009) expression, but histological alterations did not correlate with the expression of adhesion molecules. Tumor necrosis factor-alpha excretion was significantly increased in MGN (41 +/- 8 pg/mg creatinine) compared with the controls (13 +/- 2; P = 0.001), and in particular, it correlated with the interstitial expression of LFA-1 (r = 0.71, P = 0.002). This study suggests that active MGN leads not only to proteinuria but also to increased urinary TNF-alpha excretion. These may serve as triggers for the up-regulation of adhesion molecules in the peritubular capillaries and interstitial cells thus enhancing the development of the interstitial injury.

Adult↗
PubMed1997

Adhesion molecules and rejection of renal allografts.

Despite an increasing amount of immunohistochemical and molecular biology data relating to the pathogenesis of kidney transplant rejection, the pathological diagnosis of this condition still rests on routine light microscopy. The detection of changes in expression and distribution of adhesion molecules in renal allograft biopsies may open a new era of increased accuracy of rejection diagnosis. Of the various adhesion molecule reactivities, peritubular capillary VCAM-1 staining appears to be the most specific finding for chronic rejection. This same staining reaction is seen in acute rejection, but may have less specificity in that setting.

Animals↗
PubMed1996

Expression of adhesion molecules and their ligands in liver allografts during cytomegalovirus (CMV) infection and acute rejection.

Vascular adhesion molecules and their ligands are important in leukocyte-endothelial cell interactions and in T-cell activation of rejection cascade. Also, cytomegalovirus (CMV) infection is suggested to be involved in the mechanisms of rejection. In this study, the expression of vascular adhesion molecules ICAM-1, VCAM-1 and ELAM-1 in the liver allografts, the number of leukocytes positive for their ligands LFA-1, VLA-4 and SLex, and activation markers (class II, IL2-receptor) were investigated in liver allografts during CMV infection and acute rejection and compared to grafts with normal function and histology. The adhesion molecules, their ligands and activation markers were demonstrated from liver biopsy frozen sections by the immunoperoxidase technique and monoclonal antibodies. A significant induction of ICAM-1 and VCAM-1 was seen in vascular and sinusoidal endothelium associated with both CMV and rejection, and induction of ELAM-1 in vascular endothelium in rejection only. In both cases, the number of leukocytes expressing LFA-1 was significantly increased, but VLA-4-positive cells were more characteristic for CMV and SLex-positive cells more for rejection. IL2-receptor positivity was practically seen in rejection only, but class II-expressing cells were increased during both CMV infection and rejection. In conclusion, adhesion molecules were induced and the infiltrating cells expressed their ligands both in liver rejection and during CMV infection, although the expression pattern was slightly different.

Acute Disease↗