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Biomedical subjects

H G Niesters

Publications and source records attributed to H G Niesters.

At least 19 recordsLinked to original sources
PubMed2002

Intragraft interleukin 2 mRNA expression during acute cellular rejection and left ventricular total wall thickness after heart transplantation.

OBJECTIVE: To assess whether diastolic graft function is influenced by intragraft interleukin 2 (IL-2) messenger RNA (mRNA) expression in rejecting cardiac allografts. DESIGN: 16 recipients of cardiac allografts were monitored during the first three months after transplantation. The presence of IL-2 mRNA in endomyocardial biopsies (n = 123) was measured by reverse transcriptase polymerase chain reaction. To determine heart function, concurrent M mode and two dimensional Doppler echocardiograms were analysed. RESULTS: Histological signs of acute rejection (International Society for Heart and Lung Transplantation (ISHLT) rejection grade > 2) were strongly associated with IL-2 mRNA expression (IL-2 mRNA was present in 12 of 20 endomyocardial biopsies (60%) with acute rejection and in 24 of 103 endomyocardial biopsies (23%) without acute rejection, p = 0.002). No significant relation was found between either histology or IL-2 mRNA expression alone and the studied echocardiographic parameters. However, stratification of the echocardiographic data into those of patients with and those without acute rejection showed that during acute rejection IL-2 mRNA expression was significantly associated with increased left ventricular total wall thickness (mean change in total wall thickness was +0.22 cm in patients with IL-2 mRNA expression versus -0.18 cm in patients without IL-2 mRNA expression, p = 0.048). CONCLUSIONS: An increase in left ventricular total wall thickness precedes IL-2 positive acute rejection after heart transplantation. Thus, cardiac allograft rejection accompanied by intragraft IL-2 mRNA expression may be indicative of more severe rejection episodes.

Acute Disease↗
PubMed2001

Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell--depleted SCT.

Reactivation of the Epstein-Barr virus (EBV) after allogeneic stem cell transplantation (allo-SCT) may evoke a protective cellular immune response or may be complicated by the development of EBV-lymphoproliferative disease (EBV-LPD). So far, very little is known about the incidence, recurrence, and sequelae of EBV reactivation following allo-SCT. EBV reactivation was retrospectively monitored in 85 EBV-seropositive recipients of a T-cell--depleted (TCD) allo-SCT and 65 EBV-seropositive recipients of an unmanipulated allo-SCT. Viral reactivation (more than 50 EBV genome equivalents [gEq]/mL) was monitored frequently by quantitative real-time plasma polymerase chain reaction until day 180 after SCT. Probabilities of developing viral reactivation were high after both unmanipulated and TCD-allogeneic SCT (31% +/- 6% versus 65% +/- 7%, respectively). A high CD34(+) cell number of the graft appeared as a novel significant predictor (P =.001) for EBV reactivation. Recurrent reactivation was observed more frequently in recipients of a TCD graft, and EBV-LPD occurred only after TCD-SCT. High-risk status, TCD, and use of antithymocyte globulin were predictive for developing EBV-LPD. Plasma EBV DNA quantitatively predicted EBV-LPD. The positive and negative predictive values of a viral load of 1000 gEq/mL were, respectively, 39% and 100% after TCD. Treatment-related mortality did not differ significantly between TCD and non-TCD transplants, but the incidence of chronic graft-versus-host disease was significantly less in TCD patients. It is concluded that EBV reactivation occurs frequently after TCD and unmanipulated allo-SCT, especially in recipients of grafts with high CD34(+) cell counts. EBV-LPD, however, occurred only after TCD, and EBV load quantitatively predicted EBV-LPD in recipients of a TCD graft. (Blood. 2001;98:972-978)

Adolescent↗
PubMed2001

Dysfunctional Epstein-Barr virus (EBV)-specific CD8(+) T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma.

Acquired immunodeficiency syndrome-related non-Hodgkin lymphomas (AIDS-NHL) are thought to arise because of loss of Epstein-Barr Virus (EBV)-specific cellular immunity. Here, an investigation was done to determine whether cellular immunity to EBV is lost because of physical loss or dysfunction of EBV-specific cytotoxic T cells. Data on EBV-specific cellular immunity were correlated with EBV load. For comparison, individuals who progressed to AIDS with opportunistic infections (AIDS-OI) and long-term asymptomatics (LTAs) were studied. The number of virus-specific T cells was detected using tetrameric HLA-EBV-peptide complexes; function of these EBV-specific T cells was determined using the interferon-gamma (IFN-gamma) Elispot assay. It was observed that EBV-specific CD8(+) T cells were present in normal numbers in human immunodeficiency virus (HIV)-infected individuals. However, their functional capacity was decreased compared with HIV(-) individuals. In AIDS-NHL patients, EBV-specific T cells were not physically lost in the course of HIV-1 infection but showed progressive loss of their capability to produce IFN-gamma in response to EBV peptides. This loss of function correlated with lower CD4(+) T-cell numbers and was accompanied by increasing EBV load. In HIV-1-infected LTA individuals, in whom CD4(+) T-cell numbers were maintained, and progressors to AIDS-OI, IFN-gamma-producing EBV-specific T cells were stable and EBV load remained stable or decreased in the course of HIV infection, suggestive of immune control. Our data indicate that functional loss of EBV-specific CD8(+) T cells with a concomitant increase in EBV load may play a role in the pathogenesis of AIDS-NHL.

AIDS-Related Opportunistic Infections↗
PubMed2001

Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques.

Modified vaccinia virus Ankara (MVA)-based recombinant viruses have been shown to be potent vaccine candidates for several infectious and neoplastic diseases. Since a major application of these live, replication-deficient vectors would be their use in immunocompromised or potentially immunocompromised individuals, a preclinical safety study was carried out. Macaques were inoculated with high doses of MVA (10(9)) via various routes, after immune-suppression by total-body irradiation, anti-thymocyte globulin treatment, or measles virus (MV) infection. No clinical, haematological or pathological abnormalities related to MVA inoculation were observed during a 13-day follow-up period. The presence of MVA genomes was demonstrated by nested PCR during the course of the experiment in all macaques, but from none of these animals replication competent MVA could be reisolated. These data suggest that MVA can safely be used as a basis for recombinant human vaccines, and that it is also safe for use in immunocompromised individuals.

Animals↗
PubMed2001

The transforming growth factor-beta1 codon 10 gene polymorphism and accelerated graft vascular disease after clinical heart transplantation.

BACKGROUND: The multifunctional cytokine transforming growth factor- (TGF) beta1 is thought to play a role in the pathogenesis of graft vascular disease (GVD). Polymorphisms at codon 10, (Leu10-->Pro) and codon 25 (Arg25-->Pro) in the signal sequence of the TGF-beta1 gene regulate the production and secretion of the protein. We investigated whether these polymorphisms are risk factors for the development of GVD after clinical heart transplantation. METHOD: TGF-beta1 polymorphisms, Leu10-->Pro and Arg25-->Pro, were determined in DNA from heart transplant recipients (n=252) and their donors (n=213), using sequence-specific oligonucleotide probing. GVD was angiographically diagnosed 1 year after transplantation. In addition other potential risk factors including underlying disease, recipient and donor age, recipient and donor gender, number of acute rejections in the first year, cold ischemia time, and HLA mismatches were analyzed by univariate and multivariate logistic regression analysis. RESULTS: Univariate analysis showed that the recipient TGF-beta1 polymorphism Leu10-->Pro, (P=0.056, chi2 test), underlying disease (P=0.01, chi2 test), number of acute rejections in the first-year (P=0.03, analysis of variance), and donor age (P<0.001, analysis of variance) were risk factors for the development of GVD. The TGF-beta1 Arg25-->Pro polymorphism was not a risk factor. Also in the multivariate analysis, the recipient TGF-beta1 codon 10 polymorphism was associated with GVD, with patients homozygous for Pro at greatest risk (odds ratio 7.7, P=0.03). Apart for the recipient TGF-beta1 Leu10-->Pro polymorphism, donor age appeared to be an independent risk factor for the development of GVD at 1 year. Patients with older donor hearts were at greater risk than patients receiving grafts from younger donors (odds ratio 1.1/year, P<0.001). CONCLUSION: Recipient TGF-beta1 Leu10-->Pro polymorphism and higher donor age are independent risk factors for the development of GVD after clinical heart transplantation.

Adult↗
PubMed2001

Quantitation of viral load using real-time amplification techniques.

Real-time PCR amplification techniques are currently used to determine the viral load in clinical samples for an increasing number of targets. Real-time PCR reduces the time necessary to generate results after amplification. In-house developed PCR and nucleic acid sequence-based amplification (NASBA)-based systems combined with several detection strategies are being employed in a clinical diagnostic setting. The importance of these assays in disease management is still in an exploration phase. Although these technologies have the implicit capability of accurately measuring DNA and RNA in clinical samples, issues related to standardization and quality control must be resolved to enable routine implementation of these technologies in molecular diagnostics.

Calibration↗
PubMed2001

Is combination therapy with lamivudine and interferon-alpha superior to monotherapy with either drug?

For the treatment of chronic hepatitis B (CHB) two drugs have been licensed world-wide: interferon-alpha (IFN) and lamivudine. Both drugs significantly increase the hepatitis B e-antigen (HBeAg) seroconversion rate, but a sustained treatment response occurs in less than 40% of patients. To explore whether there is an additional benefit of combining these two drugs, we reviewed the literature on lamivudine-IFN combination therapy in comparison to the two monotherapies in compensated, HBeAg-positive, CHB patients. We focussed on two clinically relevant outcome measures: HBeAg seroconversion, and change in liver histology. Candidates for lamivudine-IFN combination therapy were, previously untreated, patients with moderately elevated alanine aminotransferase (ALT). Such regimen should still be considered experimental. Viral kinetics may provide insight into how long therapy should be continued; prolongation of therapy to 52 weeks currently appears a reasonable approach. According to principles of anti-viral therapy today, simultaneously dosing of both drugs is to be preferred, since rapid maximal virus suppression is thought to be essential to prevent drug resistance and enhance seroconversion. From an immunological point of view, pre-treatment with lamivudine or IFN may alter the virus-host balance and set the stage for the other drug to enhance the effect of treatment. Further clinical research on lamivudine-IFN combination therapy appears warranted.

Antiviral Agents↗
PubMed2001

Failure to down-regulate intragraft cytokine mRNA expression shortly after clinical heart transplantation is associated with high incidence of acute rejection.

BACKGROUND: Brain-death, ischemia and reperfusion damage have been implicated as initial factors that lead to a cascade of immunologic events that result in allograft rejection in experimental animals. Cytokines are thought to play a central role in this process. Therefore, we evaluated intragraft cytokine mRNA expression at an early stage after clinical heart transplantation and related these data to ischemia, immunosuppression, and rejection. METHODS: We sampled endomyocardial biopsies at 30 minutes (EMB 0) and at 1 week (EMB 1) after transplantation from 20 cardiac allograft recipients. Intragraft monocyte chemoattractant protein (MCP-1) and basic fibroblast growth factor (bFGF) mRNA expression levels were quantitatively measured using competitive template Reverse-transcriptase polymerase chain reaction (RT-PCR). RESULTS: We measured significantly lower MCP-1 and bFGF mRNA expression levels in EMB 1 compared with EMB 0 (MCP-1, p = 0.006; bFGF, p = 0.019). We found no direct correlation between the cytokine mRNA expression levels in EMB 0 or EMB 1 and ischemic times, induction therapy, or cyclosporine whole-blood trough levels. Patients with a high incidence of acute rejection episodes (>2 in the first year) had higher bFGF mRNA expression levels (p = 0.009) and comparable MCP-1 mRNA expression levels (p = 0.378) at 1 week, compared with patients with a lower rejection incidence. The MCP-1 and bFGF mRNA expression levels in the first week were not associated with the development of graft vascular disease in the first year post-transplant. CONCLUSIONS: We found a significant decrease of intragraft MCP-1 and bFGF mRNA expression levels in the first post-operative week. Patients with a high incidence of acute rejection had higher bFGF mRNA expression levels in their first week biopsy. Therefore, we conclude that patients who fail to down-regulate their bFGF mRNA expression early after transplantation are at higher risk for acute rejection.

Acute Disease↗
PubMed2001

TGF-beta1 gene polymorphisms in patients with end-stage heart failure.

BACKGROUND: The regulatory cytokine transforming growth factor (TGF)-beta1 is thought to play a role in atherosclerotic heart disease as well as in idiopathic cardiomyopathy. The production of TGF-beta1 is genetically controlled as polymorphisms in the signaling sequence of the TGF-beta1 gene leucine(10)-->proline and arginine(25)-->proline are involved in the regulation of the protein production level. We investigated whether these polymorphisms are associated with end-stage heart failure caused by dilated cardiomyopathy (CMP) or ischemic heart disease (IHD). METHODS: We determined polymorphisms using sequence specific oligonucleotide probing (SSOP) in genomic DNA samples from heart transplant recipients (n = 253) and controls (n = 94). Indications for transplantation were dilated CMP (n = 109) and IHD (n = 144). RESULTS: We found a difference in TGF-beta1 codon 10 genotype distribution among patients with IHD, dilated CMP, and controls (p = 0.034; chi(2) test). Patients with dilated CMP differed from patients with IHD (p = 0.044) and healthy controls (0.017). The genotype distribution between patients with IHD and controls was comparable. For codon 25, we found no difference in genotype distribution. CONCLUSIONS: The Leu(10)-->Pro (codon 10) polymorphism in the TGF-beta1 gene is associated with end-stage heart failure caused by dilated CMP and not with IHD. This observation suggests that TGF-beta1 is involved in the pathogenesis of CMP.

Adult↗
PubMed2001

Outbreak of Hepatitis B among injecting drug users in Denmark.

BACKGROUND: The incidence of hepatitis B is low in Denmark, but injecting drug users (IDUs) remains a high-risk group for this infection. OBJECTIVES: The aim of the study was to describe a hepatitis B outbreak among IDUs by comparing existing registers. Additionally, we wanted to analyze the genetic variation of the hepatitis B virus involved in the outbreak. STUDY DESIGN: In the County of Funen, registers of laboratory diagnosis, hospital records and reports from clinicians to the Medical Officer of Health (MOH) were compared between 1992 and 1998. HBsAg positive sera recovered from the epidemic were sequenced and compared to known HBV strains. RESULTS: We identified 648 cases of hepatitis B of which 51% (332) were acute infections. The laboratory database identified 96% (319/332) of these, 45% (150/332) were admitted to hospital and 38% (127/332) were reported to public health. By capture-recapture analysis based on MOH reports and hospital records the estimated total number of acute cases were 334 (95% C.I. 283-385). We sequenced 75 HBsAg positive samples and identified two very similar strains of genotype D (serotype ayw3) among IDUs involved in the outbreak. CONCLUSIONS: The current surveillance system did not detect the majority of acute hepatitis B cases in County of Funen. We suggest laboratory-based surveillance of hepatitis B to be implemented at a national level as this may identify new outbreaks faster and more complete than the current surveillance system.

Denmark↗
PubMed2001

Conversion from cyclosporin A to tacrolimus is safe and decreases blood pressure, cholesterol levels and TGF-beta 1 type I receptor expression.

To determine whether conversion from cyclosporin A (CsA) to tacrolimus (TAC)-based immunosuppressive therapy is safe and might lead to improvement in the clinical side effect profile we studied 55 cardiac allograft recipients. Ten stable patients were electively converted (0.2-1.5 yr after transplantation; group I) and 45 patients were converted on indication (0.5-14 yr after transplantation; group II). We studied blood pressure, cholesterol level and renal function in all patients. To unravel the mechanisms by which CsA may exert its toxic effects and to evaluate whether conversion is associated with immune activation, we analyzed the transforming growth factor (TGF)-beta 1 system and intragraft interleukin (IL)-2 and IL-15 mRNA expression by real-time reverse transcription-polymerase chain reaction (RT-PCR) and quantitative flow cytometry in the selectively converted patients (group I). Conversion did not result in immune activation as no clinical, histological or molecular signs of immune activation (increased intragraft IL-2 and IL-15 messenger RNA (mRNA) expression) leading to rejection were found. It did not improve renal function neither in patient group I nor in patient group II. However, after conversion the blood pressure decreased (group I: systolic 154+/-16 vs 143+/-21 mmHg, p=0.03, diastolic: 99+/-11 vs 90+/-11, p=0.02 and group II: systolic 155+/-17 vs 142+/-14, p<0.001, diastolic: 99+/-11 vs 91+/-8 mmHg, p<0.001). Likewise, the cholesterol levels improved (group I: 6.6+/-0.5 vs 5.7+/-0.3 mmol/L, p=0.001 and group II: 7.1+/-1.7 vs 6.1+/-1.7 mmol/L, p=0.001). When patients were treated with TAC the ongoing rejections (n=4) resolved and gum hyperplasia disappeared (n=5). Conversion was associated with a two-fold lower TGF-beta 1 type I receptor expression on peripheral lymphocytes and monocytes (p=0.02 and p=0.002, respectively). Conversion from CsA to TAC results in improvement of blood pressure and cholesterol levels and does not induce immune activation. These beneficial effects were accompanied with lower TGF-beta 1 type I receptor expression.

Adolescent↗
PubMed2001

Molecular quantification of viral load in plasma allows for fast and accurate prediction of response to therapy of Epstein-Barr virus-associated lymphoproliferative disease after allogeneic stem cell transplantation.

Epstein-Barr virus lymphoproliferative disease (EBV-LPD) following allogeneic stem cell transplantation (allo-SCT) has a poor prognosis. We used a sensitive real-time polymerase chain reaction (PCR) assay for quantitative detection of EBV-DNA in plasma and serially measured EBV-DNA levels to assess the response to treatment in allo-SCT recipients with EBV-LPD. Fourteen allo-SCT recipients with EBV-LPD who received a T cell-depleted (TCD) sibling (n = 5) or matched unrelated donor (n = 9) graft were monitored from the time of EBV-LPD diagnosis, during therapy and assessment of clinical response. Seven patients had complete responses of EBV-LPD to therapy, of whom 21% (3 out of 14) survived beyond 6 months from EBV-LPD diagnosis. Clinically responding patients showed a rapid decline of EBV-DNA plasma levels within 72 h from the start of therapy. In contrast, all clinical non-responders showed an increase of EBV-DNA levels. Absolute EBV-DNA levels at the time of EBV-LPD diagnosis did not predict for response, but the pattern of EBV-DNA levels within 72 h from the start of therapy (> 50% decrease versus increase) strongly predicted for clinical response (P = 0.001). Quantitative monitoring of EBV-DNA levels from the start of and during therapy for EBV-LPD rapidly and accurately predicts for response to therapy as early as within 72 h. It may thus provide a powerful tool to adjust and select treatment in individuals with EBV-LPD following allo-SCT.

Acute Disease↗
PubMed2001

T cells activate the tumor necrosis factor-alpha system during hemodialysis, resulting in tachyphylaxis.

BACKGROUND: The immunosuppressive state of hemodialysis (HD) patients is accompanied by activation of antigen-presenting cell-derived cytokines, for example, tumor necrosis factor-alpha (TNF-alpha), which are required for T-cell activation. To test whether an activated TNF-alpha system results in impaired T-cell response in these patients, we analyzed parameters of their antigen-presenting cell (APC) function (for example, TNF-alpha system) and T-cell function [for example, interleukin-2 (IL-2) system]. METHODS: By quantitative flow cytometry, the expression of the TNF-receptor 2 (TNF-R2 = CD120b) and the alpha and beta chain of the IL-2 receptor (IL-2R; CD25, CD122) was measured. Using reverse transcriptase-polymerase chain reaction, the mRNA for TNF-alpha, IL-2, and IL-2R were determined. Phyto-hemagglutinin (PHA)- and IL-2-stimulated proliferation and cytokine production were measured. Biological activity of soluble receptors was measured by adding recombinant cytokines to the patient's plasma. RESULTS: CD120b expression was significantly increased in HD patients, whereas CD25 and CD122 was comparable to controls. In contrast to mRNA for IL-2 and IL-2R, mRNA for TNF-alpha was increased in HD. This resulted in significantly increased TNF-alpha levels in HD patients. In peripheral blood of HD patients, high levels of soluble TNF-R (R1 and R2) and IL-2R were found. These receptors were capable of binding 40% of added TNF-alpha and 55% of added IL-2. PHA-induced TNF-alpha production by T cells from HD patients was significantly lower, while their PHA-stimulated IL-2 production and proliferation capacity by T cells were comparable to controls. CONCLUSIONS: We conclude that although the TNF-alpha system is activated during HD, the TNF-alpha production of T cells is impaired, suggesting that tachyphylaxis of T cells occurs for TNF-alpha, as their proliferative capacity and IL-2 production capacity do not imply an intrinsic T-cell defect.

Aged↗
PubMed2001

Nucleoside analogues for chronic hepatitis B.

Hepatitis B virus replicates inside the hepatocyte through an intermediate step of reverse transcription mediated by the viral polymerase. We describe five nucleoside/nucleotide analogues that interfere with the replication mechanisms of the hepatitis B virus. The resemblance of nucleoside analogues to natural nucleosides may lead to direct cytotoxicity. Therefore, antiviral activity should always be interpreted in the light of cellular toxicity. In addition, prolonged therapy with a nucleoside analogue may induce mutations in the viral polymerase, causing structural and configurational changes of the polymerase resulting in a decreased affinity for the nucleoside analogue. Subsequently, the mutated virus is capable of renewed replication during continued antiviral pressure of the nucleoside analogue. The best antiviral strategy in the future is probably combination therapy, either with several nucleoside analogues or with a nucleoside analogue and interferon.

2-Aminopurine↗
PubMed2001

Clinical utility of viral quantification as a tool for disease monitoring.

The possibility to detect viral DNA or RNA in a quantitative manner has already contributed significantly to the management and diagnosis of viral infections, as well as to the understanding of virus-host interactions. New developments in amplification techniques based on real-time detection, as well as automation of the whole process, will soon be introduced in a diagnostic laboratory setting, thereby enabling a rapid turnaround time to generate both quantitative and qualitative results. New guidelines for disease management, as well as extensive quality control and standardization programs must be introduced.

Chemistry, Clinical↗
PubMed2001

Molecular epidemiology of hepatitis A virus in Amsterdam, the Netherlands.

The transmission of sporadic community-acquired hepatitis A virus (HAV) among different risk groups in Amsterdam was verified by applying molecular techniques on fecal samples. These were collected in 1997/1998 from 33 persons with HAV infection that was confirmed serologically. From 8 of these persons serial stool samples were collected. Nested RT-PCR targeting the VP3-VP1 and VP1-P2a regions followed by sequence analysis established the duration of fecal HAV RNA excretion in stool and the epidemiological molecular relationships between patients. The samples of 31 patients were RT-PCR positive, of which 24 were positive for both regions. Fecal HAV shedding was found to occur for at least 33 days after onset of disease, which was the longest time span tested. Sequencing showed that the hepatitis A virus subgenotype circulating among persons from Moroccan descent (type IB) was different from the subgenotype circulating among Dutch homosexual men (type IA). If the latter is endemic in the Netherlands, its presence is of importance to the national vaccination strategy.

Adolescent↗