Biomedical subjects
Urban Sester
Publications and source records attributed to Urban Sester.
Transforming growth factor beta1 genotype polymorphisms determine AV fistula patency in hemodialysis patients.
BACKGROUND: In hemodialysis patients with an arteriovenous (AV) fistula, access failure is primarily due to fistula stenosis, which predisposes to thrombosis and subsequent access loss. The risk for access failure differs interindividually, an observation that is independent from vascular anatomy in a significant number of patients. Fistula stenosis is histologically characterized by intimal hyperplasia, which is induced by growth factors, among which transforming growth factor beta1 (TGF-beta1) is of major importance. The quantitative production of TGF-beta1 interindividually differs due to polymorphisms in the gene region encoding the signal sequence of the cytokine. We hypothesized that the TGF-beta1 genotype, by influencing the development of arteriovenous fistula stenosis, determines the risk for vascular access failure. METHODS: One hundred twenty patients who had undergone placement of an AV fistula for initiation of hemodialysis treatment were genotyped for the polymorphic bases at position +869 and +915 of the TGF-beta1 gene. The primary end-point was time from fistula placement to access failure. RESULTS: AV fistula patency was significantly associated with the TGF-beta1 genotype (P = 0.0046); patency was 62.4% and 81.2% after 12 months for TGF-beta1 high and intermediate producers, respectively. In contrast, AV fistula patency neither differed between diabetic and nondiabetic patients, nor between patients with and without manifest cardiovascular disease. CONCLUSION: Polymorphisms in the gene region encoding the signal sequence of TGF-beta1 influence the risk for hemodialysis access failure. By inducing synthesis of extracellular matrix proteins, overproduction of TGF-beta1 may accelerate the development of intimal hyperplasia, resulting in fistula stenosis and subsequent access failure.
Uremia-associated immune defect: the IL-10-CRP axis.
Unstable atherosclerotic disease is related to systemic inflammation. While this inflammation remains at a subclinical level in otherwise healthy individuals, chronic elevation of pro-inflammatory cytokines is a common feature in patients with end-stage renal disease (ESRD). Current hypotheses on the pathogenetic links between inflammation and atherosclerosis emphasize that cytokine-producing monocytes/macrophages can actively infiltrate atherosclerotic plaques. A high activation level of this cell type may contribute to plaque growth. In the healthy, some 15% to 20% of circulating monocytes may be activated for cytokine production. This percentage is much higher in dialysis patients (50%), which may contribute to the rapid progression of atherosclerosis. Anti-inflammatory mechanisms such as interleukin-10 (IL-10) limit the production of a broad range of pro-inflammatory factors. Animal models, as well as clinical findings, suggest an involvement of this cytokine in the pathogenesis of vascular lesions. In hemodialysis (HD) patients, a protective role of IL-10 against systemic inflammation could be proven. A high interindividual variability in IL-10 production leads to distinct patient groups who can or cannot effectively limit the uremia- and dialysis-induced inflammation. Single nucleotide polymorphisms (SNPs) in the promotor of the IL-10 gene may genetically explain this heterogeneity. The IL-10 genotype strongly influences the range of variation of C-reactive protein (CRP), the most widely used marker of inflammation in dialysis patients. By limiting the inflammatory activation in ESRD patients, the IL-10 genotype is predictive for the risk of cardiovascular disease, meaning that the IL-10 "high-producer" genotype is associated with a lower event rate, and even mortality, than the IL-10 "low-producer" genotype.
No rise in renal Doppler resistance indices at peak serum levels of cyclosporin A in stable kidney transplant patients.
BACKGROUND: The measurement of intrarenal resistance indices by duplex ultrasound plays an important role in the follow-up care of renal transplant patients. Increasing resistance indices indicate rejection episodes, but may also occur e.g. in parenchymal renal diseases. As calcineurin inhibitors induce vasoconstriction both in vivo and in vitro, we studied whether peak serum levels of cyclosporin A led to an acute rise in renal resistance indices via the induction of intrarenal vasoconstriction. METHODS: The acute impact of peak serum levels of cyclosporin A on intrarenal resistance indices was studied in 36 patients after allogeneic renal transplantation. All patients were transplanted for > 6 months and received an immunosuppressive treatment comprising cyclosporin A. Intrarenal resistance indices were measured by duplex ultrasound immediately before (trough serum level) and 2 h after (peak serum level) the oral intake of cyclosporin A at the individual maintenance dose. RESULTS: Compared with renal resistance indices measured at trough serum levels [resistive index (RI) 0.72 +/- 0.07; pulsatility index (PI) 1.40 +/- 0.27], values remained unchanged at peak serum levels of cyclosporin A (RI 0.72 +/- 0.08; PI 1.43 +/- 0.31). Renal resistance indices correlated with the age of the patients, but not with mean arterial pressure or time since transplantation. CONCLUSIONS: The oral intake of cyclosporin A does not induce an acute rise in intrarenal resistance indices in stable transplanted patients. Thus, timing of duplex ultrasound examinations with regard to the intake of cyclosporin A is not necessary in these patients.
Risk of occupational human herpesvirus 8 infection for health care workers.
Human herpesvirus 8 (HHV-8), or Kaposi's sarcoma-associated herpesvirus, is highly prevalent in certain risk groups (human immunodeficiency virus-infected patients, transplant recipients, and patients on hemodialysis). Heath care workers caring for these patients were found to be more frequently infected with HHV-8 than staff caring for other patients (P < 0.01).
The fraction of perforin-expressing HIV-specific CD8 T cells is a marker for disease progression in HIV infection.
OBJECTIVE: Perforin is an important component of the death machinery of cytotoxic T cells (CTL). To evaluate functional differences between HIV- and cytomegalovirus (CMV)-specific CTL of coinfected patients, the frequencies of the respective perforin-expressing T cells were analysed in a rapid whole blood assay. METHODS: Whole blood of HIV- and CMV-infected individuals was specifically stimulated by HIV-1 Pr55(gag) or complete CMV antigen, and activation-induced intracellular cytokine and perforin expression in CD8 T cells was analysed by flow cytometry. RESULTS: Perforin-expressing HIV-1- and CMV-specific CD8 T cells can be quantified simultaneously. Within a patient, the frequency of such HIV-specific CD8 T cells in peripheral blood was lower than the frequency of the respective CMV-specific cells. The number of the perforin-expressing HIV-specific CD8 T cells inversely correlated with the peripheral blood CD4 T cell count. CONCLUSIONS: The differential fractions of perforin-expressing virus-specific CD8 T cells in HIV and CMV double infection might be caused by differences in priming and trafficking to or from replication sites. However, without knowing the underlying mechanism, the fraction of perforin-expressing HIV-specific CD8 T cells provides another surrogate marker for disease progression.
Age-related decrease in adenovirus-specific T cell responses.
Infections with persistent viruses, such as cytomegalovirus (CMV) or adenovirus, are not, in general, clinically apparent but may cause serious complications in the immunocompromised host. As has been shown for CMV, the cellular arm of the immune response is essential in controlling viral replication. However, cellular immunity toward adenoviruses has not been well characterized in humans. The aim of the present study was the quantitative and functional analysis of adenovirus-specific T cell responses from 171 healthy individuals and 59 long-term renal transplant recipients by use of flow-cytometric, as well as standard proliferation and enzyme-linked immunosorbant, assays. Adenovirus-specific immunity is dominated by CD4 T cells with memory/effector phenotype. Of interest, the frequency of adenovirus-specific T cells decreases significantly with age. This age-related decline indicates the eventual elimination of adenoviruses within a lifetime that may explain the well-known clinical observation of a predominant incidence of adenoviral complications in children and young adults, compared with older adults, after transplantation.
Anti-inflammatory interleukin-10 genotype protects dialysis patients from cardiovascular events.
BACKGROUND: Inflammatory processes play an important role for the progression of atherosclerosis. This can be studied particularly well in patients with chronic renal failure who are on hemodialysis, as they show systemic inflammation due to uremia and dialysis while suffering from premature mortality secondary to rapidly progressing atherosclerosis. Interleukin (IL)-10 is a regulatory cytokine that limits inflammatory processes. The quantitative production of IL-10 is subject to genetic variation based on polymorphisms in the promoter of its gene. We tested the hypothesis that the IL-10 genotype, by influencing the capacity to compensate for dialysis-induced systemic inflammation, determines the risk for cardiovascular complications. METHODS: Three hundred chronic hemodialysis patients were genotyped for the polymorphic bases at positions -1082 and -819 of the IL-10 promoter sequence. They were prospectively followed for a mean of 20.2 +/- 7.3 months. End-points of the study were major events related to cardiac, cerebrovascular or peripheral artery disease. RESULTS: The -1082A* allele, which is associated with low production of the cytokine IL-10 and elevated markers of systemic inflammation such as C reactive protein, was predictive for a higher cardiovascular morbidity (relative risk for cardiovascular events 2.76, 95% confidence interval 1.31 to 4.17, P = 0.004) compared to the -1082G* genotype. CONCLUSION: The IL-10 genotype influences the risk for cardiovascular events in hemodialysis patients and allows the definition of a high risk group. The data provide further evidence for a causal role of systemic inflammation for progressive atherosclerosis in dialysis patients.
A shift in the Th(1)/Th(2) ratio accompanies the clinical remission of systemic lupus erythematosus in patients with end-stage renal disease.
BACKGROUND: Patients suffering from systemic lupus erythematosus (SLE) with renal involvement often show remission of systemic clinical activity after progression to end-stage renal disease (ESRD). SLE is characterized by predominantly humoral, T-helper (Th)(2)-mediated autoimmune responses. Since ESRD induces a state of immunodeficiency that affects the balance of Th cell subsets, we hypothesized that a Th(1) shift induced by ESRD leads to clinical remission of SLE. METHODS: Using single-cell measurement of intracellular cytokines by flow cytometry after polyclonal stimulation with PMA/ionomycin, helper cell profiles were analysed in SLE patients with preserved renal function and in SLE patients with ESRD, from both isolated peripheral blood mononuclear cells (PBMC) and whole blood. RESULTS: Using the whole-blood assay, patients with SLE and preserved renal function showed a predominance of Th(2) cells compared to healthy controls (patients, Th(1)/Th(2) ratio 6.0+/-1.0 vs controls, 9.0+/-1.0; P<0.05). In contrast, SLE patients with ESRD have significantly more Th(1) cells (36.8+/-5.0%) than those without ESRD (23.4+/-3.6%; P<0.05). This results in an enhancement of the Th(1)/Th(2) ratio to 12.1+/-2.6, which is not significantly different from healthy controls. These data were confirmed using a PBMC-based assay. CONCLUSIONS: SLE patients with preserved renal function show a bias in the differentiation of Th cells towards Th(2). Once ESRD occurs, the Th(1)/Th(2) ratio normalizes. This may contribute to the remission of Th(2)-mediated autoimmune diseases such as SLE.
Dominance of virus-specific CD8 T cells in human primary cytomegalovirus infection.
Cellular immune responses are of high importance in initiating and maintaining immunity against virus infections. Whereas the cellular immune response during persistent cytomegalovirus (CMV) infection is well assessable, the individual contribution of CD4 and CD8 T cell responses during primary infection has not been described. A novel whole-blood assay, which relies on the flow-cytometric detection of antigen-induced cytokine expression, was used to characterize CMV-specific CD4 and CD8 T cell responses during primary infection of CMV seronegative recipients of a renal allograft from a CMV seropositive donor. These T cell responses were compared with long-term CMV-positive patients with known history of transplantation-related seroconversion. Results were further correlated to CMV load and serum IgG and IgM. The long-term seroconverted patients consistently showed a dominant CMV-specific CD4 T cell response (median frequencies: CD4, 1.12% [range, 0.35 to 8.10%] versus CD8 0.13% [range, <0.05 to 0.55%]). In contrast, during primary infection, the cellular immune response is strongly dominated by CMV-specific CD8 T cells (median peak frequencies: CD4, 1.24% [range, 0.21 to 1.60%] versus CD8, 2.47% [range, 1.34 to 6.67%]). Upon receipt of ganciclovir, viral load as well as CMV-specific CD8 responses decreased. The frequency of the respective CD4 T cells fluctuated during decrease of CMV load and became dominant over CMV-specific CD8 T cell responses. These results are consistent with the view of an effective direct antiviral activity of CD8 T cells, which is most critical during periods of high viremia. Later on during persistent infection, CD4 T cells dominate the immune response to support the state of antiviral immunity.
Evaluation of use of Epstein-Barr viral load in patients after allogeneic stem cell transplantation to diagnose and monitor posttransplant lymphoproliferative disease.
Epstein-Barr virus (EBV)-induced posttransplant lymphoproliferative disease (PTLD) continues to be a serious complication following transplantation. The aim of the present study was to evaluate the EBV load as a parameter for the prediction and monitoring of PTLD. The EBV load was analyzed by a quantitative competitive PCR with 417 whole-blood samples of 59 patients after allogeneic stem cell transplantation (SCT). The EBV load was positive for all 9 patients with PTLD and for 17 patients without PTLD. The viral loads of patients with manifest PTLD differed from the loads of those without PTLD (median loads, 1.4 x 10(6) versus 4 x 10(4) copies/microg of DNA; P < 0.0001). A threshold value of 10(5) copies/microg of DNA showed the best diagnostic efficacy (sensitivity, 87%; specificity, 91%). However, in patients with less than three major risk factors for PTLD, the positive predictive value of this threshold was rather low. One week prior to the manifestation of PTLD, the EBV load was as low in patients who developed PTLD as in patients without disease (median, 2.2 x 10(4) copies/microg of DNA; P was not significant). EBV DNA tested positive first at 20 to 71 days prior to the clinical manifestation of PTLD and occurred with the same delay after transplantation regardless of disease (median delay, 52 versus 63 days; P was not significant). EBV DNA was detected earlier in patients with primary infections than in those with reactivations (33 versus 79 days; P = 0.01), but the peak levels were similar in the two groups. EBV primary infection or EBV reactivation is frequent in patients after allogeneic SCT but results in PTLD only in a subgroup of patients. Although evaluation of the EBV load has limitations, the EBV load represents a valuable parameter to guide therapy.
Sustained high frequencies of specific CD4 T cells restricted to a single persistent virus.
Replication of cytomegalovirus (CMV) is largely controlled by the cellular arm of the immune response. In this study the CMV-specific CD4 T-cell response was characterized in a cohort of apparently healthy individuals. In 11% of all individuals, extremely high frequencies, between 10 and 40%, were found. High-level frequencies of CMV-specific CD4 T cells persisted over several months and were not the result of an acute infection. Specific T cells were oligoclonal and were phenotypically and functionally characterized as mature effector cells, with both cytokine-secreting and proliferative potential. These high-level frequencies do not seem to compromise the immune response towards heterologous infections, and no signs of immunopathology were observed. Whereas a large temporary expansion of virus-specific T cells is well known to occur during acute infection, we now show that extremely high frequencies of virus-specific T cells may continuously exist in chronic CMV infection without overtly compromising the remaining protective immunity.