Impaired Insulin Sensitivity as an Underlying Mechanism Linking Hepatitis C and Posttransplant Diabetes Mellitus in Kidney Recipients

Aim of this study was to investigate the mechanism/s associating hepatitis C virus (HCV) infection and posttransplant diabetes mellitus in kidney recipients. Twenty HCV‐positive and 22 HCV‐negative kidney recipients, 14 HCV‐positive nontransplant patients and 24 HCV‐negative nontransplant (healthy) subjects were analyzed. A 3‐h intravenous glucose tolerance test was performed; peripheral insulin sensitivity was assessed by minimal modeling. Pancreatic insulin secretion, hepatic insulin uptake, pancreatic antibodies and proinflammatory cytokines in serum (tumor necrosis factor‐α, intereukin‐6, high‐sensitive C‐reactive protein) were also assessed. HCV‐positive recipients showed a significantly lower insulin sensitivity as compared to HCV‐negative recipients (3.0 ± 2.1 vs. 4.9 ± 3.0 min^?1.μU.mL^{? 1}.10⁴, p = 0.02), however, insulin secretion and hepatic insulin uptake were not significantly different. Pancreatic antibodies were negative in all. HCV status was an independent predictor of impaired insulin sensitivity (multivariate analysis, p = 0.008). The decrease of insulin sensitivity due to HCV was comparable for transplant and non‐transplant subjects. No significant correlation was found between any of the cytokines and insulin sensitivity. Our results suggest that impaired peripheral insulin sensitivity is associated with HCV infection irrespective of the transplant status, and is the most likely pathogenic mechanism involved in the development of type 2 diabetes mellitus associated with HCV infection.     

Clonotype analysis of cytomegalovirus-specific cytotoxic T lymphocytes

Cytotoxic T lymphocytes (CTL) control the replication of human cytomegalovirus (CMV). Previous studies assessed the clonotypic composition of CTL specific for individual immunodominant peptides within a certain HLA context. Such an approach has inherent limitations and may not assess the true clonal CTL response in vivo. Here, the clonotypic composition of CMV-specific CTL was determined in HLA-A2, CMV-seropositive kidney transplant recipients and healthy blood donors after stimulation of peripheral blood mononuclear cells with either a pp65 whole-peptide pool or a single immunodominant peptide. Even after stimulation with the whole peptide pool, CMV-specific CTL remained monoclonal or oligoclonal. Regarding intraindividual variation, the CDR3 motifs of the dominant clones were identical to those observed in CTL generated by the single immunodominant peptide. Sequencing of the CDR3 regions demonstrated significant interindividual variation; however, structural homology was observed for immunodominant clonotypes in three individuals. In conclusion, the highly focused T cell receptor repertoire found after stimulation with either a single immunodominant peptide or a peptide pool demonstrates a pivotal role for immunodominant epitopes in the generation of a clonal repertoire. These results provide new insights into the regulation of CMV clonal dominance and may contribute to the design and monitoring of adoptive immunotherapy.     

Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma

The IMP (IGFII mRNA-binding protein) family comprises a group of three RNA-binding proteins involved in the regulation of cytoplasmic mRNA-fate. Recent studies identified IMP proteins as oncofetal factors in various neoplasias, but knowledge of a potential role in ovarian carcinomas is still lacking. The immunohistochemical analysis of 107 ovarian carcinomas, 30 serous borderline tumors of the ovary and five normal ovaries revealed de novo synthesis of IMP1 in 69% of ovarian carcinomas. Elevated IMP1 expression was observed preferentially in high-grade and high-stage cases and was a significant prognostic indicator for reduced recurrence-free and overall survival. Phenotypic studies in ovarian carcinoma-derived ES-2 cells demonstrated that IMP1 knockdown affects proliferation and cell survival. Reduced proliferation was associated with decreased c-myc mRNA half-life, suggesting IMP1 as an oncogenic factor that is involved in promoting elevated proliferation by stabilizing the c-myc mRNA in ovarian carcinoma cells.     

Enzymersatztherapie bei Morbus Fabry

Fabry disease is unique among the lysosomal storage disorders since two preparations (agalsidase alfa and beta) are available for enzyme replacement therapy (ERT). We report on a 14-year-old boy who showed infusion-related adverse events and behavioural problems when treated with agalsidase beta. Since the family considered discontinuation of ERT, therapy was switched to agalsidase alfa. This resulted in a prompt cessation of the adverse effects, demonstrating that a change-over from one preparation to the other may be a valuable option to prevent adverse effects and to secure acceptance of ERT.     

Immunization of liver and renal transplant recipients: a seroepidemiological and sociodemographic survey

Abstract: Several life‐threatening infections, a major risk to adult solid organ transplant (SOT) recipients on immunosuppressive therapy, can be prevented by immunization. We analyzed sociodemographic parameters and the immunization status of adult liver transplant recipients (LTX‐R, n=267) and renal transplant recipients (RTX‐R, n=197) SOT recipients at the Transplantation Center, Berlin, Germany. Date, number, and provider of recommended vaccines were recorded and seroprotection rates determined. The social status in both groups was similar. Most patients (89%) were not adequately informed about immunizations; and if informed, main sources were physicians (47%) and the media (40%). Vaccinations were predominantly provided by family doctors (LTX‐R, 66%; RTX‐R, 31%) or hemodialysis centers (RTX‐R, 37%). Before transplantation, RTX‐R had significantly more often received booster vaccinations against tetanus and diphtheria (P<0.005), and a primary hepatitis B immunization (55%); whereas in LTX‐R, post‐transplant vaccinations against hepatitis A (16%) and pneumococcal disease (13%) were more frequent. Seroprotection rates against tetanus were fairly high in LTX‐R (85.3%) and RTX‐R (86.8%), and considerably lower for diphtheria, hepatitis A, and influenza. Immunization rates are too low in SOT recipients. Improvement will depend on a more active role of health care providers.     

Concordant loss of melanoma differentiation antigens in synchronous and asynchronous melanoma metastases: implications for immunotherapy

Because of its known heterogeneity, the analysis of antigen expression is crucial prior to the initiation of antigen-specific immunotherapy for melanoma. The melanoma differentiation antigens gp100, MART-1 and tyrosinase are involved in a common pathway of melanin synthesis. Peptides derived from these melanoma differentiation antigens are used in the immunotherapy of melanoma and antibodies recognizing these antigens are commonly applied to detect melanocytic lesions. One hundred and ninety-one paraffin-embedded melanoma metastases from 28 patients with 2-19 lesions (mean, 6.8) developing synchronously (n = 67) or asynchronously (n = 124) were analysed by immunohistochemistry for the expression of the melanoma differentiation antigens, as well as cancer/testis antigens of the melanoma antigen-A (MAGE-A) family (monoclonal antibodies 77B and 57B), anti-S100 and SM5-1. The overall reactivities were 81.6% (gp100), 79.5% (MART-1), 59.6% (tyrosinase), 59.1% (77B), 60.7% (57B), 93.2% (S100) and 91.6% (SM5-1). Twenty-seven lesions (14.1%) were positive for all tumour-associated antigens, 75 lesions (39.2%) were negative for one antigen and 87 lesions (45.5%) were negative for several tumour-associated antigens. Co-ordinated loss was found for lesions negative for gp100 and MART-1 (9.4%, P < 0.0005), gp100 and tyrosinase (11.0%, P = 0.009), MART-1 and tyrosinase (15.2%, P < 0.0005) and gp100, MART-1 and tyrosinase (8.9%, P < 0.0005), which is up to six times higher than the expected calculated loss. This co-ordinated loss of melanoma differentiation antigens in melanoma did not include cancer testis antigens and S100 or SM5-1. On average, the melanoma differentiation antigens stained 50-65% of cells within a lesion, and 10-39% of synchronous clusters were heterogeneous for melanoma differentiation antigen expression. In conclusion, broader polypeptide vaccines should be used for melanoma immunotherapy.