Remission of polyomavirus-induced graft nephropathy treated with low-dose leflunomide.
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Adult↗
Biomedical subjects
Jochen Wilpert
Publications and source records attributed to Jochen Wilpert.
Gene profiling of polycystic kidneys.
BACKGROUND: While the genetic basis of autosomal dominant polycystic kidney disease (ADPKD) has been clearly established, the pathogenesis of renal failure in ADPKD remains elusive. Cyst formation originates from proliferating renal tubular epithelial cells that de-differentiate. Fluid secretion with cyst expansion and reactive changes in the extracellular matrix composition combined with increased apoptosis and proliferation rates have been implicated in cystogenesis. METHODS: To identify genes that characterize pathogenical changes in ADPKD, we compared the expression profiles of 12 ADPKD kidneys, 13 kidneys with chronic transplant nephropathy and 16 normal kidneys using a 7 k cDNA microarray. RT-PCR and immunohistochemical techniques were used to confirm the microarray data. RESULTS: Hierarchical clustering revealed that the gene expression profiles of normal, ADPKD and rejected kidneys were clearly distinct. A total of 87 genes were specifically regulated in ADPKD; 26 of these 87 genes were typical for smooth muscle, suggesting epithelial-to-myofibroblast transition (EMT) as a pathogenetic factor in ADPKD. Immunohistology revealed that smooth muscle actin, a typical marker for myofibroblast transition, and caldesmon were mainly expressed in the interstitium of ADPKD kidneys. In contrast, up-regulated keratin 19 and fibulin-1 were confined to cystic epithelia. CONCLUSION: Our results show that the end stage of ADPKD is associated with increased markers of EMT, suggesting that EMT contributes to the progressive loss of renal function in ADPKD.
Cluster Analysis↗
Host cell responses induced by hepatitis C virus binding.
Initiation of hepatitis C virus (HCV) infection is mediated by docking of the viral envelope to the hepatocyte cell surface membrane followed by entry of the virus into the host cell. Aiming to elucidate the impact of this interaction on host cell biology, we performed a genomic analysis of the host cell response following binding of HCV to cell surface proteins. As ligands for HCV-host cell surface interaction, we used recombinant envelope glycoproteins and HCV-like particles (HCV-LPs) recently shown to bind or enter hepatocytes and human hepatoma cells. Gene expression profiling of HepG2 hepatoma cells following binding of E1/E2, HCV-LPs, and liver tissue samples from HCV-infected individuals was performed using a 7.5-kd human cDNA microarray. Cellular binding of HCV-LPs to hepatoma cells resulted in differential expression of 565 out of 7,419 host cell genes. Examination of transcriptional changes revealed a broad and complex transcriptional program induced by ligand binding to target cells. Expression of several genes important for innate immune responses and lipid metabolism was significantly modulated by ligand-cell surface interaction. To assess the functional relevance and biological significance of these findings for viral infection in vivo, transcriptional changes were compared with gene expression profiles in liver tissue samples from HCV-infected patients or controls. Side-by-side analysis revealed that the expression of 27 genes was similarly altered following HCV-LP binding in hepatoma cells and viral infection in vivo. In conclusion, HCV binding results in a cascade of intracellular signals modulating target gene expression and contributing to host cell responses in vivo. Reprogramming of cellular gene expression induced by HCV-cell surface interaction may be part of the viral strategy to condition viral entry and replication and escape from innate host cell responses.
Antigens, Viral↗
ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a single center experience.
BACKGROUND: For years ABO-incompatible kidney transplantations were preferentially performed in Japanese centers. In order to overcome the increased risk of humoral rejections, patients were treated with multiple sessions of plasmapheresis, intensified immunosuppressive therapy and splenectomy before transplantation. Despite good long-term results regarding patient and organ survival rates, increased morbidity during the early post-transplant period prevented a broad application of this method. Recently, a new protocol including the anti-CD20-antibody (Ab) rituximab and blood group-specific immunoadsorption instead of splenectomy and plasmapheresis was published with excellent short-term results. METHODS: From April 2004 to September 2005, 11 patients were prepared for ABO-incompatible transplantation. All patients received 375 mg/m2 rituximab intravenous 3 to 4 weeks before transplantation. Immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and prednisone and was started at least 7 days before transplantation. Intravenous immunoglobulins (0.5 g/kg) were administered the day before transplantation. Immunoglobulin G (IgG)-anti-A or -B Ab titers before starting immunoadsorption treatment ranged between 1 : 4 and 1 : 1024. Immunoadsorption treatment was started in parallel with immunosuppressive medication and was continued until the anti-A or anti -B Ab titers (IgG and IgM) were lowered to the aimed pre-transplant threshold of <1 : 8. During the early postoperative period, additional immunoadsorption treatments were performed, if the titers increased again above 1 : 8 (days 0 to 7) or 1 : 16 (days 8 to 14), respectively. RESULTS: Transplantation could be conducted in eight of 11 patients (two females, six males, mean recipient age 52+/-11 yr). The mean follow-up was 7.0 months (range 4 to 17). The blood group constellation was A1 to 0 in four cases, A2 to 0 in two cases, B to A in one case, and A1 to B in another case, respectively. On average, each patient received seven immunoadsorption treatments. All transplants showed primary function and no humoral rejections occurred. Three of our 11 patients showed rapid increases of isoagglutinin titers after each immunoadsorption treatment and thus could not be transplanted. One patient died 4 months after transplantation with a functioning graft due to sepsis secondary to pseudomembranous enterocolitis. The mean creatinine value of the remaining seven patients now is 1.6 mg/dl. SUMMARY: The use of antigen-specific immunoadsorption and an immunosuppressive regimen consisting of a conventional triple immunosuppressive therapy has shown excellent short-term results. The immunoadsorption treatment using antigen-specific columns is highly effective and even patients with high isoagglutinin titers can be transplanted. This protocol is an option for end-stage renal disease patients who have no blood group-compatible donor.
ABO Blood-Group System↗
Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF-E2.
Summary The molecular aetiology of polycythaemia vera (PV) remains unknown and the differential diagnosis between PV and secondary erythrocytosis (SE) can be challenging. Gene expression profiling can identify candidates involved in the pathophysiology of PV and generate a molecular signature to aid in diagnosis. We thus performed cDNA microarray analysis on 40 PV and 12 SE patients. Two independent data sets were obtained: using a two-step training/validation design, a set of 64 genes (class predictors) was determined, which correctly discriminated PV from SE patients. Separately 253 genes were identified to be upregulated and 391 downregulated more than 1.5-fold in PV compared with healthy controls (P < 0.01). Of the genes overexpressed in PV, 27 contained Sp1 sites: we therefore propose that altered activity of Sp1-like transcription factors may contribute to the molecular aetiology of PV. One Sp1 target, the transcription factor NF-E2 [nuclear factor (erythroid-derived 2)], is overexpressed 2- to 40-fold in PV patients. In PV bone marrow, NF-E2 is overexpressed in megakaryocytes, erythroid and granulocytic precursors. It has been shown that overexpression of NF-E2 leads to the development of erythropoietin-independent erythroid colonies and that ectopic NF-E2 expression can reprogram monocytic cells towards erythroid and megakaryocytic differentiation. Transcription factor concentration may thus control lineage commitment. We therefore propose that elevated concentrations of NF-E2 in PV patients lead to an overproduction of erythroid and, in some patients, megakaryocytic cells/platelets. In this model, the level of NF-E2 overexpression determines both the severity of erythrocytosis and the concurrent presence or absence of thrombocytosis.
Blotting, Northern↗
Expression profiling on chronically rejected transplant kidneys.
BACKGROUND: Chronic transplant nephropathy remains a poorly defined inflammatory process that limits the survival rate of most renal transplants. We analyzed the gene profile of chronically rejected kidney transplants to identify candidate genes that characterize chronic transplant nephropathy. METHODS: To distinguish genes present in normal renal tissue or specific for end-stage renal failure, we compared the gene profiles of 13 chronically rejected kidney transplants with 16 normal kidneys and 12 end-stage polycystic kidneys using a 7K human cDNA microarray. After elimination of genes with signals close to background, 2190 genes were available for statistical analysis. RESULTS: More than 20% of the examined genes were significantly regulated when compared with the expression level of normal renal tissue (P<0.0003). Hierarchic clustering based on 571 genes differentiated normal and transplant tissue, and transplant and polycystic kidney tissue. Most of these genes encoded proteins involved in cellular metabolism, transport, signaling, transcriptional activation, adhesion, and the immune response. Notably, comprehensive gene profiling of chronically rejected kidneys revealed two distinct subsets of chronically rejected transplants. Neither clinical data nor histology could explain this genetic heterogeneity. CONCLUSIONS: Microarray analysis of rejected kidneys may help to define different entities of transplant nephropathy, reflecting the multifactorial cause of chronic rejection.
Adult↗