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  • 1
    Language: English
    In: Human Pathology, September 2012, Vol.43(9), pp.1453-1462
    Description: The differential diagnosis of T cell-mediated rejection (TCMR) and BK-virus nephropathy (BKVN) in renal transplant biopsies is notoriously difficult. Therefore, attempts were made to differentiate between the two by characterizing the immune cell infiltrate. Using immunohistochemistry, the distribution of immune cell (sub)populations such as CD4 T helper (T ), T 1, T 2, CD8 cytotoxic T cells, regulatory T cells, B cells, plasma cells and follicular dendritic cells was determined in a total of 38 renal biopsy specimens. In addition, the expression of the HLA class I antigen presentation machinery (APM) components was investigated. In general, the frequency of T cells was higher than B cells, and T cells outnumbered cytotoxic T cells with a predominance of T 2 over T 1 cells. In BKVN, a significantly higher number of plasma cells was observed ( = .028), and interstitial fibrosis and tubular atrophy was more pronounced in BKVN ( = .007) compared to TCMR. The expression of components of the HLA class I APM was not affected by the infection with BK virus compared to TCMR. These findings indicate a T 2 shift in renal transplants in the context of alloreactive and virus-induced inflammation maybe as a consequence of immunosuppression, which usually targets T cell reaction. The predominance of plasma cells might underline an important role of humoral immunity in BKVN. Moreover, BK virus does not seem to modulate the expression of HLA class I APM as a strategy of immune evasion.
    Keywords: Bk-Virus Nephropathy ; HLA Class I ; Kidney ; T Cell Mediated Rejection ; Transplantation ; Medicine
    ISSN: 0046-8177
    E-ISSN: 1532-8392
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(12), p.e114345
    Description: The inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Here, we focussed on the role of macrophages (MΦ) and dendritic cells (DC).MΦ and DC infiltration was investigated in 106 cHL specimens using immunohistochemistry and cytokine expression was analyzed in a subset by real-time PCR. Human peripheral blood-derived monocytes, DC, MΦ stimulated with GM-CSF (MΦGM-CSF, pro-inflammatory MΦ-1-model) or M-CSF (MΦM-CSF, immunomodulatory MΦ-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). DC maturation or MΦ polarization were investigated by flow cytometry. Furthermore, the impact of DC or MΦ on cHL cell proliferation was analyzed by BrdU/CFSE assay.In cHL tissues mature myeloid (m)DC and MΦ predominated. High numbers of CD83+ mDC and low numbers of CD163+ MΦ were associated with improved disease specific survival. In numerous cHL specimens increased levels of both pro- and anti-inflammatory cytokines and of IL13 and GM-CSF were observed compared to reactive lymphadenopathies. Maturation of DC and induction and maintenance of an immunomodulatory MΦ phenotype were promoted by SN derived from cHL cell lines. TNFα neutralization in SN resulted in a significant inhibition of mDC maturation. DC and pro-inflammatory MΦ inhibited the proliferation of cHL cells.Adopting an immunomodulatory phenotype is a potential mechanism for how MΦ promote immune evasion in cHL. Mature DC, in contrast, might participate in antitumoral immunity.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    In: AIDS, 2013, Vol.27(13), pp.2031-2040
    Description: BACKGROUND:: Recently, a regression of precancerous lesions in HIV-1-infected patients after initiation of HAART was reported. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) as efavirenz (EFV) might be mediators of this effect, as they are known to have a cytotoxic effect on tumour cells. A potential mechanism involved in this effect may be the activation of the cannabinoid receptor to mediate tumour toxicity. METHODS:: Several tumour-derived and fibroblast cell lines were studied. Cytotoxicity of EFV was evaluated by Annexin-Pi staining. The expression of the cannabinoid receptors CB1, CB2 and GPR55 was analysed by western blot, quantitative reverse transcriptase (qRT-PCR) and fluorescence activated cell sorting. The influence of the cannabinoid agonists and antagonists on the effects of EFV was investigated. Furthermore, the effect of EFV on the phosphorylation state of the growth factors Erk, Akt and the tumour suppressor protein p53 was tested. RESULTS:: EFV revealed a selective cytotoxic effect on several tumour cell lines, whereas primary fibroblasts were not affected. The cytotoxic effect was associated with the expression of CB1. The combination of EFV with cannabinoid agonists showed an increase in toxicity. The phosphorylation state of Erk and Akt was not affected by EFV, whereas p53 showed an increased phosphorylation. CONCLUSION:: EFV has a selective cytotoxic effect on several tumour cells. Furthermore, EFV led to an activating phosphorylation of the tumour suppressor protein p53 going in line with earlier reports that EFV may be antitumourigenic and a potential cytostatic drug. The observed synergistic effect with cannabinoid agonists implicates an involvement of the cannabinoid system.
    Keywords: Efavirenz ; Western Blotting ; Non-Nucleoside Reverse Transcriptase Inhibitors ; Toxicity ; Antagonists ; Cancer ; P53 Protein ; Fibroblasts ; Flow Cytometry ; Extracellular Signal-Regulated Kinase ; Tumor Cell Lines ; Cytotoxicity ; Phosphorylation ; Highly Active Antiretroviral Therapy ; Cannabinoid Cb2 Receptors ; Akt Protein ; RNA-Directed DNA Polymerase ; Growth Factors ; Cannabinoid Cb1 Receptors ; Drugs ; Human Immunodeficiency Virus ; AIDS and HIV ; Cancer Immunology ; Cancer ; Cannabinoid ; Chemotherapy ; Efavirenz ; HIV ; Nonnucleoside Reverse Transcriptase Inhibitor;
    ISSN: 0269-9370
    E-ISSN: 14735571
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  • 4
    Language: English
    In: The Journal of clinical investigation, January 2014, Vol.124(1), pp.145-55
    Description: The renal disorder C3 glomerulopathy with dense deposit disease (C3G-DDD) pattern results from complement dysfunction and primarily affects children and young adults. There is no effective treatment, and patients often progress to end-stage renal failure. A small fraction of C3G-DDD cases linked to factor H or C3 gene mutations as well as autoantibodies have been reported. Here, we examined an index family with 2 patients with C3G-DDD and identified a chromosomal deletion in the complement factor H-related (CFHR) gene cluster. This deletion resulted in expression of a hybrid CFHR2-CFHR5 plasma protein. The recombinant hybrid protein stabilized the C3 convertase and reduced factor H-mediated convertase decay. One patient was refractory to plasma replacement and exchange therapy, as evidenced by the hybrid protein quickly returning to pretreatment plasma levels. Subsequently, complement inhibitors were tested on serum from the patient for their ability to block activity of CFHR2-CFHR5. Soluble CR1 restored defective C3 convertase regulation; however, neither eculizumab nor tagged compstatin had any effect. Our findings provide insight into the importance of CFHR proteins for C3 convertase regulation and identify a genetic variation in the CFHR gene cluster that promotes C3G-DDD. Monitoring copy number and sequence variations in the CFHR gene cluster in C3G-DDD and kidney patients with C3G-DDD variations will help guide treatment strategies.
    Keywords: Complement C3-C5 Convertases -- Metabolism ; Complement C3b Inactivator Proteins -- Genetics ; Complement System Proteins -- Genetics ; Glomerulonephritis, Membranoproliferative -- Blood ; Kidney Failure, Chronic -- Blood
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 5
    Language: English
    In: Urology, 2011, Vol.78(2), pp.427-430
    Description: A 12-year-old girl presented with recurrent gross hematuria over 3 months and regular findings in sonography of the urogenital tract. The first suspected diagnosis of familial IgA glomerulonephritis was excluded by kidney biopsy. After a further episode of gross hematuria leading to vesical tamponade, the patient received magnetic resonance imaging with angiography and urography, which was suspicious for a renal tumor. Consecutively, unilateral nephrectomy was performed and a nephroblastoma was diagnosed. This case demonstrates that even in grossly normal renal ultrasound, relapsing episodes of gross hematuria can be caused by renal tumor, and therefore in unclear situations, further diagnostic is necessary.
    Keywords: Medicine
    ISSN: 0090-4295
    E-ISSN: 1527-9995
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  • 6
    Language: English
    In: The Journal of infectious diseases, 15 January 2005, Vol.191(2), pp.238-42
    Description: Epstein-Barr virus (EBV) is transmitted through saliva, but the cellular source is controversial. Putative reservoirs include oral epithelium and salivary glands. Tongue mucosal samples, salivary glands, and tongue carcinomas were studied, by immunohistochemistry and in situ hybridization, for evidence of EBV infection. EBV replication was seen in 1.3% of tongue mucosal samples. No latent infection was found at this site. EBV infection was detected neither in normal salivary glands nor in tongue carcinomas. Thus, EBV replication occurs infrequently in tongue epithelial cells, and salivary glands are unlikely to harbor EBV. EBV is unlikely to be involved in the pathogenesis of tongue cancer.
    Keywords: Virus Replication ; Epithelium -- Virology ; Herpesvirus 4, Human -- Physiology ; Mucous Membrane -- Virology ; Salivary Glands -- Virology ; Tongue -- Cytology
    ISSN: 0022-1899
    E-ISSN: 15376613
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  • 7
    Language: English
    In: OncoImmunology, 01 September 2012, Vol.1(6), pp.982-983
    Description: The immune milieu in malignant tumors can influence the prognosis of patients. However, little is known about the effect the antitumoral therapy has on the inflammatory infiltrate. In head and neck squamous cell carcinoma we found evidence that a neoadjuvant radiochemotherapy could modulate...
    Keywords: Cytotoxic T-Cells ; Head and Neck Squamous Cell Carcinomas ; Radiochemotherapy ; Regulatory T Cells ; Biology
    ISSN: 21624011
    E-ISSN: 2162-402X
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  • 8
    Language: English
    In: PLoS ONE, Dec 3, 2014, Vol.9(12)
    Description: Background The inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Here, we focussed on the role of macrophages (M[PHI]) and dendritic cells (DC). Methods M[PHI] and DC infiltration was investigated in 106 cHL specimens using immunohistochemistry and cytokine expression was analyzed in a subset by real-time PCR. Human peripheral blood-derived monocytes, DC, M[PHI] stimulated with GM-CSF (M[PHI].sup.GM-CSF, pro-inflammatory M[PHI]-1-model) or M-CSF (M[PHI].sup.M-CSF, immunomodulatory M[PHI]-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). DC maturation or M[PHI] polarization were investigated by flow cytometry. Furthermore, the impact of DC or M[PHI] on cHL cell proliferation was analyzed by BrdU/CFSE assay. Results In cHL tissues mature myeloid (m)DC and M[PHI] predominated. High numbers of CD83+ mDC and low numbers of CD163+ M[PHI] were associated with improved disease specific survival. In numerous cHL specimens increased levels of both pro- and anti-inflammatory cytokines and of IL13 and GM-CSF were observed compared to reactive lymphadenopathies. Maturation of DC and induction and maintenance of an immunomodulatory M[PHI] phenotype were promoted by SN derived from cHL cell lines. TNF[alpha] neutralization in SN resulted in a significant inhibition of mDC maturation. DC and pro-inflammatory M[PHI] inhibited the proliferation of cHL cells. Conclusion Adopting an immunomodulatory phenotype is a potential mechanism for how M[PHI] promote immune evasion in cHL. Mature DC, in contrast, might participate in antitumoral immunity.
    Keywords: Macrophage Colony Stimulating Factor – Analysis ; Cytokines – Analysis ; Actors – Analysis ; Non-Hodgkin'S Lymphomas – Analysis ; Immune Response – Analysis ; Immunohistochemistry – Analysis ; Macrophages – Analysis ; Dendritic Cells – Analysis
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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  • 9
    Language: English
    In: International journal of cancer, 01 May 2011, Vol.128(9), pp.2085-95
    Description: Many tumor cells are characterized by a dysregulated glucose metabolism associated with increased glycolysis in the presence of oxygen ("Warburg Effect"). Here, we analyzed for the first time a possible link between glucose metabolism and immune cell infiltration in renal cell carcinoma (RCC). RCC specimens revealed a highly significant increase in the expression of lactate dehydrogenase A (LDHA) and glucose-transporter 1 (GLUT-1) compared to the corresponding normal kidney tissue on mRNA level. Accordingly, tumor cell lines of different origin such as RCC, melanoma and hepatocellular carcinoma strongly expressed LDHA and GLUT-1 compared to their nonmalignant counterparts. In line with this finding, tumor cells secreted high amounts of lactate. High expression of GLUT-1 and LDH5, a tetramer of 4 LDHA subunits, was confirmed by tissue microarray analysis of 249 RCC specimens. Overall, 55/79 (69.6%) and 46/71 (64.7%) cases of clear cell carcinoma showed a constitutive, but heterogeneous expression of GLUT-1 and LDH5, respectively. The number of CD3(+), CD8(+) and FOXP3(+) T cells was significantly elevated in RCC lesions compared to normal kidney epithelium, but effector molecules such as granzyme B and perforin were decreased in tumor infiltrating T cells. Of interest, further analysis revealed an inverse correlation between GLUT-1 expression and the number of CD8(+) T cells in RCC lesions. Together, our data suggest that an accelerated glucose metabolism in RCC tissue is associated with a low infiltration of CD8(+) effector T cells. Targeting the glucose metabolism may represent an interesting tool to improve the efficacy of specific immunotherapeutic approaches in RCC.
    Keywords: Cd8-Positive T-Lymphocytes -- Immunology ; Carcinoma, Renal Cell -- Immunology ; Glucose Transporter Type 1 -- Biosynthesis ; Kidney Neoplasms -- Immunology ; Lymphocytes, Tumor-Infiltrating -- Immunology
    E-ISSN: 1097-0215
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  • 10
    Language: German
    In: MMW Fortschritte der Medizin, 21 April 2011, Vol.153(16), pp.35-8
    Keywords: Incidental Findings ; Creatinine -- Blood ; Kidney Failure, Chronic -- Blood
    ISSN: 1438-3276
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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