TY  - JOUR
A1  - Chopra, Martin
A1  - Biehl, Marlene
A1  - Steinfatt, Tim
A1  - Brandl, Andreas
A1  - Kums, Juliane
A1  - Amich, Jorge
A1  - Vaeth, Martin
A1  - Kuen, Janina
A1  - Holtappels, Rafaela
A1  - Podlech, Jürgen
A1  - Mottok, Anja
A1  - Kraus, Sabrina
A1  - Jordán-Garotte, Ana-Laura
A1  - Bäuerlein, Carina A.
A1  - Brede, Christian
A1  - Ribechini, Eliana
A1  - Fick, Andrea
A1  - Seher, Axel
A1  - Polz, Johannes
A1  - Ottmueller, Katja J.
A1  - Baker, Jeannette
A1  - Nishikii, Hidekazu
A1  - Ritz, Miriam
A1  - Mattenheimer, Katharina
A1  - Schwinn, Stefanie
A1  - Winter, Thorsten
A1  - Schäfer, Viktoria
A1  - Krappmann, Sven
A1  - Einsele, Hermann
A1  - Müller, Thomas D.
A1  - Reddehase, Matthias J.
A1  - Lutz, Manfred B.
A1  - Männel, Daniela N.
A1  - Berberich-Siebelt, Friederike
A1  - Wajant, Harald
A1  - Beilhack, Andreas
T1  - Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion
JF  - Journal of Experimental Medicine
N2  - Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.
KW  - Tumor-necrosis-factor
KW  - Regulatory-cells
KW  - Bone marrow transplantantation
KW  - Graft-versus-leukemia
KW  - Rheumatoid arthritis
KW  - Autoimmune diseases
KW  - Factor receptor
KW  - Alpha therapy
KW  - Expression
KW  - Suppression
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187640
VL  - 213
IS  - 9
ER  - 
TY  - JOUR
A1  - Enjuanes, Anna
A1  - Fernandez, Veronica
A1  - Hernandez, Luis
A1  - Navarro, Alba
A1  - Bea, Silvia
A1  - Pinyol, Magda
A1  - Lopez-Guillermo, Armando
A1  - Rosenwald, Andreas
A1  - Ott, German
A1  - Campo, Elias
A1  - Jares, Pedro
T1  - Identification of Methylated Genes Associated with Aggressive Clinicopathological Features in Mantle Cell Lymphoma
JF  - PLoS ONE
N2  - Background: 

Mantle cell lymphoma (MCL) is genetically characterized by the t(11; 14)(q13; q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. 

Methodology/Principal Findings: 

To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n = 38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n = 25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9, HOXA9, AHR, NR2F2, and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. 

Conclusions: 

We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours.
KW  - Histone deacetylase inhibition
KW  - Genome wide analysis
KW  - Molecular pathogenesis
KW  - DNA hypermethylation
KW  - Breast-cancer
KW  - Lung-cancer
KW  - Promoter
KW  - Expression
KW  - Targets
KW  - Sox9
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140632
VL  - 6
IS  - 5
ER  -