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Heidelberg, Germany

Mielcarek M.,Kings College London | Inuabasi L.,Kings College London | Bondulich M.K.,Kings College London | Muller T.,Kings College London | And 9 more authors.
PLoS Genetics

Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been described mainly as a neurological disease, multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. Given that huntingtin is ubiquitously expressed, cardiomyocytes may be at risk of an HD-related dysfunction. In mice, the forced expression of an expanded polyQ repeat under the control of a cardiac specific promoter led to severe heart failure followed by reduced lifespan. However the mechanism leading to cardiac dysfunction in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, which might be a part of dilatated cardiomyopathy (DCM). This was accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. To our surprise, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation, even at the end stage of disease. We postulate that the HD-related cardiomyopathy is caused by altered central autonomic pathways although the pathogenic effects of mutant HTT acting intrinsically in the heart may also be a contributing factor. © 2014 Mielcarek et al. Source

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Reiners K.S.,University of Cologne | Kessler J.,University of Cologne | Sauer M.,University of Cologne | Rothe A.,University of Cologne | And 7 more authors.
Molecular Therapy

Natural killer (NK) cells represent a key component of the innate immune system against cancer. Nevertheless, malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance. Hodgkin lymphoma (HL) is characterized by CD30 + tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. The latter obviously fail to eliminate the malignant cell population. Here, we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means. We demonstrate that peripheral NK cells (pNK) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A). It artificially links the tumor receptor CD30 with the cytotoxicity NK cell receptor CD16A. Moreover, we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells. These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically. © The American Society of Gene & Cell Therapy. Source

McAleese F.,Affimed Therapeutics | Eser M.,Affimed Therapeutics
Future Oncology

Tandem diabodies (TandAbs®) are tetravalent bispecific molecules comprised of antibody variable domains with two binding sites for each antigen. RECRUIT-TandAbs can simultaneously engage an immune system effector cell, such as a natural killer cell or a cytotoxic T cell, and an antigen expressed specifically on a cancer cell, thus leading to killing of the cancer cell. Recruitment of immune effector cells is highly specific and mediated via binding of the TandAb to molecules expressed on the surface of these cells. Furthermore, the absence of an Fc domain allows TandAbs to avoid certain IgG-mediated side effects. With a molecular weight of approximately 110 kDa, TandAbs are far above the first-pass renal clearance limit, offering a pharmacokinetic advantage compared with smaller bispecific antibody formats. This article reviews the RECRUIT-TandAb technology and the therapeutic potential of these molecules. © 2012 Future Medicine Ltd. Source

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.53M | Year: 2012

In the research part we will deal with the basic principles of the innate immune defense used to control tumors and viral infections with a focus on NK and NK/T cells, including analysis of NK receptor genomics/epigenetics, gene polymorphisms/disease linkage, differentiation of hitherto unrecognized NK cell subpopulations and novel ligands for NK receptors exposed by tumor and/or virally infected cells. We will investigate the mechanisms installed by tumors and viruses to avoid or subvert immune defenses. This will include the investigation of the role of NK/T cell subpopulations in the defense against tumors and infections by herpes virus family members, some being involved in tumor formation, in the development of inflammatory diseases and/or constituting a frequent complication during tumor therapy. The project will support anti-tumor and anti-viral therapies by developing novel technology for NK cell generation from cord blood stem cells for NK cell infusions in patients, by genetic engineering of NK cells and by using NK receptors and their ligands to develop novel reagents for amplifying anti-tumor and -viral activities of NK/T cells. It will further undertake basic studies on the potential of the newly emerging iPS cell technology for reconstituting immune systems including NK cells in patients with hematologic cancers. All students of this ITN will be trained in state-of-the-art immunotechnology including wider aspects of molecular medicine at the individual partner universities. An exchange of students between the different partners will be organized to ensure that every participant will be trained in several laboratories/universities with different expertise. It will further include network-wide training modules with cutting-edge lectures of internationally recognized research experts in the field, state-of-the-art seminars in the front-line technologies used in this project as well as courses in genome-wide bioinformatics, business and patent rights.

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