@article{BeyersdorfWernerWolfetal.2011,
  author    = {Beyersdorf, Niklas and Werner, Sandra and Wolf, Nelli and Herrmann, Thomas and Kerkau, Thomas},
  title     = {Characterization of a New Mouse Model for Peripheral T Cell Lymphoma in Humans},
  series = {PLoS One},
  volume    = {6},
  journal   = {PLoS One},
  number    = {12},
  doi       = {10.1371/journal.pone.0028546},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137946},
  pages     = {e28546},
  year      = {2011},
  abstract  = {Peripheral T cell lymphomas (PTCLs) are associated with a poor prognosis due to often advanced disease at the time of diagnosis and due to a lack of efficient therapeutic options. Therefore, appropriate animal models of PTCL are vital to improve clinical management of this disease. Here, we describe a monoclonal CD8\(^+\) CD4\(^-\) αβ T cell receptor Vβ2\(^+\) CD28\(^+\) T cell lymphoma line, termed T8-28. T8-28 cells were isolated from an un-manipulated adult BALB/c mouse housed under standard pathogen-free conditions. T8-28 cells induced terminal malignancy upon adoptive transfer into syngeneic BALB/c mice. Despite intracellular expression of the cytotoxic T cell differentiation marker granzyme B, T8-28 cells appeared to be defective with respect to cytotoxic activity as read-out in vitro. Among the protocols tested, only addition of interleukin 2 in vitro could partially compensate for the in vivo micro-milieu in promoting growth of the T8-28 lymphoma cells.},
  language  = {en}
}
@article{HarterHaukeHeitzetal.2017,
  author    = {Harter, Philipp and Hauke, Jan and Heitz, Florian and Reuss, Alexander and Kommoss, Stefan and Marm{\´e}, Frederik and Heimbach, Andr{\´e} and Prieske, Katharina and Richters, Lisa and Burges, Alexander and Neidhardt, Guido and de Gregorio, Nikolaus and El-Balat, Ahmed and Hilpert, Felix and Meier, Werner and Kimmig, Rainer and Kast, Karin and Sehouli, Jalid and Baumann, Klaus and Jackisch, Christian and Park-Simon, Tjoung-Won and Hanker, Lars and Kr{\"o}ber, Sandra and Pfisterer, Jacobus and Gevensleben, Heidrun and Schnelzer, Andreas and Dietrich, Dimo and Neunh{\"o}ffer, Tanja and Krockenberger, Mathias and Brucker, Sara Y. and N{\"u}rnberg, Peter and Thiele, Holger and Altm{\"u}ller, Janine and Lamla, Josefin and Elser, Gabriele and du Bois, Andreas and Hahnen, Eric and Schmutzler, Rita},
  title     = {Prevalence of deleterious germline variants in risk genes including \(BRCA1/2\) in consecutive ovarian cancer patients (AGO-TR-1)},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {10},
  doi       = {10.1371/journal.pone.0186043},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173553},
  year      = {2017},
  abstract  = {Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in \(BRCA1/2\) in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (\(ATM\), \(BRCA1\), \(BRCA2\), \(CDH1\), \(CHEK2\), \(MLH1\), \(MSH2\), \(MSH6\), \(NBN\), \(PMS2\), \(PTEN\), \(PALB2\), \(RAD51C\), \(RAD51D\), \(STK11\), \(TP53\)) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93) and 406 patients (77.6\%) had a high-grade serous ovarian cancer. In total, 27.9\% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4\% in the defined 16 risk genes. Deleterious variants were most prevalent in the \(BRCA1\) (15.5\%), \(BRCA2\) (5.5\%), \(RAD51C\) (2.5\%) and \(PALB2\) (1.1\%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in \(BRCA1/2\) (and in all 16 risk genes) in patients <60 years was 30.2\% (33.2\%) versus 10.6\% (18.9\%) in patients \(\geq\)60 years. Family history was positive in 43\% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6\% (36.0\%) versus 11.4\% (17.6\%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2\% (29.1\%) and 10.2\% (14.8\%), respectively. Testing only for \(BRCA1/2\) would miss in our series more than 5\% of the patients with a deleterious variant in established risk genes. Conclusions 26.4\% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10\% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to \(BRCA1/2\) seems to be not sufficient.},
  language  = {en}
}
@article{UriWernerLuehderetal.2017,
  author    = {Uri, Anna and Werner, Sandra and L{\"u}hder, Fred and H{\"u}nig, Thomas and Kerkau, Thomas and Beyersdorf, Niklas},
  title     = {Protection of mice from acute graft-versus-host disease requires CD28 co-stimulation on donor CD4\(^{+}\) Foxp3\(^{+}\) regulatory T Cells},
  series = {Frontiers in Immunology},
  volume    = {8},
  journal   = {Frontiers in Immunology},
  number    = {721},
  doi       = {10.3389/fimmu.2017.00721},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158469},
  year      = {2017},
  abstract  = {Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell plus T cell transplantation (allo-HSCT). In this study, we investigated the requirement for CD28 co-stimulation of donor CD4\(^{+}\) conventional (CD4\(^{+}\)CD25\(^{-}\)Foxp3\(^{-}\), Tconv) and regulatory (CD4\(^{+}\)CD25\(^{+}\)Foxp3\(^{+}\), Treg) T cells in aGvHD using tamoxifen-inducible CD28 knockout (iCD28KO) or wild-type (wt) littermates as donors of CD4\(^{+}\) Tconv and Treg. In the highly inflammatory C57BL/6 into BALB/c allo-HSCT transplantation model, CD28 depletion on donor CD4\(^{+}\) Tconv reduced clinical signs of aGvHD, but did not significantly prolong survival of the recipient mice. Selective depletion of CD28 on donor Treg did not abrogate protection of recipient mice from aGvHD until about day 20 after allo-HSCT. Later, however, the pool of CD28-depleted Treg drastically declined as compared to wt Treg. Consequently, only wt, but not CD28-deficient, Treg were able to continuously suppress aGvHD and induce long-term survival of the recipient mice. To our knowledge, this is the first study that specifically evaluates the impact of CD28 expression on donor Treg in aGvHD. Moreover, the delayed kinetics of aGvHD lethality after transplantation of iCD28KO Treg provides a novel animal model for similar disease courses found in patients after allo-HSCT.},
  language  = {en}
}
@article{BergfeldDasariWerneretal.2017,
  author    = {Bergfeld, Arne and Dasari, Prasad and Werner, Sandra and Hughes, Timothy R. and Song, Wen-Chao and Hortschansky, Peter and Brakhage, Axel A. and H{\"u}nig, Thomas and Zipfel, Peter F. and Beyersdorf, Niklas},
  title     = {Direct binding of the pH-regulated Protein 1 (Pra1) from Candida albicans inhibits cytokine secretion by mouse CD4\(^{+}\) T cells},
  series = {Frontiers in Microbiology},
  volume    = {8},
  journal   = {Frontiers in Microbiology},
  number    = {844},
  doi       = {10.3389/fmicb.2017.00844},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158274},
  year      = {2017},
  abstract  = {Opportunistic infections with the saprophytic yeast Candida albicans are a major cause of morbidity in immunocompromised patients. While the interaction of cells and molecules of innate immunity with C. albicans has been studied to great depth, comparatively little is known about the modulation of adaptive immunity by C. albicans. In particular, direct interaction of proteins secreted by C. albicans with CD4\(^{+}\) T cells has not been studied in detail. In a first screening approach, we identified the pH-regulated antigen 1 (Pra1) as a molecule capable of directly binding to mouse CD4\(^{+}\) T cells in vitro. Binding of Pra1 to the T cell surface was enhanced by extracellular Zn\(^{2+}\) ions which Pra1 is known to scavenge from the host in order to supply the fungus with Zn\(^{2+}\). In vitro stimulation assays using highly purified mouse CD4\(^{+}\) T cells showed that Pra1 increased proliferation of CD4\(^{+}\) T cells in the presence of plate-bound anti-CD3 monoclonal antibody. In contrast, secretion of effector cytokines such as IFNγ and TNF by CD4\(^{+}\) T cells upon anti-CD3/ anti-CD28 mAb as well as cognate antigen stimulation was reduced in the presence of Pra1. By secreting Pra1 C. albicans, thus, directly modulates and partially controls CD4\(^{+}\) T cell responses as shown in our in vitro assays.},
  language  = {en}
}
@article{BergesKerkauWerneretal.2016,
  author    = {Berges, Carsten and Kerkau, Thomas and Werner, Sandra and Wolf, Nelli and Winter, Nadine and H{\"u}nig, Thomas and Einsele, Hermann and Topp, Max S. and Beyersdorf, Niklas},
  title     = {Hsp90 inhibition ameliorates CD4\(^{+}\) T cell-mediated acute Graft versus Host disease in mice},
  series = {Immunity, Inflammation and Disease},
  volume    = {4},
  journal   = {Immunity, Inflammation and Disease},
  number    = {4},
  doi       = {10.1002/iid3.127},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168318},
  pages     = {463-473},
  year      = {2016},
  abstract  = {Introduction: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co-transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life-threatening complication. Methods: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4\(^{+}\) T cell transplantation with the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia-bearing mice after transplantation of allogeneic CD4\(^{+}\) and CD8\(^{+}\) T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4\(^{+}\) T cells with a relative resistance of CD4\(^{+}\) regulatory and CD8\(^{+}\) T cells toward Hsp90 inhibition. Conclusions: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.},
  language  = {en}
}