@phdthesis{RomerRoche2012,
  author    = {Romer Roche, Paula Sofia},
  title     = {Separation from self explains failure of circulating T-cells to respond to the CD28 superagonist TGN1412},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-74933},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Stimulatory or superagonistic (SA) CD28-specific monoclonal antibodies (mAbs) are potent polyclonal activators of regulatory T cells and have proven highly effective as treatment in a wide range of rodent models for autoimmune and inflammatory diseases. In these models, a preferential activation of regulatory T cells was observed by in vivo administration of CD28SA. In stark contrast, human volunteers receiving TGN1412, a humanized CD28-specific mAb, experienced a life-threatening cytokine release syndrome during the first-in-man trial. Preclinical tests employing human peripheral blood mononuclear cells (PBMC) failed to announce the rapid cytokine release measured in the human volunteers in response to TGN1412. The aim of this thesis project was to find an explanation of why standard PBMC assays failed to predict the unexpected TGN1412-induced "cytokine storm" observed in human volunteers. CD28 superagonists can activate T cells without T cell receptor (TCR) ligation. They do depend, however, on "tonic" TCR signals received by MHC scanning, signals that they amplify. PBMC do not receive these signals in the circulation. Short-term in vitro preculture of human PBMC at a high cell density (HDC) resulted in massive cytokine release during subsequent TGN1412 stimulation. Restoration of reactivity was cell-contact dependent, associated with TCR polarization and tyrosine-phosphorylation, and blocked by HLA-specific mAb. In HDC, both CD4 T cells and monocytes functionally mature in a mutually dependent fashion. However, only CD4 memory T-cells proliferate upon TGN1412 stimulation, and were identified as the main source of pro-inflammatory cytokines. Importantly, responses to other T-cell activating agents were also enhanced if PBMC were first allowed to interact under tissue-like conditions. A new in vitro protocol is provided that returns circulating T-cells to a tissue-like status where they respond to TGN1412 stimulation, and it might represent a more reliable preclinical in vitro test for both activating and inhibitory immunomodulatory drugs. Finally, the surprising observation was made that the IgG1 "sibling" of TGN1412, which is of the poorly Fc receptor-binding IgG4 isotype, has a much lower stimulatory activity. We could exclude steric hindrance as an explanation and provide evidence for removal of TGN1112 from the T-cell surface by trans-endocytosis.},
  subject      = {T-Lymphozyten-Rezeptor},
  language  = {en}
}
@article{ThiryScheerGoessens1988,
  author    = {Thiry, Marc and Scheer, Ulrich and Goessens, Guy},
  title     = {Localization of DNA within Ehrlich tumour cells nucleoli by immunoelectron microscopy},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-39327},
  year      = {1988},
  abstract  = {The distribution of DNA in Ehrlich tumour cell nucleoli was investigated by means of an immunocytochemical approach , involving a monoclonal antibody directed against double- and single-stranded DNA. Immunolabelling was performed . either before or after the embedding process. The postembedding labelling method allows better ultrastructural preservation than the preembedding labelling method. In particular, the various nucleolar components are well preserved and identifiable. In the nucleolus, labelling is particularly concentrated over the perinucleolar chromatin and over its intranucleolar invaginations, which penetrate the nucleolar body and often terminate at the fibrillar centres. In addition, aggregates of gold particles are found in the fibrillar centres, preferentially towards the peripheral regions. By contrast, the dense fibrillar component is completely devoid of labelling. The results seem to indicate that DNA containing the rDNA genes is located in the fibrillar centres, with a preference for the peripheral regions. This finding suggests that transcription of the rDNA genes should occur within the confines of the fibrillar centre, probably close to the boundary region of the surrounding dense fibrillar component. The results are discussed in the light of present knowledge of the functional organization of the nucleolus.},
  language  = {en}
}
@phdthesis{Bittner2007,
  author    = {Bittner, Thomas},
  title     = {Immunhistologische Analyse Chemokinrezeptor positiver Zellen in der humanen decidua basalis der Fr{\"u}hschwangerschaft},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-22852},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Das Ziel dieser Arbeit war, eine qualitative Darstellung des Verteilungsmusters von Chemokinrezeptoren in der Dezidua der Fr{\"u}hschwangerschaft. Ferner sollte eine morphologische Zuordnung positiver Zellen zu den einzelnen Populationen (Cytotrophoblasten CTB, Stromazellen, Leukozyten) stattfinden. Eine Reihe von 15 Deciduageweben aus legaler Abtreibung wurde lichtmikroskopisch untersucht. Hierzu wurde eine immunhistochemischen F{\"a}rbung verwendet mit monoklonalen Antik{\"o}rpern gegen folgende Antigene: CCR6, CCR7, CCR9,CXCR2,CXCR3, CXCR4 und Panzytokeratin Die gr{\"o}sste Anzahl von CXCR4 Rezeptoren zeigten Zytotrophoblasten an der Spitze von auswachsenden Zells{\"a}ulen der Plazenta und an der Oberfl{\"a}che der Dezidua. Im Gegensatz dazu waren die CTB an der Basis der Zells{\"a}ulen und in den tiefen Schichten der Dezidua deutlich schw{\"a}cher gef{\"a}rbt.. Diesem Rezeptor kommt wohl eine entscheidende Rolle bei der Chemotaxis, Zellproliferation und dem infiltrativen Wachstum zu. In den von uns gef{\"a}rbten Schnitten zeigte keine Population von Trophoblasten positive Anf{\"a}rbungen f{\"u}r CCR7. Das F{\"a}rbebild von CCR9 zeigte bei uns unerwartet eine Kernf{\"a}rbung der invasiven CTB. Es ließ sich eine sehr geringe Rezeptorausstattung der Lymphozyten feststellen.. CXCR 3 und CCR 6 jedoch zeigten in der Mehrzahl der F{\"a}lle positive Lymphozyten. Auffallend war, dass diese jedoch deutlich schw{\"a}cher f{\"a}rbten als die vergleichbaren Zellen in der positiv Kontrolle gef{\"a}rbte Tonsille. Die Dezidua in der Fr{\"u}hschwangerschaft scheint also durch das Herunterregulieren von Chemokinrezeptoren auf immunkompetenten Zellen ein Raum der Immuntoleranz zu sein.},
  language  = {de}
}
@phdthesis{Beyer2004,
  author    = {Beyer, Ines},
  title     = {Immunhistochemische Analyse der Expression des CFR-1/PAM-1-Rezeptors auf Karzinomen und deren Pr{\"a}kanzerosen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-13463},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2004},
  abstract  = {Die humane Hybridomatechnologie ist ein guter Ansatz um tumorspezifische humane monoklonale Antik{\"o}rper zu gewinnen. Der humane monoklonale IgM-Antik{\"o}rper PAM-1 wurde aus einem Patienten mit Magenkarzinom mit Hilfe der humanen Hybridomatechnik isoliert und bindet an eine neue, post-transkriptionell modifizierte Variante des CFR-1 Rezeptors. Dieser Rezeptor ist auf fast allen Karzinomen unabh{\"a}ngig von Lokalisation und Art exprimiert, aber nicht auf gesundem Gewebe. CFR-1/ PAM-1 ist auch auf Pr{\"a}kanzerosen nachgewiesen worden: Helicobacter pylori-assoziierte Gastritis, Dysplasie des Magens, Colitis ulcerosa assozierte Dysplasie und Kolonadenome, Barrettmetaplasie, -dysplasie des {\"O}sophagus, Plattenepitheldysplasie der Lunge und cervicale intraepitheliale Neoplasie I-III. Das auf pr{\"a}kanzer{\"o}s ver{\"a}nderte und maligne entartetet Zellen beschr{\"a}nkte Expressionsmuster des CFR-1/PAM-1 Rezeptors bietet interessante Angriffspunkte f{\"u}r weitere Forschungen.},
  language  = {de}
}
@article{DanhofRascheMottoketal.2021,
  author    = {Danhof, Sophia and Rasche, Leo and Mottok, Anja and Steinm{\"u}ller, Tabea and Zhou, Xiang and Schreder, Martin and Kilian, Teresa and Strifler, Susanne and Rosenwald, Andreas and Hudecek, Michael and Einsele, Hermann and Gerhard-Hartmann, Elena},
  title     = {Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns},
  series = {Annals of Hematology},
  volume    = {100},
  journal   = {Annals of Hematology},
  number    = {6},
  issn      = {1432-0584},
  doi       = {10.1007/s00277-021-04447-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266468},
  pages     = {1537-1546},
  year      = {2021},
  abstract  = {Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40\% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.},
  language  = {en}
}
@article{StijnisDijkmansBartetal.2015,
  author    = {Stijnis, Kees and Dijkmans, Anneke C. and Bart, Aldert and Brosens, Lodewijk A. A. and Muntau, Birgit and Schoen, Christoph and Barth, Thomas F. and van Gulik, Thomas and van Gool, Tom and Grobusch, Martin P. and Tappe, Dennis},
  title     = {Echinococcus vogeli in Immigrant from Suriname to the Netherlands},
  series = {Emerging Infectious Diseases},
  volume    = {21},
  journal   = {Emerging Infectious Diseases},
  number    = {3},
  doi       = {10.3201/eid2103.141205},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143953},
  pages     = {528-530},
  year      = {2015},
  language  = {en}
}
@phdthesis{Geis2005,
  author    = {Geis, Steffen},
  title     = {Die Rolle des Signalmolek{\"u}ls Ca 2+ in der Signaltransduktion der SC-1-induzierten Apoptose},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-17032},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {In der vorliegenden Arbeit wurde das Thema "Die Rolle des Signalmolek{\"u}ls Ca2+ in der Signaltransduktion der SC-1-induzierten Apoptose" anhand von immunhisto-chemischen, proteinbiochemischen und fluoreszenzmikroskopischen Methoden erarbeitet. Die SC-1-induzierte Apoptose stellt einen neuen intrinsischen, „death domain"-unabh{\"a}ngigen Signalweg in der Vermittlung des programmierten Zelltodes dar, der {\"u}ber die Bindung dieses Antik{\"o}rpers an CD55SC-1 ausgel{\"o}st wird. Dem Signalmolek{\"u}l Ca2+ galt besonderes Interesse bei der Charakterisierung der durch SC-1 ausgel{\"o}sten Signaltransduktion. Nach Aktivierung von CD55SC-1 durch SC-1 steigt das intrazellul{\"a}re Ca2+ um Faktor 2,7 an, stabilisiert sich danach auf dem 1,5fachen Ausgangsniveau. Dies hat keinerlei Einfluss auf die Ausf{\"u}hrung des Apoptoseprogramms, ist aber maßgeblich in das Expressionsverhalten involviert. Der Ca2+ - Einstrom ist somit nicht direkt in die Ausf{\"u}hrung der Apoptose beteiligt, durch die Hochregulation der Expression des Apoptoserezeptors verst{\"a}rkt es jedoch die Wahrscheinlichkeit der Tumorzelle, den programmierten Zelltod zu vollziehen, da durch die verst{\"a}rkte Expression dieses Apoptose-induzierenden Rezeptors auch die Wahrscheinlichkeit steigt, dass mehrere SC-1-Antik{\"o}rper binden k{\"o}nnen. Da die Quervernetzung mehrerer Rezeptoren mittels des SC-1-Antik{\"o}rpers in der Apoptoseinduktion von N{\"o}ten ist, stellt diese durch Ca2+ getriggerte {\"U}berexpression von CD55SC-1 einen essentiellen Bestandteil in der Exekution dieses Selbstmordprogrammes dar. Dieses Ergebnis gibt einen interessanten Einblick in den Signalweg der durch SC-1 induzierten Apoptose. Weiterf{\"u}hrende Experimente sind notwendig, um genauere Erkenntnisse dieser einzigartigen Form einer gewebespezifischen Apoptose zu erlangen.},
  language  = {de}
}