Redirecting T Cells to Ewing's Sarcoma Family of Tumors by a Chimeric NKG2D Receptor Expressed by Lentiviral Transduction or mRNA Transfection

We explored the possibility to target Ewing's sarcoma family of tumors (ESFT) by redirecting T cells. To this aim, we considered NKG2D-ligands (NKG2D-Ls) as possible target antigens. Detailed analysis of the expression of MICA, MICB, ULBP-1, -2, and -3 in fourteen ESFT cell lines revealed consistent expression of at least one NKG2D-L. Thus, for redirecting T cells, we fused a CD3ζ/CD28-derived signaling domain to the ectodomain of NKG2D, however, opposite transmembrane orientation of this signaling domain and NKG2D required inverse orientation fusion of either of them. We hypothesized that the particularly located C-terminus of the NKG2D ectodomain should allow reengineering of the membrane anchoring from a native N-terminal to an artificial C-terminal linkage. Indeed, the resulting chimeric NKG2D receptor (chNKG2D) was functional and efficiently mediated ESFT cell death triggered by activated T cells. Notably, ESFT cells with even low NKG2D-L expression were killed by CD8pos and also CD4pos cells. Both, mRNA transfection and lentiviral transduction resulted in high level surface expression of chNKG2D. However, upon target-cell recognition receptor surface levels were maintained by tranfected RNA only during the first couple of hours after transfection. Later, target-cell contact resulted in strong and irreversible receptor down-modulation, whereas lentivirally mediated expression of chNKG2D remained constant under these conditions. Together, our study defines NKG2D-Ls as targets for a CAR-mediated T cell based immunotherapy of ESFT. A comparison of two different methods of gene transfer reveals strong differences in the susceptibility to ligand-induced receptor down-modulation with possible implications for the applicability of RNA transfection

Polybios über pietas, religio und fides (zu Buch 6, Kap. 56). Griechische Theorie und römisches Selbstverständnis

Dörrie Heinrich. Polybios über pietas, religio und fides (zu Buch 6, Kap. 56). Griechische Theorie und römisches Selbstverständnis. In: Mélanges de philosophie, de littérature et d'histoire ancienne offerts à Pierre Boyancé. Rome : École Française de Rome, 1974. pp. 251-272. (Publications de l'École française de Rome, 22

La manifestation du logos dans la création. Quelques remarques à propos d’une contribution du platonicien Thrasyllos à la théorie des Idées

It is thanks to a quotation made by Porphyrus that we know the only philosophic statement made by Thrasyllos, a mathematician and astrologer from Tiberius. This precious fragment gives a clear indication of the philosophical standpoint of its author, who relates the doctrine of Ideas —in the Platonic sense— to an interpretation of the Stoic Logos, allowing himself to be guideb by Aristotelian logic. But Porphyrus suggests a bolder interpretation : he finds in the sentence, which he quotes for that very reason, the entire neoplatonic doctrine concerning the realisation of the logos as mediator of the transient.C’est grâce à une citation de Porphyre qu’on connaît la seule énonciation philosophique de Thrasyllos, mathématicien et astrologue de Tibère. Ce précieux fragment laisse deviner l’attitude philosophique de son auteur, qui rapproche la doctrine des Idées -comprises au sens platonicien- d’une interprétation du logos stoïcien, en se laissant guider par la logique aristotélicienne. Mais Porphyre propose une interprétation plus hardie : il trouve en effet dans la phrase, qu’il cite expressément pour cette raison, toute la doctrine néoplatonicienne touchant la réalisation du logos comme médiateur du transcendant.Dörrie Heinrich. La manifestation du logos dans la création. Quelques remarques à propos d’une contribution du platonicien Thrasyllos à la théorie des Idées. In: Cahiers de Fontenay, n°19-22, 1981. Néoplatonisme, mélanges offerts à Jean Trouillard. pp. 141-157