Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation

Synthesis of a stable Radical Anion via the One Electron Reduction of a 1,1-Bis-Phosphinosulfide Alkene Derivative.

International audienc

Iron(III) chelation: Tuning of the pH dependence by mixed ligands

International audienceThe iron(III) chelating properties of two heteropodands with 8-hydroxyquinoline and catechol binding groups were examined and compared to those of the corresponding homopodal analogues, O-TRENSOX and TRENCAMS. Like the parent homopodands, the two heteropodands are based on the TREN scaffold and the chelating units are connected by amide groups, TRENSOX2CAMS having two 8-hydroxyquinoline and one catechol arms and TRENSOXCAMS2 one 8-hydroxyquinoline and two catechol moieties. The aqueous coordination chemistry of these ligands was examined by potentiometric and spectrophotometric methods in combination with 1H NMR spectroscopy. The respective pFeIII values showed a cooperative effect of the mixed chelating units. Moreover, the pFeIII dependence on pH showed that the mixed ligands exhibit a higher complexing ability than the parent ligands over the pH range 5-9 which is of biological relevance. This result could be of great interest for medical applications

Structural insights into the semiquinone form of human Cytochrome P450 reductase by DEER distance measurements between a native flavin and a spin labelled non-canonical amino acid

The flavoprotein Cytochrome P450 reductase (CPR) is the unique electron pathway from NADPH to Cytochrome P450 (CYPs). The conformational dynamics of human CPR in solution, which involves transitions from a "locked/closed" to an "unlocked/open" state, is crucial for electron transfer. To date, however, the factors guiding these changes remain unknown. By Site-Directed Spin Labelling coupled to Electron Paramagnetic Resonance spectroscopy, we have incorporated a non-canonical amino acid onto the flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) domains of soluble human CPR, and labelled it with a specific nitroxide spin probe. Taking advantage of the endogenous FMN cofactor, we successfully measured for the first time, the distance distribution by DEER between the semiquinone state FMNH• and the nitroxide. The DEER data revealed a salt concentration-dependent distance distribution, evidence of an "open" CPR conformation at high salt concentrations exceeding previous reports. We also conducted molecular dynamics simulations which unveiled a diverse ensemble of conformations for the “open” semiquinone state of the CPR at high salt concentration. This study unravels the conformational landscape of the one electron reduced state of CPR, which had never been studied before

Project CLIMA mooring F 1995 data analysis

Consiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7 Rome / CNR - Consiglio Nazionale delle RichercheSIGLEITItal