The Signal Sequence of Lymphocytic Choriomeningitis Virus Contains an Immunodominant Cytotoxic T Cell Epitope That Is Restricted by both H-2Dband H-2KbMolecules

AbstractInfection of H-2bmice with lymphocytic choriomeningitis virus (LCMV) generates three well-characterized H-2Db-restricted immunodominant epitopes delineated in the NP, GP1, and GP2 proteins. Here we report that the H-2Db-restricted GP1 epitope GP33-41/43 (KAVYNFATC/GI) located in the signal sequence of LCMV is also the immunodominant epitope recognized by CTL at the surface of the same infected cells in the context of H-2Kbrestriction. The GP1 epitope bound to H-2Dband H-2Kbmolecules with comparable affinities. The respective binding processes involved different sets of peptide anchoring residues and required dramatically different conformations of the peptide backbone as well as rearrangement of residue side chains. The 10-mer peptide GP34-43 (AVYNFATCGI) was the optimal H-2Kb-binding sequence and the 8-mer peptide GP34-41 (AVYNFATC) the minimal sequence for optimal H-2Kb-restricted CTL recognition. Comparison of lytic activities of primary splenic anti-LCMV CTL from C57BL/6 (Db+/Kb+), B10A.[5R] (Db−/Kb+), and B10A.[2R] (Db+/Kb−) mice against LCMV-infected or peptide-coated target cells expressing either one or the two MHC alleles revealed that the H-2Kb-restricted component of the anti-GP1 CTL response was mounted independently of but as efficiently as its H-2Dbcounterpart. Analysis of the immune response against a GP1 variant that escapes CTL recognition showed that the GP1 epitope: (i) was likely the only immunodominant LCMV epitope in the context of H-2Kb, and (ii) could efficiently evade H-2Dband H-2Kb-restricted CTL mediated lysis

Measles Virus Recognizes Its Receptor, CD46, via Two Distinct Binding Domains within SCR1-2

AbstractMeasles virus (MV) enters cells by attachment of the viral hemagglutinin to the major cell surface receptor CD46 (membrane cofactor protein). CD46 is a transmembrane glycoprotein whose ectodomain is largely composed of four conserved modules called short consensus repeats (SCRs). We have previously shown that MV interacts with SCR1 and SCR2 of CD46. (M. Manchesteret al.(1995)Proc. Natl. Acad. Sci. USA92, 2303–2307) Here we report mapping the MV interaction with SCR1 and SCR2 of CD46 using a combination of peptide inhibition and mutagenesis studies. By testing a series of overlapping peptides corresponding to the 126 amino acid SCR1-2 region for inhibition of MV infection, two domains were identified that interacted with MV. One domain was found within SCR1 (amino acids 37–56) and another within SCR2 (amino acids 85–104). These results were confirmed by constructing chimeras with complementary regions from structurally similar, but non-MV-binding, SCRs of decay accelerating factor (DAF; CD55). These results indicate that MV contacts at least two distinct sites within SCR1-2

Melanoma Chemotherapy Leads to the Selection of ABCB5-Expressing Cells

Metastatic melanoma is the most aggressive skin cancer. Recently, phenotypically distinct subpopulations of tumor cells were identified. Among them, ABCB5-expressing cells were proposed to display an enhanced tumorigenicity with stem cell-like properties. In addition, ABCB5+ cells are thought to participate to chemoresistance through a potential efflux function of ABCB5. Nevertheless, the fate of these cells upon drugs that are used in melanoma chemotherapy remains to be clarified. Here we explored the effect of anti-melanoma treatments on the ABCB5-expressing cells. Using a melanoma xenograft model (WM266-4), we observed in vivo that ABCB5-expressing cells are enriched after a temozolomide treatment that induces a significant tumor regression. These results were further confirmed in a preliminary study conducted on clinical samples from patients that received dacarbazine. In vitro, we showed that ABCB5-expressing cells selectively survive when exposed to dacarbazine, the reference treatment of metastatic melanoma, but also to vemurafenib, a new inhibitor of the mutated kinase V600E BRAF and other various chemotherapeutic drugs. Our results show that anti-melanoma chemotherapy might participate to the chemoresistance acquisition by selecting tumor cell subpopulations expressing ABCB5. This is of particular importance in understanding the relapses observed after anti-melanoma treatments and reinforces the interest of ABCB5 and ABCB5-expressing cells as potential therapeutic targets in melanoma

Une Nouvelle génération d'analogues de l'antigène tumoral humain Melan-A/MART-1 (conception, propriétés fonctionnelles et perspectives d'utilisation en immunothérapie antitumorale)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Évaluation sur un modèle cellulaire d'hépatocarcinome d'extraits de plantes andino-amazoniennes sélectionnées à partir d'une démarche ethnopharmacologique

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Évaluation sur un modèle cellulaire d'hépatocarcinome d'extraits de plantes andino-amazoniennes sélectionnées à partir d'une démarche ethnopharmacologique

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Recherche exploratoire de substances actives en pharmacologie antitumorale à partir des Bryophytes

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

La prise en charge thérapeutique de la schizophrénie (problèmes d'observance, possibilités d'amélioration et rôle du pharmacien d'officine)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Troubles bipolaires et traitement par le lithium

La maladie maniaco-dépressive est une affection psychiatrique qui touche environ 1% de la population. Cette pathologie se caractérise par l'alternance de périodes d'excitation et de désarroi, entrecoupées de périodes de rémission pendant lesquelles le sujet est asymptomatique. Aucun traitement médicamenteux n'est en mesure à l'heure actuelle de guérir définitivement les patients. Les différents thymorégulateurs utilisés permettent de traiter les symptômes de la maladie. Parmi eux se trouve le lithium. Ce simple ion, première molécule utilisée dès 1960, est aujourd'hui encore le médicament le plus efficace pour stabiliser les patients, malgré sa simplicité chimique et structurale. Cependant, en raison d'une fourchette thérapeutique étroite et des nombreux effets indésirables potentiels, l'instauration d'une lithiothérapie ainsi que la surveillance du traitement doivent être très rigoureux.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF