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Logo of transmedBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleJournal of Translational MedicineJournal Front Page
 
J Transl Med. 2011; 9(Suppl 2): P38.
Published online Nov 23, 2011. doi:  10.1186/1479-5876-9-S2-P38
PMCID: PMC3242266
Targeted delivery to inflammatory monocytes for efficient RNAi-mediated immuno-intervention in auto-immune arthritis
Jessy Présumey,#1,2 Gabriel Courties,#1,2 Louis-Marie Charbonnier,1,2 Virginie Escriou,3,4,5,6 Daniel Scherman,3,4,5,6 Yves-Marie Pers,1,2,7 Pascale Louis-Plence,1,2 Diego Kyburz,8 Steffen Gay,8 Christian Jorgensen,1,2,7 and Florence Apparaillycorresponding author1,2,7
1Inserm, U 844, CHU Saint Eloi University Hospital, Montpellier, France
2University of Medicine, Montpellier, France
3Inserm, U 1022, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France
4CNRS, UMR8151, Paris, France
5University of Pharmacy Paris Descartes, Laboratoire de Pharmacologie Chimique, Génétique et Imagerie, Paris, France
6Ecole Nationale Supérieure de Chimie de Paris, Paris, France
7CHU Lapeyronie University Hospital, Clinical Dept. for Osteoarticular Diseases, Montpellier, France
8Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology, Zurich, Switzerland
corresponding authorCorresponding author.
#Contributed equally.
Supplement
6th European Workshop on Immune-Mediated Inflammatory Diseases
Florence Apparailly, Dominique L Baeten, Christian Jorgensen, Timothy R D J Radstake and Ola Winqvist
Conference
6th European Workshop on Immune-Mediated Inflammatory Diseases
23-25 November 2011
Nice, France
 
Inflammatory mouse Ly6Chigh monocyte subset and its human counterpart, defined as CD14+ CD16-, represent a valuable cellular target for innovative immunotherapeutic strategies against immune-mediated inflammatory disorders (IMID). However, delivery systems able to differentially target both subsets in vivo are still missing as well as demonstration for efficient immuno-modulation. The present work aims at providing evidences for the selective delivery of a siRNA-containing lipid formulation to the Ly-6Chigh monocyte population and at evaluating the therapeutic potential of targeting this subset as well as their human counterpart for immuno-intervention in a prototype IMID like rheumatoid arthritis (RA). The pre-B-cell colony enhancing factor (PBEF/visfatin/Nampt) is an essential enzyme in the NAD biosynthetic pathway that exerts a key role in the persistence of inflammation through the induction of the expression of the TNF-α and IL-6 pro-inflammatory cytokines and is highly expressed in patients with a variety of IMID. Mice with collagen-induced arthritis (CIA) display Ly-6Chigh monocytosis in the circulation that infiltrate into the inflamed joints. The systemic delivery of siRNAs formulated with the cationic liposome DMAPAP provides specific and functional down-regulation of PBEF within inflammatory monocytes. Moreover, decreased production of the PBEF-induced pro-inflammatory cytokines TNF-α and IL-6 was evidenced in both mouse and human inflammatory monocytes. PBEF gene silencing within Ly-6Chigh monocytes resulted in reduced disease severity in mice with CIA, associated with an overall systemic immuno-modulation of the effector T cell balance. These results identify PBEF as a critical target to modulate autoimmune responses and inflammation in arthritis and provide novel evidence that silencing of a master gene within inflammatory monocytes is a promising strategy for future therapeutic intervention in the context of IMID.
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