Volume 9 Supplement 2

6th European Workshop on Immune-Mediated Inflammatory Diseases

Open Access

Targeted delivery to inflammatory monocytes for efficient RNAi-mediated immuno-intervention in auto-immune arthritis

  • Jessy Présumey1, 2,
  • Gabriel Courties1, 2,
  • Louis-Marie Charbonnier1, 2,
  • Virginie Escriou3, 4, 5, 6,
  • Daniel Scherman3, 4, 5, 6,
  • Yves-Marie Pers1, 2, 7,
  • Pascale Louis-Plence1, 2,
  • Diego Kyburz8,
  • Steffen Gay8,
  • Christian Jorgensen1, 2, 7 and
  • Florence Apparailly1, 2, 7
Contributed equally
Journal of Translational Medicine20119(Suppl 2):P38

https://doi.org/10.1186/1479-5876-9-S2-P38

Published: 23 November 2011

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.

Notes

Authors’ Affiliations

(1)
Inserm, U 844, CHU Saint Eloi University Hospital
(2)
University of Medicine
(3)
Inserm, U 1022, UFR des Sciences Pharmaceutiques et Biologiques
(4)
CNRS, UMR8151
(5)
Laboratoire de Pharmacologie Chimique, University of Pharmacy Paris Descartes
(6)
Ecole Nationale Supérieure de Chimie de Paris
(7)
Clinical Dept. for Osteoarticular Diseases, CHU Lapeyronie University Hospital
(8)
Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology

Copyright

© Présumey et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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