Both authors contributed equally to this work.
Transient depletion of specific immune cell populations to improve adenovirus-mediated transgene expression in the liver
Article first published online: 9 MAY 2014
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 35, Issue 4, pages 1274–1289, April 2015
How to Cite
Liver Int. 2015; 35: 1274–1289
- Issue published online: 11 MAR 2015
- Article first published online: 9 MAY 2014
- Accepted manuscript online: 22 APR 2014 12:05PM EST
- Manuscript Accepted: 17 APR 2014
- Manuscript Received: 7 JUN 2013
- Spanish Department of Science. Grant Numbers: BIO2009/09295, SAF2009-08524, SAF2012-39578, SAF2012-40003, SAF2012-39504
- RNAREG. Grant Number: CSD2009-00080
- Fondo de Investigación Sanitaria. Grant Number: PI11/02327
- Fundación Barrié de la Maza
- Condesa de Fenosa
- UTE project CIMA
- MEC. Grant Number: RYC-2007-00928
- B cells;
- CD4+ T cells;
- CD8+ T cells;
- clodronate liposomes;
- Kupffer cells;
- monoclonal antibodies;
- neutralizing antibodies;
- NK cells
Background & Aims
Adenoviral (Ad) vectors are currently one of the most efficient tools for in vivo gene transfer to the liver. However, anti-Ad immune responses limit the safety and efficacy of these vectors. The initial inflammatory reaction is a concern in terms of toxicity, and it favours the development of cellular and humoral responses leading to short transgene persistence and inefficient vector re-administrations. Therefore, safe and simple ways to interfere with these processes are needed. Study ways to deplete specific immune cell populations and their impact on liver-directed gene transfer.
First-generation Ad vectors encoding reporter genes (luciferase or β-galactosidase) were injected intravenously into Balb/c mice. Kupffer cells and splenic macrophages were depleted by intravenous administration of clodronate liposomes. B lymphocytes, CD4+, CD8+ T lymphocytes or NK cells were depleted by intraperitoneal injection of anti-M plus anti-D, anti-CD4, anti-CD8 or anti-asialo-GM1 antibodies respectively. Long-term evolution of luciferase expression in the liver was monitored by bioluminescence imaging.
The anti-CD4 monoclonal antibody impaired cellular and humoral immune responses, leading to efficient vector re-administration. Clodronate liposomes had no impact on humoral responses but caused a 100–1000 fold increase in liver transduction, stabilized transgene expression, reduced the concentration of inflammatory cytokines, and inhibited lymphocyte activation.
Transient CD4+ T-cell depletion using antibodies is a clinically feasible procedure that allows efficient Ad redosing. Systemic administration of clodronate liposomes may further increase the safety and efficacy of vectors.