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Transient depletion of specific immune cell populations to improve adenovirus‐mediated transgene expression in the liver
Author(s) -
Alzuguren Pilar,
HervasStubbs Sandra,
GonzalezAseguinolaza Gloria,
Poutou Joanna,
Fortes Puri,
Mancheno Uxua,
Bunuales Maria,
Olagüe Cristina,
Razquin Nerea,
Van Rooijen Nico,
Enguita Monica,
HernandezAlcoceba Ruben
Publication year - 2015
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12571
Subject(s) - immune system , transgene , cd8 , biology , lymphocyte , genetic enhancement , antibody , immunology , viral vector , systemic administration , in vivo , pharmacology , gene , biochemistry , microbiology and biotechnology , recombinant dna
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. Methods 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, CD 4 + , CD 8 + T lymphocytes or NK cells were depleted by intraperitoneal injection of anti‐M plus anti‐D, anti‐ CD 4, anti‐ CD 8 or anti‐asialo‐ GM 1 antibodies respectively. Long‐term evolution of luciferase expression in the liver was monitored by bioluminescence imaging. Results The anti‐ CD 4 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. Conclusions Transient CD 4 + 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.