Pulmonary cytokine responses associated with PEI-DNA aerosol gene therapy

被引:77
作者
Gautam, A [1 ]
Densmore, CL [1 ]
Waldrep, JC [1 ]
机构
[1] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA
关键词
aerosol; PEI; cationic lipids; TNF-alpha; IL-1; beta; gene therapy;
D O I
10.1038/sj.gt.3301369
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pulmonary gene therapy with nonviral vectors delivered by instillation or intravenously has typically been associated with co-induction of cytokine responses attributed to the CpG motifs in the bacterial plasmid Alternative delivery systems are being developed to circumvent the cytokine responses to the plasmid. Aerosol delivery of polyethylenimine-DNA (PEI-DNA) complexes leads to localized, high levels of transgene expression in the lungs. In this study we show that PEI-DNA aerosol delivery is also associated with induction of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) in the lung and bronchoalveolar lavage fluid (BALF). However, there is no increase in the serum levels of these cytokines. The levels of these cytokines peak at 5-8 h after aerosol exposure for lung tissue and at 24h for BALF. However, the levels detected are much fewer than those observed when PEI-DNA complexes, guanidinum-cholesterol: dioleoylphosphatldyl-ethanolamine liposome-DNA (BGTC:DOPE-DNA) complexes or 1,2-dioleoyl-sn-glycero-3-trimethylammonium-propane-cholesterol:DNA (DOTAP-Chol:DNA) complexes were delivered intravenously. Also, the lung cytokine levels were higher when BGTC:DOPE-DNA complexes were delivered by aerosol to the mice. Although the mechanism remains to be elucidated the data suggest that aerosol exposure to PEI-DNA complexes can achieve high levels of transgene expression in the lungs without inducing high levels of cytokine responses.
引用
收藏
页码:254 / 257
页数:4
相关论文
共 17 条
[1]  
Ballas ZK, 1996, J IMMUNOL, V157, P1840
[2]   Aerosol delivery of robust polyethyleneimine-DNA complexes for gene therapy and genetic immunization [J].
Densmore, CL ;
Orson, FM ;
Xu, B ;
Kinsey, BM ;
Waldrep, JC ;
Hua, P ;
Bhogal, B ;
Knight, V .
MOLECULAR THERAPY, 2000, 1 (02) :180-188
[3]  
Densmore CL, 1999, J GENE MED, V1, P251
[4]  
Freimark BD, 1998, J IMMUNOL, V160, P4580
[5]   Enhanced gene expression in mouse lung after PEI-DNA aerosol delivery [J].
Gautam, A ;
Densmore, CL ;
Xu, B ;
Waldrep, JC .
MOLECULAR THERAPY, 2000, 2 (01) :63-70
[6]   Inhibition of experimental lung metastasis by aerosol delivery of PEI-p53 complexes [J].
Gautam, A ;
Densmore, CL ;
Waldrep, JC .
MOLECULAR THERAPY, 2000, 2 (04) :318-323
[7]   Bacterial DNA induces murine interferon-gamma production by stimulation of interleukin-12 and tumor necrosis factor-alpha [J].
Halpern, MD ;
Kurlander, RJ ;
Pisetsky, DS .
CELLULAR IMMUNOLOGY, 1996, 167 (01) :72-78
[8]   CPG MOTIFS IN BACTERIAL-DNA TRIGGER DIRECT B-CELL ACTIVATION [J].
KRIEG, AM ;
YI, AK ;
MATSON, S ;
WALDSCHMIDT, TJ ;
BISHOP, GA ;
TEASDALE, R ;
KORETZKY, GA ;
KLINMAN, DM .
NATURE, 1995, 374 (6522) :546-549
[9]   Effect of immune response on gene transfer to the lung via systemic administration of cationic lipidic vectors [J].
Li, S ;
Wu, SP ;
Whitmore, M ;
Loeffert, EJ ;
Wang, L ;
Watkins, SC ;
Pitt, BR ;
Huang, L .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 1999, 276 (05) :L796-L804
[10]   In vivo gene transfer via intravenous administration of cationic lipid-protamine-DNA (LPD) complexes [J].
Li, S ;
Huang, L .
GENE THERAPY, 1997, 4 (09) :891-900