Characterization of factors involved in modulating persistence of transgene expression from recombinant adenovirus in the mouse lung

被引:99
作者
Kaplan, JM [1 ]
Armentano, D [1 ]
Sparer, TE [1 ]
Wynn, SG [1 ]
Peterson, PA [1 ]
Wadsworth, SC [1 ]
Couture, KK [1 ]
Pennington, SE [1 ]
StGeorge, JA [1 ]
Gooding, LR [1 ]
Smith, AE [1 ]
机构
[1] EMORY UNIV, SCH MED, DEPT MICROBIOL & IMMUNOL, ATLANTA, GA 30322 USA
基金
中国国家自然科学基金;
关键词
D O I
10.1089/hum.1997.8.1-45
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
One potential limitation of adenovirus (Ad)-based vectors for the gene therapy of cystic fibrosis (CF) and other genetic diseases is the transience of expression observed in most in vivo systems, In this study, the influence of various factors on persistence of transgene expression in the lung was investigated, In the absence of immune pressure, such as in the nude mouse, the genomic structure of the vector was found to be predominant in determining the persistence of expression; Ad vector constructs with an E1(-)E3(+)E40RF6(+) backbone encoding beta-galactosidase (beta-Gal) or the cystic fibrosis transmembrane conductance regulator (CFTR) produced declining levels of expression while an Ad/CMV beta Gal vector with an E1(-)E3(+)E4(+) backbone gave rise to sustained, long-term reporter gene expression, The ability of the latter vector to persist was in turn limited in part by the presence of cytotoxic T lymphocytes (CTLs), Adoptive transfer experiments indicated that CTLs directed against either viral proteins or the beta-Gal reporter gene product were able to reduce expression in nude C57BL/6 mice stably expressing beta-Gal from the E4(+) vector. Finally, the specificity and strength of the CTL response elicited by Ad vector was found to vary considerably depending on mouse strain haplotype, These results indicate that persistence of transgene expression in a given system is determined by the interplay between several factors including genomic structure of the vector, host background, and immune response.
引用
收藏
页码:45 / 56
页数:12
相关论文
共 44 条
[11]  
Fang B, 1996, GENE THER, V3, P217
[12]   EXPRESSION OF ALPHA(NU)BETA(5) INTEGRIN IS NECESSARY FOR EFFICIENT ADENOVIRUS-MEDIATED GENE-TRANSFER IN THE HUMAN AIRWAY [J].
GOLDMAN, MJ ;
WILSON, JM .
JOURNAL OF VIROLOGY, 1995, 69 (10) :5951-5958
[13]  
GOODING LR, 1977, J IMMUNOL, V118, P920
[14]  
GOODING LR, 1979, J IMMUNOL, V122, P1002
[15]   INEFFICIENT GENE-TRANSFER BY ADENOVIRUS VECTOR TO CYSTIC-FIBROSIS AIRWAY EPITHELIA OF MICE AND HUMANS [J].
GRUBB, BR ;
PICKLES, RJ ;
YE, H ;
YANKASKAS, JR ;
VICK, RN ;
ENGELHARDT, JF ;
WILSON, JM ;
JOHNSON, LG ;
BOUCHER, RC .
NATURE, 1994, 371 (6500) :802-806
[16]  
Kaplan JM, 1996, GENE THER, V3, P117
[17]   AEROSOL DELIVERY OF A BETA-GALACTOSIDASE ADENOVIRAL VECTOR TO THE LUNGS OF RODENTS [J].
KATKIN, JP ;
GILBERT, BE ;
LANGSTON, C ;
FRENCH, K ;
BEAUDET, AL .
HUMAN GENE THERAPY, 1995, 6 (08) :985-995
[18]   LONG-TERM HEPATIC ADENOVIRUS-MEDIATED GENE-EXPRESSION IN MICE FOLLOWING CTLA4LG ADMINISTRATION [J].
KAY, MA ;
HOLTERMAN, AX ;
MEUSE, L ;
GOWN, A ;
OCHS, HD ;
LINSLEY, PS ;
WILSON, CB .
NATURE GENETICS, 1995, 11 (02) :191-197
[19]   Use of transient CD4 lymphocyte depletion to prolong transgene expression of E1-deleted adenoviral vectors [J].
Kolls, JK ;
Lei, DH ;
Odom, G ;
Nelson, S ;
Summer, WR ;
Gerber, MA ;
Shellito, JE .
HUMAN GENE THERAPY, 1996, 7 (04) :489-497
[20]   EVALUATION OF THE EFFICACY AND SAFETY OF IN-VITRO, ADENOVIRUS-MEDIATED TRANSFER OF THE HUMAN CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR CDNA [J].
MITTEREDER, N ;
YEI, SP ;
BACHURSKI, C ;
CUPPOLETTI, J ;
WHITSETT, JA ;
TOLSTOSHEV, P ;
TRAPNELL, BC .
HUMAN GENE THERAPY, 1994, 5 (06) :717-729