Prolonged cardiac allograft survival in rats systemically injected adenoviral vectors containing CTLA4Ig-gene

被引:47
作者
Kita, Y
Li, XK
Ohba, M
Funeshima, N
Enosawa, S
Tamura, A
Suzuki, K
Amemiya, H
Hayashi, S
Kazui, T
Suzuki, S
机构
[1] Natl Childrens Med Res Ctr, Dept Expt Surg & Bioengn, Setagaya Ku, Tokyo 1548509, Japan
[2] Hamamatsu Univ Sch Med, Dept Surg 1, Hamamatsu, Shizuoka 43131, Japan
[3] Nagoya Univ, Sch Med, Dept Surg 2, Nagoya, Aichi, Japan
关键词
D O I
10.1097/00007890-199909270-00007
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background CTLA4Ig, a soluble recombinant fusion protein that contains the extracellular domain of the CTLA4 and Fc portion of IgG1, strongly adheres to the B7 molecule to block CD28-mediated costimulatory signals and inhibits in vitro and in vivo immune responses, In vivo gene transfer using adenovirus vector achieves a high transfection rate into organ cells that usually contain adenoviral receptors, In this study, we investigated expression levels of the transfected gene and the survival times of the allografts in cardiac recipients systemically administered adenoviral vectors containing CTLA4Ig. Methods. Hearts from DA rats (RT-1(a)) were transplanted into a cervical location in LEW recipients (RT-1(1)), The adenoviral vectors containing CTLA4Ig was injected via a recipient rein immediately after grafting, Results. The serum level of CTLA4Ig reached to maximum at 51-93 mu g/ml 3 to 7 days after gene-transfection and declined after 14 days, although detectable levels were observed up to 49 days. The median survival time of the allografts in the gene-transfected group were significantly prolonged (27 days) in compared to the control group (6 days). In addition, down-regulation of IL-2 and IFN-gamma mRNAs and persistence of IL-4 and TL-10 transcripts were observed in the graft infiltrating cells. Conclusion. The adenovirous-mediated CTLA4Ig gene transfer into a recipient liver by systemic administration resulted in remarkable prolongation of cardiac allograft survival. Its action mechanisms may be mediated by inhibition of CD28-associated signal transduction, reduction of Th1-type cytokine production, and continuous expression of Th2 type cytokines in the activating lymphocytes.
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页码:758 / 766
页数:9
相关论文
共 59 条
[51]   A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation [J].
Suzuki, S ;
Enosawa, S ;
Kakefuda, T ;
Shinomiya, T ;
Amari, M ;
Naoe, S ;
Hoshino, Y ;
Chiba, K .
TRANSPLANTATION, 1996, 61 (02) :200-205
[52]   T-CELL ACTIVATION BY THE CD28 LIGAND-B7 IS REQUIRED FOR CARDIAC ALLOGRAFT-REJECTION INVIVO [J].
TURKA, LA ;
LINSLEY, PS ;
LIN, H ;
BRADY, W ;
LEIDEN, JM ;
WEI, RQ ;
GIBSON, ML ;
ZHENG, XG ;
MYRDAL, S ;
GORDON, D ;
BAILEY, T ;
BOLLING, SF ;
THOMPSON, CB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (22) :11102-11105
[53]   CTLA-4 ligation blocks CD28-dependent T cell activation [J].
Walunas, TL ;
Bakker, CY ;
Bluestone, JA .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 183 (06) :2541-2550
[54]   Blockade of multiple costimulatory receptors induces hyporesponsiveness - Inhibition of CD2 plus CD28 pathways [J].
Woodward, JE ;
Qin, LH ;
Chavin, KD ;
Lin, JX ;
Tono, T ;
Ding, YZ ;
Linsley, PS ;
Bromberg, JS ;
Baliga, P .
TRANSPLANTATION, 1996, 62 (07) :1011-1018
[55]   CYTOKINE GENE-EXPRESSION IN REJECTING CARDIAC ALLOGRAFTS [J].
WU, CJ ;
LOVETT, M ;
WONGLEE, J ;
MOELLER, F ;
KITAMURA, M ;
GORALSKI, TJ ;
BILLINGHAM, ME ;
STARNES, VA ;
CLAYBERGER, C .
TRANSPLANTATION, 1992, 54 (02) :326-332
[56]   A MAJOR COSTIMULATORY MOLECULE ON ANTIGEN-PRESENTING CELLS, CTLA4 LIGAND-A, IS DISTINCT FROM B7 [J].
WU, Y ;
GUO, Y ;
LIU, Y .
JOURNAL OF EXPERIMENTAL MEDICINE, 1993, 178 (05) :1789-1793
[57]   INACTIVATION OF E2A IN RECOMBINANT ADENOVIRUSES IMPROVES THE PROSPECT FOR GENE-THERAPY IN CYSTIC-FIBROSIS [J].
YANG, YP ;
NUNES, FA ;
BERENCSI, K ;
GONCZOL, E ;
ENGELHARDT, JF ;
WILSON, JM .
NATURE GENETICS, 1994, 7 (03) :362-369
[58]   CELLULAR-IMMUNITY TO VIRAL-ANTIGENS LIMITS E1-DELETED ADENOVIRUSES FOR GENE-THERAPY [J].
YANG, YP ;
NUNES, FA ;
BERENCSI, K ;
FURTH, EE ;
GONCZOL, E ;
WILSON, JM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) :4407-4411
[59]   MHC CLASS I-RESTRICTED CYTOTOXIC T-LYMPHOCYTES TO VIRAL-ANTIGENS DESTROY HEPATOCYTES IN MICE INFECTED WITH E1-DELETED RECOMBINANT ADENOVIRUSES [J].
YANG, YP ;
ERTL, HCJ ;
WILSON, JM .
IMMUNITY, 1994, 1 (05) :433-442