Skip Navigation

Cardiovascular Research 2006 69(1):289-297; doi:10.1016/j.cardiores.2005.07.021
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Izawa, A.
Right arrow Articles by Uede, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Izawa, A.
Right arrow Articles by Uede, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2005, European Society of Cardiology

Cre/loxP-mediated CTLA4IgG gene transfer induces clinically relevant immunosuppression via on–off gene recombination in vivo

Atsushi Izawaa, Kenji Sanob, Megumi Takeharac, Manabu Inobec, Jun-ichi Suzukid, Hiroshi Imamurae, Masafumi Takahashia, Uichi Ikedaa, Mitsuaki Isobed,* and Toshimitsu Uedec

aDepartment of Organ Regeneration, Shinshu University Graduate School of Medicine, Matsumoto, Japan
bDepartment of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
cDivision of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
dDepartment of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
eDivision of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan

* Corresponding author. Tel.: +81 3 5803 5951; fax: +81 3 5803 0238. Email address: isobemi.cvm{at}tmd.ac.jp

Objective: Transfer of the CTLA4IgG gene induces long-term and high levels of CTLA4IgG expression, which can result in generalized immunosuppression. In this study, we utilized Cre/loxP-mediated on–off switch recombination to eliminate transgene expression of CTLA4IgG following acceptance of murine cardiac allografts.

Methods: Fully MHC-mismatched hearts from BALB/c donor mice were transplanted into C3H/He recipient mice. Adenovirus-containing CTLA4IgG flanked between two loxP sites was administered via a recipient tail vein immediately after transplantation. Cre-recombinase gene was subsequently transferred at day 30 posttransplantation.

Results: Long-term allograft survival was observed in recipients that received the CTLA4IgG gene. Cre-mediated recombination reduced CTLA4IgG gene expression without any adverse effect on the graft survival. Secondary skin grafts of donor type and of third party were promptly rejected in the recipients that accepted cardiac allografts. In addition, the B cell response against ovalbumin was suppressed during high levels of serum CTLA4IgG, but recovered after Cre-mediated inactivation of CTLA4IgG gene.

Conclusion: CTLA4IgG gene transfer promoted long-term survival of murine cardiac allografts; however, this was not sufficient to induce tolerance. Cre/loxP-mediated on–off switch recombination was useful to inactivate the CTLA4IgG gene so that recipients' immune responses against neoantigens were restored without an influence on the allograft survival. This system may open novel strategies to orchestrate clinically relevant immunosuppression.

KEYWORDS CTLA4IgG; Transplantation; Gene therapy; Allograft rejection; Cre/loxP recombination

Time for primary review 25 days


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.