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Ex Vivo Transfer of Adenovirus-Mediated CTLA4Ig Gene Combined with a Short Course of Rapamycin Therapy Prolongs Free Flap Allograft Survival

Xiao, Bo M.D.; Xia, Wei M.D.; Zhao, Kefeng M.D.; Yang, Yang M.D.; Fu, Su M.D.; Li, Yang M.D.; Liu, Bei M.D.; Guo, Shuzhong M.D.

Plastic and Reconstructive Surgery: May 2011 - Volume 127 - Issue 5 - p 1820-1829
doi: 10.1097/PRS.0b013e31820cf264
Experimental: Original Articles

Background: Adenovirus-mediated cytotoxic T-lymphocyte–associated antigen-4 immunoglobulin (AdCTLA4Ig) gene transfer has been reported to enhance both organ and composite tissue grafts survival in rodent transplantation models. The authors tested the efficacy of local expression of CTLA4Ig gene on the survival of rat free flap allografts.

Methods: Brown Norway rat groin flaps were transplanted in Lewis rat recipients. The donor flaps were perfused ex vivo with AdCTLA4Ig via the afferent artery before transplantation. The distribution and duration of CTLA4Ig transgene expression in the flaps were assessed by immunohistochemical staining and semiquantitative reverse transcriptase polymerase chain reaction after transplantation. A mixed lymphocyte reaction was performed to test the antigen-specific immune response. Flow cytometry was used to detect the variations of CD4+25+Foxp3+ T cells in recipients' spleens.

Results: Immunohistochemical staining and reverse transcriptase polymerase chain reaction demonstrated expression of CTLA4Ig transgene in AdCTLA4Ig-perfused free flap allografts. AdCTLA4Ig-perfused free flap allografts survived significantly longer compared with survival of enhanced green fluorescent protein adenovirus–perfused free flap allografts. When combined with a short course of rapamycin, the survival time of AdCTLA4Ig-perfused free flap allografts was remarkably prolonged. The mixed lymphocyte reaction results indicate that ex vivo transfer of AdCTLA4Ig induces antigen-specific unresponsiveness. AdCTLA4Ig perfusion did not change the proportion of CD4+25+Foxp3+ T cells in recipients' spleens.

Conclusion: The authors demonstrated that a singular ex vivo perfusion of AdCTLA4Ig gene induced efficient transduction of the flaps and, when combined with a short course of rapamycin, promoted the remarkably longer survival of flap allografts.

Xi'an, China

From the Department of Plastic Surgery, Xijing Hospital, University of the Fourth Military Medical University.

Received for publication June 7, 2010; accepted November 8, 2010.

The first two authors contributed equally to this article.

Disclosure:None of the authors has any commercial associations or financial disclosures that might pose or create a conflict of interest with information presented in this article.

Shuzhong Guo, M.D., Department of Plastic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China,

©2011American Society of Plastic Surgeons