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Immunosuppression with a Combination of Triptolide and Cyclosporin A in Rat Vascularized Groin Flap Allotransplantation

Liu, Fei M.D.; Luo, Xusong M.D., Ph.D.; Lan, Shenghui M.D., Ph.D.; Zhang, Xianrong Ph.D.; Wang, Shoubao M.D.; Yang, Jun M.D.; Levin, L. Scott M.D.

Plastic and Reconstructive Surgery: March 2013 - Volume 131 - Issue 3 - p 343e–350e
doi: 10.1097/PRS.0b013e31827c6daa
Experimental: Original Articles

Background: Triptolide is an immunosuppressive fraction purified from a Chinese medicinal plant. In an effort to develop a new immunosuppressive strategy for vascularized composite allotransplantation, the authors investigated the effects of combined treatment with cyclosporin A and triptolide on the survival of rat groin flap allotransplants.

Methods: Groin flap transplantation was performed from Brown Norway rats to Fischer 344 recipients, which were then treated with triptolide, cyclosporin A, or both. Flap biopsy specimens were harvested, stained, and submitted to histopathologic evaluation. Levels of CCR5, CCR7, CCL19, CCL21, and Foxp3 in spleen were examined by real-time polymerase chain reaction, and the percentage of CD4+CD25+ regulatory T cells was detected by flow cytometry.

Results: The mean survival time for allografts in recipients receiving triptolide and cyclosporin A was 57 ± 7.7 days compared with 20.5 ± 2.3 days for cyclosporin A alone, 23.3 ± 3.6 days for triptolide alone, and 7.8 ± 0.8 days for no treatment. Histologic examination also showed that inflammatory cell infiltration was reduced in grafts with combination treatment. Down-regulation of CCR5, CCR7, and CCL19 in the combination treatment was accompanied by increased expression of Foxp3. Flow cytometric analysis also revealed that the percentage of CD4+CD25+ regulatory T cells in the combination treatment was higher than in the monotherapy groups.

Conclusions: Combination therapy with triptolide and cyclosporin A substantially prolonged allograft survival, which means calcineurin inhibitor–related drug-toxicity may be alleviated and treatment cost reduced. This immunosuppressive effect is mediated by inhibition of dendritic cells maturation and the expansion of regulatory T cells.

Shanghai, People's Republic of China; and Philadelphia, Pa.

From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital; the Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania; and McKay Orthopaedic Laboratory, University of Pennsylvania.

Received for publication July 14, 2012; accepted September 28, 2012.

Presented at the 2012 Annual Meeting of the American Society for Reconstructive Microsurgery, in Las Vegas, Nevada, January 14 through 17, 2012.

The first two authors contribute equally to this work.

Disclosure: The authors have no financial interest in any of the products, devices, or drugs mentioned in this article.

Jun Yang, M.D.; 639 Zhi Zao Ju Road, Shanghai, People's Republic of China 200011,

©2013American Society of Plastic Surgeons