Molecules 2011, 16(5), 3969-3984; doi:10.3390/molecules16053969
Article

Consecutive Low Doses of Cyclosporine A Induce Pro-Inflammatory Cytokines and Accelerate Allograft Skin Rejection

Received: 24 February 2011; in revised form: 29 April 2011 / Accepted: 6 May 2011 / Published: 11 May 2011
(This article belongs to the collection Bioactive Compounds)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: Cyclosporine A (CsA) is a fungus-derived molecule with potent immunosuppressive activity that has been largely used to downregulate cell-mediated immune responses during transplantation. However, previous data have indicated that CsA shows immunomodulatory activity that relays on the antigen concentration and the dose of CsA used. To test the hypothesis that minimal doses of CsA may show different outcomes on grafts, we used an experimental model for skin transplants in mice. ICR outbred mice received skin allografts and were either treated daily with different doses of CsA or left untreated. Untreated mice showed allograft rejection within 14 days, with graft necrosis, infiltration of neutrophils and macrophages and displayed high percentages of CD8+ T cells in the spleens, which were associated with high serum levels of IL-12, IFN-g and TNF-α. As expected, mice treated with therapeutic doses of CsA (15 mg/kg) did not show allograft rejection within the follow-up period of 30 days and displayed the lowest levels of IL-12, IFN-g and TNF-α as well as a reduction in CD8+ lymphocytes. In contrast, mice treated with consecutive minimal doses of CsA (5 × 10−55 mg/kg) displayed an acute graft rejection as early as one to five days after skin allograft; they also displayed necrosis and strong inflammatory infiltration that was associated with high levels of IL-12, IFN-g and TNF-α. Moreover, the CD4+ CD25hiFoxP3+ subpopulation of cells in the spleens of these mice was significantly inhibited compared with animals that received the therapeutic treatment of CsA and those treated with placebo. Our data suggest that consecutive, minimal doses of CsA may affect Treg cells and may stimulate innate immunity.
Keywords: cyclosporine A; Treg; graft rejection
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MDPI and ACS Style

López-Flores, R.; Bojalil, R.; Benítez, J.C.; Ledesma-Soto, Y.; Terrazas, C.A.; Rodríguez-Sosa, M.; Terrazas, L.I. Consecutive Low Doses of Cyclosporine A Induce Pro-Inflammatory Cytokines and Accelerate Allograft Skin Rejection. Molecules 2011, 16, 3969-3984.

AMA Style

López-Flores R, Bojalil R, Benítez JC, Ledesma-Soto Y, Terrazas CA, Rodríguez-Sosa M, Terrazas LI. Consecutive Low Doses of Cyclosporine A Induce Pro-Inflammatory Cytokines and Accelerate Allograft Skin Rejection. Molecules. 2011; 16(5):3969-3984.

Chicago/Turabian Style

López-Flores, Roberto; Bojalil, Rafael; Benítez, José C.; Ledesma-Soto, Yadira; Terrazas, César A.; Rodríguez-Sosa, Miriam; Terrazas, Luis I. 2011. "Consecutive Low Doses of Cyclosporine A Induce Pro-Inflammatory Cytokines and Accelerate Allograft Skin Rejection." Molecules 16, no. 5: 3969-3984.

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