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Cyclosporin A inhibits DNA synthesis by epidermal Langerhans cells
M Haftek1, A Urabe, J Kanitakis
1Department of Dermatology, INSERM U.209, CNRS, Hôpital E. Herriot, Lyon, France.
Abstract:
Cyclosporin A, a potent immunosuppressive drug currently used in organ transplant recipients, has been shown to exert in vitro a direct antiproliferative effect on a number of cell types present in the skin, including keratinocytes, fibroblasts, and endothelial cells. Although in vitro studies suggest that cyclosporin A may interfere with the functional capacities of epidermal Langerhans cells, there is no evidence that the treatment influences the distribution or number of Langerhans cells in vivo. We used a model of normal human skin graft to "nude" mice, which is free of the human systemic control mechanisms, for studies on the DNA synthesis of human Langerhans cells under the influence of cyclosporin A. The grafted animals were given daily subcutaneous (50 mg/kg) or intraperitoneal (5, 12.5, and 25 mg/kg) drug injections during three weeks, which resulted in mean blood levels comparable to those observed in treated patients with organ transplants or psoriasis, respectively. BrdU administered during the last week of the experiment was incorporated by all cells synthesizing DNA, including those passing through S-phase. Langerhans cells were detected on deparaffinized or frozen tissue sections of xenografts with anti-CD1a and anti-HLA DR monoclonal antibodies, and the number of BrdU-positive cells was determined by double labeling. Our results indicate that the Langerhans cell DNA synthesis is impaired by therapeutic levels of cyclosporin A.
Insights
Therapeutic levels of Cyclosporin A impair DNA synthesis in human epidermal Langerhans cells. This immunosuppressive drug impacts skin cell function in vivo, affecting immune responses.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Cyclosporin A (CsA) is an immunosuppressant used in organ transplantation.
- In vitro studies suggest CsA affects skin cell proliferation, including Langerhans cells.
- In vivo effects of CsA on Langerhans cell number and function remain unclear.
Purpose of the Study:
- To investigate the in vivo effect of Cyclosporin A on human epidermal Langerhans cell DNA synthesis.
- To determine if therapeutic CsA levels impact Langerhans cell proliferation in a human skin xenograft model.
Main Methods:
- Human skin grafts on nude mice were treated with Cyclosporin A via subcutaneous or intraperitoneal injection for three weeks.
- Bromodeoxyuridine (BrdU) was administered to label cells undergoing DNA synthesis.
- Langerhans cells were identified using anti-CD1a and anti-HLA DR antibodies, and BrdU incorporation was quantified via double labeling.
Main Results:
- Therapeutic levels of Cyclosporin A were achieved in the grafted animals.
- Cyclosporin A significantly impaired DNA synthesis in human epidermal Langerhans cells within the xenografts.
- The drug's antiproliferative effect extended to Langerhans cells in vivo.
Conclusions:
- Cyclosporin A, at therapeutic concentrations, inhibits the DNA synthesis of human epidermal Langerhans cells in vivo.
- These findings suggest a direct impact of CsA on Langerhans cell function, potentially influencing skin immunity.
- Further research is warranted to understand the clinical implications of CsA-induced Langerhans cell suppression.