Specific therapeutic immunosuppressant administration schedules alter the UVB induced cutaneous inflammatory response in Skh-1 hairless mice Free

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Background: Transplant recipients have a greatly increased incidence of non-melanoma skin cancers due to the immunosuppressive therapy needed to inhibit allograft rejection. Our laboratory has previously shown that drugs which decrease ultraviolet light B (UVB) induced inflammation can reduce skin tumor formation in the Skh-1 hairless mouse model. Thus, reducing skin inflammation can have beneficial effects. This study was designed to test the hypothesis that altering the treatment schedule of immunosuppressants would reduce the UVB induced cutaneous inflammatory response. We examined the effects of daily (D) vs. alternate-day (AD) ip administration of two clinically used immunosuppressants, Cyclosporine A (CsA) and Sirolimus (SRL). Methods: 30 female Skh-1 mice were randomly assigned to 5 treatment groups: Vehicle, 20mg/kg CsA daily (CsA-D), 40mg/kg CsA on alternate days (CsA-AD), 2mg/kg SRL daily (SRL-D), or 4mg/kg SRL on alternate days (SRL-AD). The mice were treated for a total of 9 days. On the 8^th day 3 mice from each group were irradiated with 2240 J/m² UVB. All mice were sacrificed on day 10 (48 hours after UVB treatment). The cutaneous inflammatory response was determined by measuring: skin thickness, myeloperoxidase (MPO) activity, dermal neutrophil number and the number of 8-hydroxy-guanine adduct positive (8OHG+) epidermal cells. Results: Consistent with previous findings in our laboratory, UVB caused a significant increase in skin thickness, MPO activity, dermal neutrophils, and 8OHG⁺ cells. Both UVB CsA-D and UVB CsA-AD treatments caused a ∼4 fold increase in the number of dermal neutrophils compared to UVB vehicle. Conversely only UVB CsA-D treatment caused a significant increase in MPO activity. We found that the number 8OHG⁺ cells increased in the epidermis of unirradiated mice that received either CsA-D or CsA-AD compared to vehicle. UVB irradiation did not further increase the number of 8OHG⁺ cells in CsA-treated mice. UVB SRL-D and UVB SRL-AD treatments were similar to vehicle in regard to MPO activity but showed a trend towards decreased skin thickness. UVB SRL-D treatment caused a ∼4 fold increase in dermal neutrophil numbers compared to UVB vehicle. This increase was not evident with UVB SRL-AD treatment. 8OHG⁺ cells were increased in unirradiated SRL-AD compared to both SRL-D treatment and vehicle, but there was no difference between the three groups following UVB treatment. Conclusions: The treatment schedule influences the impact of immunosuppressant therapy on UVB induced skin inflammation. Importantly, systemic CsA can increase reactive oxygen species induced DNA damage in the skin even without UVB exposure. Further studies are necessary to explore other treatment schedules and their effects on the cutaneous inflammatory response as well as the effects of these alternate treatment schedules on the host-graft interaction.