*Purpose: “Atypical” forms of skin rejection have been described in some hand transplanted patients mainly manifesting on the palm including dryness, scaling and thickening of the palmar skin after experiencing mechanical or thermal stress. The aim of the study is to investigate skin irritation and its effect on skin rejection after limb transplantation in rodents.

*Methods: Syngeneic and allogeneic orthotopic hind limb transplantations have been performed using male Lewis and Brown-Norway rats. Immunosuppression consisted of anti-lymphocyte serum (ALS, 0.5ml) and tacrolimus, which was individually tapered (final dose of 0.1-0.2mg/kg/day). Mechanical skin irritation was applied to the planta pedis of the transplanted limb using a mechanical irritation device. Irritation was performed for 10 days, four times/day for 10 minutes applying 5 Newton force. Skin biopsies were taken immediately after the last stimulation and after a five days’ observational period. Samples were assessed histopathologically and protein expression was measured using luminex technology.

*Results: Allogeneic transplanted + irritated animals displayed significant aggravated macroscopic skin alterations compared to naïve irritated (p<0.0001) and syngeneic transplanted + irritated controls (p= 0.0023). Overall, histopathology showed a trend towards higher rejection/inflammation grades in allogeneic irritated animals than in syngeneic (mean rejection grade 2.3±0.95 vs. 1.7±0.81; ns.). After 10 days of irritation, minor skin alterations in syngeneic transplanted animals recovered quickly, however, in allogeneic transplanted animals macroscopic features were more pronounced (p<0.0001) and improved only little over the following five days without irritation. In allogeneic transplanted + irritated animals IL-1b and INF-y levels were insignificantly up-regulated compared to irritated controls.

*Conclusions: Standardized mechanical skin irritation in vascularized composite allotransplantation can trigger localized skin alterations consistent with rejection. Our findings hence indicate that disproportionate external stimuli are able to trigger alloimmune activation and thus localized “atypical” rejection in this setting.

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