Mechanical Irritation in Vascularized Composite Tissue Allotransplantation Triggers Localized Skin Rejection

Background. Mechanical and thermal stress has been observed to trigger skin rejection in hand-transplanted patients. This study aims to investigate this phenomenon. Methods. Syngeneic and allogeneic orthotopic hindlimb transplantations were performed using male rats (Brown Norway to Lewis). Using a specially designed device, standardized mechanical skin irritation at a force of 5 N was applied to the planta pedis of the transplanted limb for 10 days, 4 times daily for 10 minutes. Biopsies, taken on day 10 and after a 5-day observational period, were assessed for macroscopic alterations using a standardized scale, by histopathology and immunohistochemistry, and for inflammatory protein expression using Luminex technology. Results. Allogeneic animals displayed significant aggravated macroscopic skin alterations compared with naive (P < 0.0001) and syngeneic controls (P = 0.0023). Histopathology showed a trend toward higher rejection/inflammation grades in allogeneic animals compared with syngeneic controls. Minor skin alterations in syngeneic limbs recovered quickly; however, in allogeneic limbs, macroscopic skin alterations were significantly more pronounced (P < 0.0001) 5 days after irritation. Interleukin-1b and interferon-gamma levels were upregulated in skin of allogeneic limbs. Conclusions. Mechanical skin irritation in vascularized composite allotransplantation can trigger localized skin inflammation consistent with rejection.