The Impact of Skin Type and Area on Skin Rejection in Limb Transplantation

Abstract

Atypical manifestation of skin rejection observed in a series of hand transplant recipients suggests that appearance and mechanisms of rejection may vary and depend on skin type and location. We herein characterize skin rejection and inflammation at 3 defined areas of a rat hind-limb allograft. Allograft skin was harvested at the thigh, dorsum and planta pedis on postoperative day 5 and analyzed for histopathology, T-cell composition and expression of cytokines associated with skin inflammation. Isografts and naïve animals served as controls. Histology of the allograft skin collected on day 5 showed a diffuse cell infiltrate in the dermis and at the dermal-epidermal interface in the thigh and dorsum, whereas in the planta pedis it was mainly located perivascularly in the dermis. At all areas, epidermal involvement such as apoptotic keratinocytes and infiltrating lymphocytes were observed. Isograft skin showed only very mild or no signs of inflammation at all 3 locations. No significant difference was observed in the proportion of skin infiltrating CD45+CD3+CD4+ T-cells and CD45+CD3+CD8+ T-cells between the 3 sampling areas. Significant differences in cytokine protein expression were observed between hair bearing (thigh, dorsum) and hairless (planta pedis) skin, but not between the thigh and the dorsum (both hair bearing). MCP-1, IL-4, and GRO-KC exhibited the greatest individual expression at both locations thigh and dorsum in comparison with planta pedis. Differences in histopathologic appearance and cytokine expression in skin suggest area-specific mechanisms of rejection in a limb allograft, which should be considered for assessment and treatment of rejection.

Keywords:

• cytokines/chemokines
• hand transplantation
• inflammatory cell infiltrate
• skin rejection
• skin types
• vascularized composite allotransplantation

Abbreviations:

• VCA, vascularized composite allotransplantation
• POD, postoperative day
• H&E, haematoxylin-eosin
• IL, interleukin
• MCP, monocyte chemotactic protein
• LEW, Lewis
• BN, Brown Norway
• IFN, interferon
• TNF, tumor necrosis factor
• GM-CSF, granulocyte-macrophage colony stimulating factor
• ANOVA, analysis of variance
• RM-ANOVA, repeated measure analysis of variance
• FDR, false discovery rate
• TH, thigh
• PP, planta pedis
• DO, dorsum

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.