Best practices in mouse models of skin transplantation

The murine skin transplant model has been used for decades as a sensitive in vivo model in which to dissect mechanistic aspects of alloreactivity. Indeed, seminal work defining the nature of alloreactivity was accomplished in the murine skin graft model. In the modern era, the incorporation of genetically altered animals, pharmacologic manipulation, and multiomics approaches in the murine skin graft model has significantly increased the mechanistic insight that can be gleaned from these studies. Because skin grafts are not primarily vascularized, the immune response against them is dominated by a CD8⁺ T cell response, with a lesser but important contribution of alloreactive CD4⁺ T cells. In contrast, donor-reactive antibody plays a lesser role in mediating skin transplant rejection. Importantly, the results of pharmacologic inhibition of T cell-directed novel targets for immunosuppression in transplantation in the murine skin graft model have largely reflected the results subsequently obtained in nonhuman primate renal transplant studies, demonstrating the physiologic relevance of the model. In this minireview, we further discuss the relative benefits and limitations of murine skin transplantation as a model of alloreactivity.