The allogeneic response to cultured human skin equivalent in the hu-PBL-SCID mouse model of skin rejection

Background Engineered tissues have been proposed for the treatment of a var iety of conditions including the partial or complete replacement of human o rgans. To determine the basis for the rejection of these tissues, we analyz ed the immune response to allogeneic human skin equivalent (NSE, also calle d Apligraf) in the humanized SCID mouse (hu-PBL-SCID). Methods. Two models of hu-PBL-SCID were used for these studies. In one mode l, human skin or HSE was transplanted onto humanized mice so that graft sur vival could be analyzed. In the other model, skin grafts were allowed to he al on naive mice before humanization. This model was used to analyze the im munologic response to the vascularized skin allograft, Humanization was per formed by adoptive transfer of human PBL into SCID mice by i.p. injection. Results. Both human foreskin and HSE successfully engrafted onto naive SCID mice and remained stable for more than 6 months. In contrast, human foresk in was rejected by 21 days posttransplant in hu-PBL-SCID, whereas HSE consi stently engrafted for more than 28 days. Treatment of HSE grafts with inter feron-gamma for 5 days to induce maximal MHC class II molecule expression b efore grafting failed to induce rejection. HSE also engrafted onto hu-PBL-S CID mice that were exposed to alloantigen by prior injection with interfero n-gamma-treated keratinocytes identical to those used to generate the HSE. In addition, we determined that humanization of SCID mice following engraft ment and vascularization of human foreskin resulted in marked CD3(+) T cell infiltrates and a lymphocyte-induced vasculitis. In contrast, the response in vascularized HSE was associated with minimal CD3(+) T cell infiltration in the absence of vasculitis or morphological features of rejection. Conclusion. These results support the use of HSE and other allogeneic engin eered tissues in humans provided that such tissues are limited in their ant igen presenting capabilities. In addition, our findings suggest a critical function for the donor endothelial cell in rejection.