HUMAN CELL-MEDIATED REJECTION OF PORCINE XENOGRAFTS IN AN IMMUNODEFICIENT MOUSE MODEL

Background. In this study, we describe the development of a novel expe rimental system in which rejection of porcine skin grafts by human per ipheral blood cells can be studied directly in vivo in immunodeficient mice. Methods. To construct a small animal model of discordant xenogr aft rejection, recombinase-activating gene-deficient mice (R-) lacking both mature B and T cells were grafted with porcine skin grafts and a dministered, by adoptive cell transfer, human cells stimulated in vitr o with irradiated porcine peripheral blood cells to create Hu-R- mice. Results. R- mice accepted porcine skin grafts indefinitely without th e need for immunosuppression. In contrast, Hu-R- mice were able to rej ect porcine skin grafts. Immunohistochemical analysis of rejecting ski n grafts revealed the accumulation of human T cells around dermal porc ine vessels and focally in the epidermis. Graft rejection was manifest ed by vascular endothelial cell proliferation, edema at the dermal-epi dermal border, and perivascular hemorrhage. The tissue damage observed in the rejecting grafts was similar to that observed in delayed prima te anti-porcine cell-mediated rejection of vascularized organ xenograf ts. Conclusions. The development and characterization of a small anima l model, to study cellular immune responses of human cells to discorda nt xenografts in vivo, should provide a convenient means for asking me chanistic questions related to discordant xenotransplantation, and may also provide a practical system for testing new approaches designed t o prevent xenograft rejection.