Alloimmune Injury and Rejection of Human Skin Grafts on Human Peripheral Blood Lymphocyte–Reconstituted Non-Obese Diabetic Severe Combined Immunodeficient β 2 -Microglobulin-Null Mice

Abstract

Small animal models with the capacity to support engraftment of a functional human immune system are needed to facilitate studies of human alloimmunity. In the present investigation, non-obese diabetic (NOD) severe combined immunodeficient (scid) β₂-microglobulin-null (B2m^null) mice engrafted with human peripheral blood lymphocytes (hu-PBL-NOD-sc/d B2m^null mice) were used as in vivo models for studying human skin allograft rejection. Hu-PBL-NOD-scid B2m^null mice were established by injection of human spleen cells or PBLs and transplanted with full-thickness allogeneic human skin. Human cell engraftment was enhanced by injection of anti-mouse CD122 antibody. The respective contributions of human CD4⁺ and CD8⁺ cells in allograft rejection were determined using depleting antibodies. Human skin grafts on unmanipulated NOD-scid B2m^null mice uniformly survived but on chimeric hu-PBL-NOD-scid B2m^null mice exhibited severe immune-mediated injury that often progressed to complete rejection. The alloaggressive hu-PBLs did not require prior in vitro sensitization to elicit targeted effector cell activity. Extensive mononuclear cell infiltration directed towards human-origin endothelium was associated with thrombosis and fibrin necrosis. No evidence of graft-versushost disease was detected. Either CD4⁺ or CD8⁺ T cells may mediate injury and alloimmune rejection of human skin grafts on hu-PBL-NOD-sc/d B2m^null mice. It is proposed that Hu-PBL-NOD-sc/d B2m^null mice engrafted with human skin will provide a useful model for analysis of interventions designed to modulate human allograft rejection.