Alloimmune injury and rejection of human skin grafts on human peripheral blood lymphocyte-reconstituted non-obese diabetic severe combined immunodeficient beta2-microglobulin-null mice
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Medicine, Diabetes Division; Department of Medicine, Division of Endocrinology and Metabolism
Medical Subject Headings
Animals; Antigens, CD3; Antigens, CD4; Antigens, CD45; Antigens, CD8; Female; Flow Cytometry; Graft Rejection; *Graft vs Host Disease; Humans; Immunohistochemistry; Leukocytes, Mononuclear; Lymphocytes; Male; Mice; Mice, Inbred NOD; Mice, SCID; Receptors, Interleukin-2; Skin Transplantation; Spleen; beta 2-Microglobulin
Life Sciences | Medicine and Health Sciences
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) beta2-microglobulin-null (B2mnull) mice engrafted with human peripheral blood lymphocytes (hu-PBL-NOD-scid B2mnull mice) were used as in vivo models for studying human skin allograft rejection. Hu-PBL-NOD-scid B2mnull 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 B2mnull mice uniformly survived but on chimeric hu-PBL-NOD-scid B2mnull 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-versus-host disease was detected. Either CD4+ or CD8+ T cells may mediate injury and alloimmune rejection of human skin grafts on hu-PBL-NOD-scid B2mnull mice. It is proposed that Hu-PBL-NOD-scid B2mnull mice engrafted with human skin will provide a useful model for analysis of interventions designed to modulate human allograft rejection.
Rights and Permissions
Citation: Exp Biol Med (Maywood). 2003 Oct;228(9):1096-104.