title: Alloimmune injury and rejection of human skin grafts on human peripheral blood lymphocyte-reconstituted non-obese diabetic severe combined immunodeficient beta2-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) 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.
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachussetts 01605, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Turgeon
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Banuelos
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Lyons
authors.forename: Neal
authors.initials: N
authors.lastname: Iwakoshi
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rossini
authors.forename: Michael C
authors.initials: MC
authors.lastname: Appel
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection; D006086:Graft vs Host Disease; D006801:Humans; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016038:Skin Transplantation / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D001613:beta 2-Microglobulin / Q000235:genetics
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D015375:Receptors, Interleukin-2; D001613:beta 2-Microglobulin; D017493:Leukocyte Common Antigens