title: Regulation of human cell engraftment and development of EBV-related lymphoproliferative disorders in Hu-PBL-scid mice.
abstract: Human PBMC engraft in mice homozygous for the severe combined immunodeficiency (Prkdcscid) mutation (Hu-PBL-scid mice). Hu-PBL-NOD-scid mice generate 5- to 10-fold higher levels of human cells than do Hu-PBL-C.B-17-scid mice, and Hu-PBL-NOD-scid beta2-microglobulin-null (NOD-scid-B2mnull) mice support even higher levels of engraftment, particularly CD4+ T cells. The basis for increased engraftment of human PBMC and the functional capabilities of these cells in NOD-scid and NOD-scid-B2mnull mice are unknown. We now report that human cell proliferation in NOD-scid mice increased after in vivo depletion of NK cells. Human cell engraftment depended on CD4+ cells and required CD40-CD154 interaction, but engrafted CD4+ cells rapidly became nonresponsive to anti-CD3 Ab stimulation. Depletion of human CD8+ cells led to increased human CD4+ and CD20+ cell engraftment and increased levels of human Ig. We further document that Hu-PBL-NOD-scid mice are resistant to development of human EBV-related lymphoproliferative disorders. These disorders, however, develop rapidly following depletion of human CD8+ cells and are prevented by re-engraftment of CD8+ T cells. These data demonstrate that 1) murine NK cells regulate human cell engraftment in scid recipients; 2) human CD4+ cells are required for human CD8+ cell engraftment; and 3) once engrafted, human CD8+ cells regulate human CD4+ and CD20+ cell expansion, Ig levels, and outgrowth of EBV-related lymphoproliferative disorders. We propose that the Hu-PBL-NOD-scid model is suitable for the in vivo analysis of immunoregulatory interactions between human CD4+ and CD8+ cells.
authors.affiliation: Department of Medicine, Pediatric Immunology, and Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Wagar
authors.forename: M A
authors.initials: MA
authors.lastname: Cromwell
authors.forename: L D
authors.initials: LD
authors.lastname: Shultz
authors.forename: B A
authors.initials: BA
authors.lastname: Woda
authors.forename: J L
authors.initials: JL
authors.lastname: Sullivan
authors.forename: R M
authors.initials: RM
authors.lastname: Hesselton
authors.forename: D L
authors.initials: DL
authors.lastname: Greiner
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D017635:Clonal Anergy / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016130:Immunophenotyping; D007399:Interphase / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008212:Lymphocyte Depletion; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010529:Peritoneal Cavity / Q000473:pathology; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000637:transplantation
chemical_list: D019013:CD40 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand