Regulation of human cell engraftment and development of EBV-related lymphoproliferative disorders in Hu-PBL-scid mice
Graduate School of Biomedical Sciences; Department of Medicine, Division of Diabetes; Department of Pediatrics; Department of Pathology
Medical Subject Headings
Adoptive Transfer; Animals; Antigen-Presenting Cells; Antigens, CD40; CD4-Positive T-Lymphocytes; CD40 Ligand; CD8-Positive T-Lymphocytes; Cell Division; Cell Line, Transformed; Clonal Anergy; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunity, Natural; Immunophenotyping; Interphase; Killer Cells, Natural; Leukocytes, Mononuclear; Ligands; Lymphocyte Activation; Lymphocyte Depletion; Lymphoproliferative Disorders; control; Membrane Glycoproteins; Mice; Mice, Inbred NOD; Mice, SCID; Peritoneal Cavity; Severe Combined Immunodeficiency; T-Lymphocytes; T-Lymphocytes, Cytotoxic
Life Sciences | Medicine and Health Sciences
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.
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Citation: J Immunol. 2000 Jul 1;165(1):518-27.
Journal of immunology (Baltimore, Md. : 1950)
Wagar, Eric J.; Cromwell, Mary A.; Shultz, Leonard D.; Woda, Bruce A.; Sullivan, John L.; Hesselton, RuthAnn M.; and Greiner, Dale L., "Regulation of human cell engraftment and development of EBV-related lymphoproliferative disorders in Hu-PBL-scid mice" (2000). GSBS Student Publications. 1322.