title: NOD/LtSz-Rag1nullPfpnull mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment.
abstract: BACKGROUND
  A critical need exists for effective small-animal models that accept engraftment of human hematopoietic progenitor cells and mature lymphocytes. The purpose of this study was to determine the phenotypic effects of perforin (Pfp) deficiency on nonobese diabetic (NOD)-Rag1null mice and to evaluate the ability of NOD/LtSz-Rag1nullPfpnull recipients to support engraftment with human hematolymphoid cells.
  
  
  METHODS
  A new genetic stock of NOD mice doubly homozygous for targeted mutations at the recombination activating gene (Rag)-1 and Pfp genes was developed. NOD/LtSz-Rag1nullPfpnull mice were studied for immunopathologic and hematologic abnormalities. The ability of these mice to support engraftment with human peripheral blood mononuclear cells (PBMC) and umbilical-cord blood hematopoietic progenitor cells was assessed.
  
  
  RESULTS
  NOD/LtSz-Rag1nullPfpnull mice lacked mature B cells, T cells, natural killer (NK) cell cytotoxic activity and were devoid of serum immunoglobulin (Ig) throughout a 37-week lifespan. These mice supported heightened engraftment with human PBMC as compared with NOD/LtSz-Rag1null controls as evidenced by a 4- to 5-fold increase in percentages of human lymphocytes and a 7- to 13-fold increase in percentages of CD4+ T cells in the peripheral blood and spleen. Total numbers of human CD4+ T cells were increased approximately 20-fold in the spleens of NOD/LtSz-Rag1nullPfpnull mice. These mice also showed approximately 12-fold higher levels of engraftment with human umbilical-cord blood cells compared with NOD/LtSz-Rag1null mice.
  
  
  CONCLUSIONS
  NOD/LtSz-Rag1nullPfpnull mice are devoid of mature B cell, T cell, and NK cell cytotoxic activity, engraft at high levels with human PBMC, and hematopoietic progenitor cells and provide a new NK cell-deficient model for human hematolymphoid cell engraftment.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. lds@jax.org.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Scott
authors.initials: S
authors.lastname: Banuelos
authors.forename: Bonnie
authors.initials: B
authors.lastname: Lyons
authors.forename: Rebecca
authors.initials: R
authors.lastname: Samuels
authors.forename: Lisa
authors.initials: L
authors.lastname: Burzenski
authors.forename: Bruce
authors.initials: B
authors.lastname: Gott
authors.forename: Pamela
authors.initials: P
authors.lastname: Lang
authors.forename: Jean
authors.initials: J
authors.lastname: Leif
authors.forename: Michael
authors.initials: M
authors.lastname: Appel
authors.forename: Aldo
authors.initials: A
authors.lastname: Rossini
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001773:Blood Cells / Q000637:transplantation; D001947:Breeding; D003602:Cytotoxicity, Immunologic; D005312:Fetal Blood / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D007694:Killer Cells, Natural; D017708:Leukocyte Transfusion; D008136:Longevity; D008221:Lymphoid Tissue / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD / Q000378:metabolism*; D018345:Mice, Knockout / Q000235:genetics; D009000:Monocytes / Q000637:transplantation; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D013154:Spleen / Q000473:pathology / Q000503:physiopathology; D014916:Whole-Body Irradiation
chemical_list: D018398:Homeodomain Proteins; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C064658:RAG-1 protein