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.
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: Dana C Baiu; Ian R Marsh; Alexander E Boruch; Ankita Shahi; Saswati Bhattacharya; Justin J Jeffery; Qianqian Zhao; Lance T Hall; Jamey P Weichert; Bryan P Bednarz; Mario Otto Journal: J Nucl Med Date: 2017-07-26 Impact factor: 10.057
Authors: T Pearson; L D Shultz; J Lief; L Burzenski; B Gott; T Chase; O Foreman; A A Rossini; R Bottino; M Trucco; D L Greiner Journal: Diabetologia Date: 2008-06-19 Impact factor: 10.122
Authors: Michael A Brehm; Rita Bortell; Philip Diiorio; Jean Leif; Joseph Laning; Amy Cuthbert; Chaoxing Yang; Mary Herlihy; Lisa Burzenski; Bruce Gott; Oded Foreman; Alvin C Powers; Dale L Greiner; Leonard D Shultz Journal: Diabetes Date: 2010-06-22 Impact factor: 9.461
Authors: Michael A Brehm; Amy Cuthbert; Chaoxing Yang; David M Miller; Philip DiIorio; Joseph Laning; Lisa Burzenski; Bruce Gott; Oded Foreman; Anoop Kavirayani; Mary Herlihy; Aldo A Rossini; Leonard D Shultz; Dale L Greiner Journal: Clin Immunol Date: 2010-01-21 Impact factor: 3.969
Authors: Lisa J Giassi; Todd Pearson; Leonard D Shultz; Joseph Laning; Kristin Biber; Morey Kraus; Bruce A Woda; Madelyn R Schmidt; Robert T Woodland; Aldo A Rossini; Dale L Greiner Journal: Exp Biol Med (Maywood) Date: 2008-08