NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells
Graduate School of Biomedical Sciences; Department of Medicine, Division of Diabetes
Medical Subject Headings
*Adoptive Transfer; Aging; Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Erythrocyte Count; Female; Fetal Blood; Genes, RAG-1; HIV Infections; *Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins; Immunologic Deficiency; Syndromes; Immunophenotyping; Killer Cells, Natural; Leukocyte Count; Leukocytes, Mononuclear; Longevity; Lymphoid Tissue; Lymphoma; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Poly I-C; Radiation Tolerance; Spleen; T-Lymphocytes
Life Sciences | Medicine and Health Sciences
Development of a small animal model for the in vivo study of human immunity and infectious disease remains an important goal, particularly for investigations of HIV vaccine development. NOD/Lt mice homozygous for the severe combined immunodeficiency (Prkdcscid) mutation readily support engraftment with high levels of human hematolymphoid cells. However, NOD/LtSz-scid mice are highly radiosensitive, have short life spans, and a small number develop functional lymphocytes with age. To overcome these limitations, we have backcrossed the null allele of the recombination-activating gene (Rag1) for 10 generations onto the NOD/LtSz strain background. Mice deficient in RAG1 activity are unable to initiate V(D)J recombination in Ig and TCR genes and lack functional T and B lymphocytes. NOD/LtSz-Rag1null mice have an increased mean life span compared with NOD/LtSz-scid mice due to a later onset of lymphoma development, are radioresistant, and lack serum Ig throughout life. NOD/LtSz-Rag1null mice were devoid of mature T or B cells. Cytotoxic assays demonstrated low NK cell activity. NOD/LtSz-Rag1null mice supported high levels of engraftment with human lymphoid cells and human hemopoietic stem cells. The engrafted human T cells were readily infected with HIV. Finally, NOD/LtSz-Rag1null recipients of adoptively transferred spleen cells from diabetic NOD/Lt+/+ mice rapidly developed diabetes. These data demonstrate the advantages of NOD/LtSz-Rag1null mice as a radiation and lymphoma-resistant model for long-term analyses of engrafted human hematolymphoid cells or diabetogenic NOD lymphoid cells.
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Citation: J Immunol. 2000 Mar 1;164(5):2496-507.
Journal of immunology (Baltimore, Md. : 1950)
Shultz, Leonard D.; Lang, Pamela A.; Christianson, Sherri W.; Gott, Bruce; Lyons, Bonnie L.; Umeda, Syuji; Leiter, Edward H.; Hesselton, RuthAnn M.; Wagar, Eric J.; Leif, Jean H.; Kollet, Orit; Lapidot, Tsvee; and Greiner, Dale L., "NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells" (2000). GSBS Student Publications. 1113.