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.
Document Type
Article
Publication Date
2000
Keywords
Aging, Animal, Diabetes-Mellitus-Insulin-Dependent, Disease-Models-Animal, Erythrocyte-Count, Female, Fetal-Blood, Genes-RAG-1, Hematopoietic-Stem-Cell-Transplantation, Human, HIV-Infections, Immunoglobulins, Immunologic-Deficiency, 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, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, T-Lymphocytes
First Page
2496
Last Page
2507
JAX Source
J Immunol 2000 Mar; 164(5):2496-2507.
Grant
AI30389/AI/NIAID, DK57199/DK/NIDDK, DK32520/DK/NIDDK
Abstract
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.
Recommended Citation
Shultz LD,
Lang PA,
Christianson SW,
Gott B,
Lyons B,
Umeda S,
Leiter E,
Hesselton R,
Wagar EJ,
Leif JH,
Kollet O,
Lapidot T,
Greiner DL.
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. J Immunol 2000 Mar; 164(5):2496-2507.