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
Authors
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
Greiner, Dale L.
UMass Chan Affiliations
Department of Medicine, Division of DiabetesGraduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2000-02-29Keywords
*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-LymphocytesLife Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
J Immunol. 2000 Mar 1;164(5):2496-507.
DOI
10.4049/jimmunol.164.5.2496Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32549PubMed ID
10679087Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.164.5.2496