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.
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.
Shultz
L D
LD
The Jackson Laboratory, Bar Harbor, ME 04609, USA. lds@jax.org
Lang
P A
PA
Christianson
S W
SW
Gott
B
B
Lyons
B
B
Umeda
S
S
Leiter
E
E
Hesselton
R
R
Wagar
E J
EJ
Leif
J H
JH
Kollet
O
O
Lapidot
T
T
Greiner
D L
DL
D019264:Adoptive Transfer / Q000379:methods; D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004906:Erythrocyte Count; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D016654:Genes, RAG-1 / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D008136:Longevity; D008221:Lymphoid Tissue / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011070:Poly I-C / Q000494:pharmacology; D011836:Radiation Tolerance / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D013601:T-Lymphocytes / Q000637:transplantation*
D007136:Immunoglobulins; D011070:Poly I-C