JAX Notes January 01, 1999

An improved scid mouse for cancer and immunological research

Severe combined immune deficiency in the mouse is a result of a mutation in the protein kinase, DNA activated, catalytic polypeptide gene (Prkdcscid). The lack of functional T and B cells in these mice has made them useful for many experiments involving reconstitution of human hematopoietic cells. However, most inbred strains express normal levels of natural killer (NK) cells, hemolytic complement and myeloid function, precluding long term repopulation of homozygous scid mice with human cells. In addition, scid mutant mice on some background strains produce immunoglobulin and functional T-cells at low levels.

Mice homozygous for this mutation are available from The Jackson Laboratory as congenics on several different inbred strain backgrounds (C57BL/6J, BALB/cByJ, C3H/SmnJ and NOD/LtSz).

To develop a mouse stock with defective lymphoid function and nonadaptive immunologic function, the scid mutation was backcrossed to NOD/Lt for 10 generations. The NOD/Lt strain is characterized by a functional deficit in NK cells, absence of circulating complement and defects in the differentiation and function of APC's. Although NOD/Lt mice develop T cell mediated autoimmune, insulin-dependent diabetes mellitus, NOD/LtSz-scid mice remain insulitis and diabetes-free. However, because of the high incidence of thymic lymphomas, the mean lifespan of NOD/LtSz-scid mice is only 8.5 months under specific pathogen-free conditions.

The NOD/LtSz-scid has been used to successfully transplant a variety of normal and malignant human cell populations and tissues. Splenic engraftment of human CEM T-lymphoblastoid cells was four-fold greater in NOD/LtSz-scid mice than in the C.B-17/Sz-scid mice. Although C.B-17/Sz-scid mice exhibit robust NK cell activity, this activity is markedly reduced in NOD/LtSz-scid mice. The macrophage population in NOD/LtSz-scid is functionally less mature than in C.B-17/Sz-scid mice. Although C.B-17/Sz-scid and C57BL/6Sz-scid mice have elevated serum hemolytic complement activity compared with their respective wildtype controls, both NOD/LtSz-+/+ and NOD/LtSz-scid mice lack this activity. Age-dependent increases in serum Ig levels (>1 µg/ml) were observed in only 2 of 30 NOD/LtSz-scid mice vs. 21 of 29 C.B-17/Sz-scid animals. The multiple defects in innate and adaptive immunity unique to the NOD/LtSz-scid mouse provide an excellent in vivo environment for reconstitution with human hematopoietic cells. NOD/LtSz- Prkdcscid/J mice (stock # 001303) and the further improved model, NOD scid gamma mice (NSG, stock # 005557), are exclusively available from The Jackson Laboratory.

This article was adapted from:

Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL, Leiter, EH. 1995. Multiple Defects of Innate and Adaptive Immunologic Function in NOD/LtSz-scid Mice. J Immunol 154:180-191.

Defects in Innate Immunity

NOD/LtSz - scid C.B-17/Sz - scid

NK cell activity

Low

High

Complement activity

Absent

High

Macrophage development

Impaired

Normal

Anitgen presenting cell function

Impaired

Normal

Helpful Reading

Authors in bold indicate Jackson Laboratory scientists

Strain-dependent leakiness of the scid mutation

 Christianson SW, Greiner DL, Schweitzer IB, Gott B, Beamer GL, Schweitzer PA, Hesselton RM, Shultz LD. 1996. Role of natural killer cells on engraftment of human lymphoid cells and on metastasis of human Tlymphoblastoid leukemia cells in C57BL/6J-scid mice and in C57BL/6J-scid bg mice. Cell Immunol 171:186-199.

• Nonoyama S, Smith FO, Bernstein ID, Ochs HD. 1993. Strain-dependent leakiness of mice with severe combined immune deficiency. J Immunol 150:3817-24.

Transplantation experiments using NOD/LtSz-Prkdcscid

• Baersch G, Mollers T, Hotte A, Dockhorn-Dworniczak B, Rube C, Ritter J, Jurgens H, Vormoor J. 1997. Good engraftment of B-cell precursor ALL in NOD-SCID mice. Klin Padiatr 209:178-85.

• Greiner DL, Shultz, LD. 1998. The use of NOD/LtSzscid/scid mice in biomedical research. In: NOD Mice and Related Strains: Research Applications in Diabetes, AIDS, Cancer and Other Diseases, Leiter E, Atkinson M (eds), R. G. Landes Company, pp. 173-203.

• Greiner DL, Hesselton RA, Shultz LD. 1998. SCID mouse models of human stem cell engraftment. Stem Cells 16:166-177.

 Pelsue SC, Leif J, Rajan TV. 1995. Improved engraftment of human spleen cells in NOD/LtSz-scid/scid mice as compared with C.B-17-scid /scid mice. Am J Path 146: 888-902.

• Hogan CJ, Shpall EJ, McNulty O, McNiece I, Dick JE, Shultz LD, Keller G. 1997. Engraftment and Development of Human CD34+-Enriched Cells From Umbilical Cord Blood in NOD/LtSz-scid/scid Mice. Blood 90:85-96.

• Larochelle A, Vormoor J, Lapidot T, Sher G, Furukawa T, Li Q, Shultz LD, Olivieri NF, Stamatoyannopoulos G, Dick JE. 1995. Engraftment of immune-deficient mice with primitive hematopoietic cells from bthalassemia and sickle cell anemia patients: implications for evaluating human gene therapy protocols. Hum Mol Genet 4:163-172.

• Ramirez M, Rottman GA, Shultz LD, Civin CI. 1998. Mature human hematopoietic cells in donor bone marrow complicate interpretation of stem/progenitor cell assays in xenogeneic hematopoietic chimeras. Exp Hematol 26:332-44.

• Wang JC, Lapidot T, Cashman JD, Doedens M, Addy L, Sutherland DR, Nayar R, Laraya P, Minden M, Keating A, Eaves AC, Eaves CJ, Dick JE. 1998. High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 91:2406-14.

Another scid Model of Interest - NOD/LTSZ-Prkdcscid/J B2mtm1Unc

The Jackson Laboratory is establishing a production colony of NOD/LtSz-Prkdcscid/J B2mtm1Unc (Stock # 002570). This mouse was generated by backcrossing the Class I deficient B2m targeted mutation on to the NOD/LtSz-Prkdcscid strain. You can help us determine the most appropriate colony size by contacting Customer Service with your interest in this strain: tel:1-800-422-MICE or 207-288-5845; fax: 207-288-6150.

REFERENCE

Authors in bold indicate Jackson Laboratory scientists

Christianson SW, Greiner DL, Hesselton RA, Leif JH, Wagar EJ, Schweitzer IB, Rajan TV, Gott B, Roopenian DC, Shultz LD. 1997. Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice. J Immunol 158:3578-86.