SCID Mice and SCIDHuman Mice Are a Valuable Animal Model for Immunodeficiency

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An autosomal recessive mutation resulting in severe combined immunodeficiency disease (SCID) developed spontaneously in a strain of mice called CB-17. These CB-17 SCID mice fail to develop mature T and B cells and consequently are severely compromised immunologically. This defect is due to a failure in V(D)J recombination. SCID mice must be housed in a sterile (germ-free) environment, because they cannot fight off microorganisms of even low pathogenicity. The absence of functional T and B cells enables these mice to accept foreign cells and grafts from other strains of mice or even from other species.

Apart from their lack of functional T and B cells, SCID mice appear to be normal in all respects. When normal bone-marrow cells are injected into SCID mice, normal T and B cells develop, and the mice are cured of their immunodeficiency. This finding has made SCID mice a valuable model system for the study of immunodeficiency and the process of differentiation of bone-marrow stem cells into mature T or B cells.

Interest in SCID mice mushroomed when it was found that they could be used to study the human immune system. In this system, portions of human fetal liver, adult thymus,

TABLE 23-2l Some inbred mouse strains commonly used in immunology

Strain Common substrains Characteristics

A A/He High incidence of mammary tumors in some substrains

A/WySn

AKR AKR/J High incidence of leukemia

AKR/N

AKR/Cum Thy 1.2 allele in AKR/Cum, and Thy 1.1 allele in other substrains (Thy gene encodes a T-cell surface protein)

BALB/c BALB/cy Sensitivity to radiation

BALB/c AnN Used in hybridoma technology

BALB/cBy Many myeloma cell lines were generated in these mice

CBA CBA/J Gene (rd) causing retinal degeneration in CBA/J

CBA/H

CBA/N Gene (xid) causing X-linked immunodeficiency in CBA/N

C3H C3H/He Gene (rd) causing retinal degeneration

C3H/HeJ High incidence of mammary tumors in many substrains (these carry a C3H/HeN mammary-tumor virus that is passed via maternal milk to offspring)

C57BL/6 C57BL/6J High incidence of hepatomas after irradiation

C57BL/6By High complement activity C57BL/6N

C57BL/10 C57BL/10J Very close relationship to C57BL/6 but differences in at least two loci

C57BL/10ScSn

C57BL/10N Frequent partner in preparation of congenic mice

C57BR C57BR/cd/ High frequency of pituitary and liver tumors

Very resistant to x-irradiation

C57L C57L/J Susceptibility to experimental autoimmune encephalomyelitis (EAE)

C57L/N High frequency of pituitary and reticular cell tumors

C58 C58/J High incidence of leukemia

C58/LwN

DBA/1 DBA/1 J High incidence of mammary tumors

DBA/1 N

DBA/2 DBA/2J Low immune response to some antigens

DBA/2N Low response to pneumococcal polysaccharide type III

HRS HRS/J Hairless (hr) gene, usually in heterozygous state

NZB NZB/BINJ High incidence of autoimmune hemolytic anemia and lupus-like nephritis

NZB/N Autoimmune disease similar to systemic lupus erythematosus (SLE) in F1 progeny from crosses with NZW

NZW NZW/N SLE-type autoimmune disease in F1 progeny from crosses with NZB

P P/J High incidence of leukemia

SJL SJL/J High level of aggression and severe fighting to the point of death, especially in males

Tendency to develop certain autoimmune diseases, most susceptible to EAE

SWR SWR/J Tendency to develop several autoimmune diseases, especially EAE

129 129/J High incidence of spontaneous teratocarcinoma

129/SvJ

SOURCE: Adapted from Federation of American Societies for Experimental Biology, 1979, Biological Handbooks, Vol. III: Inbred and Genetically Defined Strains of Laboratory Animals.

and adult lymph nodes are implanted into SCID mice (Figure 23-1). Because the mice lack mature T and B cells of their own, they do not reject the transplanted human tissue. The implanted human fetal liver contains immature lymphocytes (stem cells), which migrate to the implanted human tissues, where they mature into T and B cells, producing a SCID-human mouse. Because the human lymphocytes are exposed to mouse antigens while they are still immature, they later recognize mouse cells as self and do not mount an immuno-logic response against the mouse host.

FIGURE 23-1

SCID mouse

Transplant human thymus and lymph-node tissue under kidney capsule

Inject with human fetal liver cells (stem cells)

Stem cells migrate to the human thymus

Human thymus releases mature human T cells into circulation

SCID-human mouse then be grown in a chemically defined basal medium (containing saline, sugars, amino acids, vitamins, trace elements, and other nutrients) to which various serum supplements are added. For some experiments, serum-free culture conditions are employed. Because in vitro culture techniques require from 10- to 100-fold fewer lymphocytes than do typical in vivo techniques, they have enabled immunologists to assess the functional properties of minor subpopulations of lymphocytes. It was by means of cell-culture techniques, for example, that immunologists were first able to define the functional differences between CD4+ T helper cells and CD8+ T cytotoxic cells.

Cell-culture techniques have also been used to identify numerous cytokines involved in the activation, growth, and differentiation of various cells involved in the immune response. Early experiments showed that media conditioned, or modified, by the growth of various lymphocytes or antigen-presenting cells would support the growth of other lymphoid cells. Conditioned media contain the secreted products from actively growing cells. Many of the individual cytokines that characterized various conditioned media have subsequently been identified and purified, and in many cases the genes that encode them have been cloned. These cytokines, which play a central role in the activation and regulation of the immune response, are described in Chapter 12 and elsewhere.

FIGURE 23-1

Production of SCID-human mouse. This system permits study of human lymphocytes within an animal model. In this example, human T-cells are transferred to SCID mouse, but B-cells also can be transferred by the use of bone-marrow precursors.

The beauty of the SCID-human mouse is that it enables one to study human lymphocytes within an animal model. This valuable system has proved useful in research on the development of various lymphoid cells and also as an important animal model in AIDS research, since mouse lymphocytes cannot be infected with HIV, whereas the lymphocytes of a SCID-human mouse are readily infected.

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