Immunodeficient Rodents A Guide to Their Immunobiology, Husbandry, and Use (1989) / Chapter Skim
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2 HEREDITARY IMMUNODEFICIENCIES
2 HEREDITARY IMMUNODEFICIENCIES
Pages 36-139
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From page 36... ...
; Ityr, Ids (Resistance and Susceptibility to Salmonella typhimurium) ; [star, [shS (Resistance and Susceptibility to L`eishmania Donovan Genetics Resistance and susceptibility alleles of Beg, Itcy, and Lsh define relative resistance to in vivo infection with Mycobacterium bovis (Gros et al., 1981)
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73 - + + + op (osteopetrosis) 75 - + + + scid (severe combined immunodeficiency)
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From page 38... ...
DBA/2Ha MRL/Mp NOD NON NZB NZB x NZW F~ (BWFi) NZB x SWRF~or SWR x NZB F~, both abbreviated SNF~ PN SAM-P SJL/J SL/Ni / 108 112 82 84 - + 85 87 89 90 90 91 91 91 92 92 93 93 94 94 96 98 98 100 + 103 104 + + + + + + + _ + _ + + + 1 + + + + + + _ _ + + + + + + + + _ _ + - + + - _ + +
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From page 39... ...
immunity immune Care Special Breeding Techniques Special Husbandry Procedures Outbred mice SWAN Rat mutants ia (incisor absent) op (osteopetrosis)
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recommended that the symbol sit be dropped if the mutant proved to be identical to bg. Another mutant allele, Egg, occurred spontaneously in the C57BL/6J strain at the Jackson Laboratory, Bar Harbor, Maine (Lane, 1962~.
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Photograph courtesy of the Jackson Laboratory, Bar Harbor, Maine. Pa thop hys to logy Homozygous beige mice have a light coat color and reduced ear and tail pigmentation.
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B Roths, The Jackson Laboratory, Bar Harbor, Maine, unpublished data)
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From page 43... ...
on chromosome 4 is a spontaneous autosomal recessive obesity gene discovered at the Jackson Laboratory, Bar Harbor, Maine, in the C57BL/KsJ inbred strain (Hummer et al., 19661. The gene has been transferred to the C57BL/6J and a number of other inbred strains.
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Photograph courtesy of the Jackson Laboratory, Bar Harbor, Maine. levels, beta-cell necrosis, and pancreatic islet atrophy)
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. Husbandry Special procedures are not required to maintain these animals; however, their life span can be prolonged by dietary restriction, and the severity of the syndrome can be significantly diminished by feeding carbohydrate-free, protein-enriched defined diets (Letter et al., 19831.
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From page 46... ...
Morphological abnormalities include depletion of lymphocytes in the thymus-dependent regions of lymph nodes and periarteriolar sheaths of the spleen follicles and a gradually progressive lymphopenia. This abnormality culminates in the development of progressive atrophy of lymphoid tissue, signs of wasting and infection, and early death.
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Heterozygotes have enlarged lymph nodes and elevated numbers of circulating lymphocytes, granulocytes, and thrombocytes (Lozzio, 19721. They show decreased serum levels of IgM and IgG2 immunoglobulins but normal levels of IgG1.
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Photograph courtesy of the Jackson Laboralo~, Bar Harbor. Maine.
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Photograph courtesy of the Jackson Laboratory, Bar Harbor, Ma~ne.
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Peripheral lymph nodes are small, and the spleen has only one-tenth the normal number of lymphoid cells. Peripheral lymphoid tissues show hypocellularity, especially in the T-cell-dependent areas (paracortical areas of the lymph nodes and perifollicular sheaths in the spleen)
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The gilgl mouse is anemic and has a reduced white cell count, although the granulocyte count is slightly elevated. Spleen cellularity is reduced; however, the number of splenic stem cells is increased (Wiktor-Jedrzejczak et al., 19811.
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The gilgl mouse does not form normal bone marrow cavities in long bones. Responsiveness of splenic lymphocytes to T- and B-cell mitogens and of thymocytes to ConA is equal to or better than that of normal littermates, at least early in life (Wiktor-Jedrzejczak et al., 19811.
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Mice affected with generalized lymphoproliferative disease develop enlarged lymph nodes, as shown by this animal's enlarged prescapular lymph node. Photograph courtesy of the Jackson Laboratory, Bar Harbor, Maine.
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From page 54... ...
However, clones of T cells with a normal surface phenotype that are established from the lymph nodes of gld homozygotes are fully capable of recognizing class I molecules on target cells and functioning as cytotoxic lymphocytes (Yui et al., 19871. Splenomegaly, in which the spleens become eight times heavier than those of controls by 47 weeks of age, is primarily caused by the expansion of white pulp.
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Husbandry Special husbandry procedures are not required based on the presence of Hc° alone. However, specific-pathogen-free conditions are recommended for certain strains bearing Hc° (e.g., DBA/2)
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Rhino homozygotes are hairless and have excessive skin folding. Photographs courtesy of the Jackson Laboratory, Bar Harbor, Maine.
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Reduced humoral immune responses to thymic-dependent antigens have also been reported in these mice (Heiniger et al., 19749. An association between defective immune function and lymphomagenesis in hairless mice is suggested by the reduced immune responsiveness of this mutant to syngeneic lymphoma cells and to purified murine leukemia viruses (MuLVs)
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(19651. Lymphoid organs of Ihllh mice, including thymus, spleen, lymph nodes, and Peyer's patches, are smaller than those of normal littermates.
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Mice homozygous for the mutation lymphoproliferation develop enlarged lymph nodes, as shown by this animal's enlarged prescapular node. Photograph courtesy of the Jackson Laboratory, Bar Harbor, Maine.
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While lymphoid tissue in the area of the thymus appears enlarged in moribund mice, most of the mass is due to enlarged lymph nodes rather than to an enlarged thymus. MRL/Mp-lpr/lpr mice develop immune complex glomerulonephritis.
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Muraoka and Miller (1988) found that MRL-lpr/lpr and C57BL/6-lprllpr mice, but not MRL/Mp or C57BL/6 mice, develop lymph node and bone marrow-derived cytotoxic lymphocytes directed against self (H-2k)
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From page 62... ...
. Mice homozygous for the Lpsn locus have normal in vivo and in vitro responses to endotoxin, while mice carrying the Lps~ allele have defective responses.
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Spleen cells from the Apse strain C3H/HeJ cannot support LPS-induced herpes simplex virus (HSV) replication, and the C3H/HeJ strain is resistant to lethal challenge with HSV (Kirchner et al., 19781.
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Genetics The recessive mutation motheaten (me) occurred spontaneously in 1965 in the C57BL/6J strain at the Jackson Laboratory, Bar Harbor, Maine (Dickie, 19671.
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. Photograph courtesy of the Jackson Laboratory, Bar Harbor, Maine.
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(1986a) have postulated that a subset of TdT+ bone marrow cells are almost totally depleted in me homozygotes, and prothymocytes appear to be developmentally arrested at the pre-TdT + -cell stage.
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Husbandry Special husbandry procedures are not required for maintaining me and met mice. Life span is not increased by maintaining these animals under germfree conditions (Lutzner and Hansen, 19761.
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, using ficoll-hypaque separated splenic lymphoid cells, did not observe reduced lymphocyte function. They suggest that the reduced immune responsiveness might be due to the dilution of immunocompetent cells by stem cells and immature hematopoietic cells.
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. Mutant mice can be cured by transplanting bone marrow or spleen cells from normal litterrnates (Walker, 1975a,c)
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There is no intrinsic defect of T-cell precursors in nude mice; the T-cell defect can be corrected by transplanting mature T cells, thymocytes, or normal thymic epithelium (Wortis et al., 19711. Cytotoxic T-cell activity can be induced in nude mice by the administration of IL-2 (Hunig and Bevan, 1980)
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Under these conditions their life span approaches that of normal littermates. Outbred nude mice are hardier than inbred nude mice and can be maintained under less stringent conditions if isolated from conventionally housed mice.
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on chromosome 6 is a spontaneous autosomal recessive mutation discovered in 1949 at the Jackson Laboratory, Bar Harbor, Maine (Ingalls et al., 19501. The mutation is maintained on the C57BL/6J and C57BL/KsJ inbred backgrounds.
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It arose spontaneously in the C57BL/6Jbf stock at the Jackson Laboratory, Bar Harbor, Maine (Dickie, 19671.
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Photograph courtesy of the Jackson Laboratory, Bar Harbor, Maine. Pa thop hys lo logy Homozygous oc mice can be recognized at about 10 days of age.
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is an autosomal recessive mutation that arose spontaneously in a C57BL/6J-dw stock maintained at the Jackson Laboratory, Bar Harbor, Maine (Lane, 19731. It has been mapped to chromosome 3 (Lane, 1979~.
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The disease induced by the op mutation undergoes spontaneous partial resolution in adulthood; however, these mice cannot be cured by transplantation of normal bone marrow or spleen cells (Marks et al., 19841. Conversely, the transfer of spleen cells from op homozygotes to lethally irradiated, normal littermates does not transfer the defect (S.
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Mice homozygous for the mutation severe combined immunodeficiency have no abnormal external characteristics when they are maintained under germfree conditions. Photograph courtesy of the Jackson Laboratory.
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The presence of early B cells is, nonetheless, evident from the ability of Abelson murine leukemia virus (A-MuLV) to transform scid bone marrow cells (Fulop et al., 19881.
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L Sidman, The Jackson Laboratory, Bar Harbor, Maine, unpublished data)
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S Russell at the Jackson Laboratory, Bar Harbor, Maine, as a spontaneous mutation that occurred in the C57BL/6J strain.
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Both C57BL/6JLer-vit/vit and normal C57BL/6J mice were sensitized with SRBCs given intravenously and challenged with intradermal SRBC injections. Young vitlvit mice had delayed hypersensitivity reactions comparable to those of age-matched controls; however, 24-week-old depigmented vitlvit mice demonstrated enhanced reponsiveness (Amornsiripanitch et al., 19881.
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Photograph courtesy of the Jackson Laboratory, Bar Harbor. Maine.
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Lymphopoietic cells also appear to be abnormal. A lymphocytic stem cell population absent in We homozygotes can be demonstrated in lymph nodes of homozygotes transplanted with normal bone marrow (Harrison and Astle, 19761.
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is an autosomal recessive, lethal mutation that arose spontaneously in 1972 in the HRS/J strain at the Jackson Laboratory, Bar Harbor, Maine (Lane, 19811. It has been mapped to chromosome 2 (Sweet, 19841.
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O ~ Husbandry Special husbandry procedures are not required. Reproduction Wasted mice can be perpetuated by mating heterozygotes.
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Responses to the mitogen Nocardia are diminished, and the frequency of sIg+ B cells, particularly in the lymph nodes, is greatly reduced. It has been proposed that those B cells present are nonresponsive to some of the T-cell-generated lymphokines.
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From page 87... ...
Pathophysiology BXSB-Yaa males are generally 10-15 percent smaller than their female siblings prior to and at weaning. They develop moderate lymphadenopathy, which is most noticeable as enlargement of the cervical and axillary lymph nodes, by 3-4 months of age.
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From page 88... ...
lymphocytes in the lymph nodes by 4 months of age (Theofilopoulos et al., 19791. The Yaa gene appears to play a significant role in the abnormal resistance to tolerance induction to heterologous IgG (Izui and Masuda, 19841.
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locus, is structurally similar to human and guinea pig C4, is testosterone dependent in many strains, but has no hemolytic activity (Hobart, 19841. A second closely linked gene, C4 (formerly designated Ss)
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This gene is called the regulator of complement activation (RCA', and perhaps similar loci regulate the expression of multiple complement genes in mice (De Cordoba and Rubinstein, 1986~. Husbandry Special husbandry procedures are not required.
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From page 91... ...
At 6 months of age, histologically defined renal disease and proteinuria are markedly reduced in Iprllpr xid mice, and their life span is nearly double that of mice homozygous for the Ipr gene alone. Possibly, this is due to the effect of the xid mutation on the maturation of the B-cell subset necessary for high autoantibody production, which requires nonspecific Tcell helper factors (Fieser et al., 19841.
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. In addition, low NK cell activity has not been associated with increased lung colony formation in a metastasis model in which intravenously injected human LOX or murine B16F10 melanoma cells are used.
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From page 93... ...
Some of the deficits in the double mutant (e.g., the histologic organization of lymph nodes) are predictable.
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They concluded that the autoimmune disease of BXSB/Mp-Yaa males is dependent on B-cell subset depletion in xid individuals. INBRED STRAINS OF MICE BSVR, BSVS Genetics In 1930 Webster developed, from Rockefeller Institute stock, lines of mice that were resistant (BR)
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19731. A defect in thymus-dependent antibody responses in BSVS mice has been suggested (Briles et al., 19791.
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. BXSB/Mp Females Genetics BXSB/Mp is a recombinant inbred strain of mice derived from a cross between a C57BL/6J female and a SB/Le male.
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SB/Le females also develop autoimmune disease. Presumably, both the Y-linked autoimmune accelerator gene (Yaa)
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Husbandry Special husbandry procedures are not required. Reproduction These animals reproduce normally.
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Although special husbandry procedures are not required, these animals are maintained at the Jackson Laboratory, Bar Harbor, Maine, on a diet of pelleted 96W chow (21.9 percent protein, 7.2 percent fat)
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H Leiter, The Jackson Laboratory, Bar Harbor, Maine, unpublished data)
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From page 101... ...
H Leiter, The Jackson Laboratory, Bar Harbor, Maine, unpublished data)
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From page 102... ...
NOD bone marrow cells can transfer diabetes to irradiated diabetesresistant F1 hybrids, showing that the polygenes controlling diabetes susceptibility must be expressed in marrow-derived effecter cells (Serreze et al., 1988c; Wicker et al., 19881. NOD mice exhibit a spectrum of immunoregulatory defects.
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From page 103... ...
L Coleman, The Jackson Laboratory, Bar Harbor, Maine, personal communication to E
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From page 104... ...
H Leiter, The Jackson Laboratory, Bar Harbor, Maine, unpublished data)
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From page 105... ...
Quimby, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York. strain and the NZB x NZW Fat hybrid strain have been used as prototype strains for the study of spontaneous autoimmune disease.
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From page 106... ...
Lymphoproliferative lesions resulting in hyperplasia of spleen, lymph nodes, bone marrow, thymus, lung, kidney, liver, and salivary glands are consistent features of the disease process in NZB mice. Two phases of lymphoproliferation are seen.
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From page 107... ...
Transplantation of bone marrow from autoimmune-resistant mice to NZB mice corrects all the abnormalities in immunity and prevents the development of autoimmune disease. Likewise, transplantation of bone marrow from NZB
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From page 108... ...
Although mice of this strain have relatively normal life spans, they do develop anti-DNA antibodies, high serum levels of retroviral gp70 antigen, and nephritis later in life (Kelley and Winkelstein, 19801. NZB x NZW Fat hybrids (hereafter called BWF~)
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From page 109... ...
Pa thop hys lo logy BWF~ mice develop a disease characterized by high levels of antibodies directed toward nucleic acid antigens, progressive immune complex glomerulonephritis, and a marked enhancement of the disease in females. As early as 2 months of age, ANA can be detected in some BWF~ mice.
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From page 110... ...
BWF~ hybrids have a generalized lymphoid hyperplasia involving the spleen and all lymph nodes and an increased incidence of lymphoma (East et al., 19671. Newborn hybrids have thymic medullary epithelial cell hyperplasia, increased Hassall's corpuscles, and abundant lymphoid tissue; however, severe thymic cortical atrophy occurs early in life (Andrews et al., 19781.
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From page 111... ...
The defect of BWF1 hybrid mice, like that of the NZB parent, probably resides in the bone marrow stem cell, because the immune disorders are preventable by early bone marrow transplantation (Ikehara et al., 19871. Bone marrow transplantation decreases the concentration of autoantibodies and circulating immune complexes, abrogates the development of morphologic abnormalities in the kidney and thymus, and restores cell-mediated immune function in old BWF~ mice (Ikehara et al., 19871.
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From page 112... ...
Pathophysiology The NZB parent of the SNIP hybrid spontaneously develops autoimmune hemolytic anemia, expresses high levels of retroviruses and retroviral gp70 antigen, and infrequently develops glomerulonephritis (see page 1044. The SWR parent, by contrast, does not express retroviruses, has very low serum gp70 levels, and does not develop autoimmune disease or circulating autoantibodies (Datta et al., 1978a,b; Eastcott et al., 19831.
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From page 113... ...
Both IdS64 and IdS 12 antibodies could be found in the serum of old SNIP mice but not in the serum of either parental strain, suggesting that these nephritogenic idiotypes were dormant in the NZB and SWR parents and became deregulated and expanded in SNIP hybrids (Gavalchin and Datta, 19871. Studies directed at elucidating an immunoregulatory defect present in SNIP mice showed that Th cells were essential for inducing B cells to produce highly cationic, IgG anti-DNA antibodies in vitro (Datta et al., 19871.
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From page 114... ...
A 13 percent incidence of lymphoma was described. In mice studied histologically from 1 to 21 months of age, hyperplastic lymph nodes were a common finding.
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From page 115... ...
Analyses of IgG subclasses show that there is a shift away from the expected predominance of IgG1-specific PFC (Walker, 19881. Husbandry Special husbandry procedures are not required.
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From page 116... ...
. Pathophysiology SAM-P/1 and SAM-P/2 strains have a mean life span of 9 months when they are raised under conventional conditions (Hosokawa et al., 1987a)
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From page 117... ...
B Roths, The Jackson Laboratory, Bar Harbor, Maine, unpublished data)
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From page 118... ...
Primary RCSs are thought to arise in germinal centers of Peyer's patches and mesenteric lymph nodes (Siegler and Rich, 1968) and to spread to other lymph nodes, spleen, liver, and ovaries (Haran-Ghera et al., 19731.
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From page 119... ...
, and Corynebacterium parvam (Fitzgerald and Ponzio, 1981; Kaminsky et al., 19831. SJLlJ-nu/nu mice have elevated levels of endogenous NK cell activity compared with those in
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From page 120... ...
pertussis administration to SJL/J x BALB/c Fit hybrids, and the induction of EAE might be inhibited by vasoactive amine antagonists (Linthicum et al., 19821. Thus, SJL/J mice might be a good model for autoimmune disease, based on the strain's high lymphokine production and macrophage activity, decreased suppressor cell activity, high vasoactive amine sensitivity, and a skewed Via T-cell receptor gene repertoire.
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From page 121... ...
Granular deposition of gp70 immune complexes is found in vessel walls and along glomerular capillary loops and mesangium (Yoshiki et al., 1979; Miyazawa et al., 19871. The renal disease has a progressive and protracted clinical course and affects females earlier than males.
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The life span of these mice is unknown. Husbandry Special husbandry procedures are not required.
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From page 123... ...
In all three mutants, skeletal growth is abnormal; long bones have no flared ends or marrow cavities. In ialia rats, bone resorption is reduced by about 30 percent compared to normal littermates (Marks, 19731.
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From page 124... ...
. The defect in iamb rats is curable by transplantation of bone marrow, thymus, or spleen cells from normal animals (Milhaud et al., 1975; Marks, 1976b, 1978; Marks and Schneider, 1978; Miller and Marks, 19821.
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From page 125... ...
(1985) could not confirm a decreased responsiveness for spleen cells; however, the response of thymic and lymph node T cells to PHA was lower in oplop rats over 12 days of age than in normal littermates of the same age.
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From page 126... ...
The degree of hairlessness is not due to a genetic variation in the strain on which the genes are carried (Festing, 1981~; the same phenotypic differences are present when rnu and rnuN are backcrossed onto identical inbred strains. Under conventional conditions, Rowett nude rats survive for approximately 9 months, whereas New Zealand nude rats rarely survive for longer than 4 months.
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From page 127... ...
Less than 2 percent of the cells are OX19+ in rnulrnu and rnuNlrnuN rats that are less than 8 weeks old. Whereas New Zealand nude rats show no increase in T-cell marker expression, Rowett nude rats older than 6 months of age have about 35 percent of lymph node cells that are OX19+ .
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From page 128... ...
Genetics Toothless (tl) is an autosomal recessive mutation that arose spontaneously in a partially inbred colony of Osborne-Mendel-derived rats (Cotton and Gaines, 19741.
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From page 129... ...
In vitro responsiveness of spleen cells to T- and B-cell mitogens exceeds that of normal littermates and appears to be a function primarily of the adherent cell population (WiktorJedrzejczak et al., 19811. Toothless rats are not cured by transplantation of normal bone marrow or spleen cells (Marks, 1977)
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From page 130... ...
Husbandry Special husbandry procedures are not required. Reproduction Although no precise mechanism has been identified, the reproductive efficiency of this colony is lower than expected (small litter size)
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From page 131... ...
This susceptibility is thought to be coded for by the dominant gene Pli (pancreatic lymphocytic infiltration) , which segregates independently of RT1 (Colle et al.
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From page 132... ...
Furthermore, it is possible to prevent the manifestation of diabetes mellitus by the application of antibodies directed against class II MHC gene products (Boitard et al., 1985) , by bone marrow transplantation (Naji et al., 1983)
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From page 133... ...
(1988) suggest that a deficiency in suppressor cell activity results in an unchecked effecter cell-induced ,Bcell cytotoxicity.
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From page 134... ...
GUINEA PIG MUTANTS C2 Deficiency Genetics Deficiency of the second component of complement (C2) in guinea pigs was the first C2 deficiency reported in an animal other than humans (Hammer et al., 19811.
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From page 135... ...
The C2 deficiency is more common in women than in men, and the incidence of lupuslike syndromes is more common in C2-deficient women than in C2-deficient men. C2-deficient guinea pigs have hypergammaglobulinemia, anti-DNP antibodies, and rheumatoid factor; however, overt autoimmune disease is not seen (Bottger et al., 1986a)
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From page 136... ...
These in vivo abnormalities in humoral immunity are shared with guinea pigs with deficiencies of C2 or C4 (Bottger et al., 19851. However, in contrast to C2D and C4D guinea pigs, C3D guinea pigs do not have elevated IgM levels, nor do they have circulating immune complexes (Bottger et al., 1986b)
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From page 137... ...
(1971) have demonstrated a slight but significant defect in the ability of C4-deficient guinea pigs to make an antibody response to DNPbovine y-globulin.
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From page 138... ...
Pa thophys to logy Nude hamsters, like nude mice and nude rats, are hairless and have only a rudimentary thymus. At 1 month of age, decreased numbers of mature lymphocytes are found in lymph nodes and the spleen.
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From page 139... ...
. Husbandry Special husbandry procedures are not required.
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