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Transplantation and metastasis of NB rat prostate neoplasia in congenitally athymic (nude) mice, nude mice treated with antilymphocyte sera and congenitally athymic rats.

The androgen-dependent NB rat prostate adenocarcinoma 2PR 129 and the autonomous tumor 102PR were transplanted into groups of both male and female nude mice, nude rats, and NB rats. Significant growth of the 2PR 129 tumor at the site of transplantation was noted in male but not female nude mice, nude rats or NB rats. Indeed, successful transplantation of 2PR 129 was not achieved in female nude mice even with usage of antilymphocyte sera. In contrast, the autonomous tumor 102PR grew at a significant rate at the local site of transplantation in mice and rats of both sexes. Although significant tumor masses were found at the injection site of male nude mice transplanted with 2PR 129 and in both male and female nude mice injected with 102PR, metastasis was not found. Further, antilymphocyte sera increased the rate of growth of both tumors in nude mice but did not change the apparent metastatic potential. Nonetheless, metastasis was readily observed in male nude rats transplanted with 2PR 129 and nude rats of both sexes transplanted with 102PR. Such metastatic lesions of nude rats were found in lung, liver and kidney with a similar frequency and histologic profile as NB rats. These results suggest that the nude rat, at least for this rat tumor system, is a more versatile and biologically relevant system than nude mice and further cautions against use of xenotransplants as models of tumor natural history. Moreover, it suggests the possible relationship between host recognition of species-determined genetic loci and metastatic potential.

Animals↗

Suppression and contrasuppression in athymic nude mice: nude mice produce the antigen-specific component of a T suppressor factor that inhibits the late 24-hr phase of DTH but do not generate suppression nor contrasuppression of the early initiating phase of DTH.

Previous studies demonstrated that the initiation of murine delayed-type hypersensitivity (DTH), as exemplified by contact sensitivity induced by picryl chloride (PCI) or oxazolone (OX), is due to antigen-specific, T cell-derived, DTH-initiating factors called, respectively, PCl-F and OX-F. These factors participate in the extravascular recruitment of CD4+, Th-1, DTH effector T cells in the elicitation of DTH. Related factors also participate, together with nonantigen binding factors derived from CD8+ T cells, to constitute an antigen-specific T cell-derived suppressor factor (TsF) that can down regulate the ability of Th-1 effector T cells to mediate DTH. Since it was shown recently that athymic nude mice can make antigen-specific, DTH-initiating T cell factors, the current study tested whether nude mice also could produce the antigen-specific component of the TsF that suppresses DTH effector T cells. We found that antigen-specific factors from nu/nu mice could complement the nonantigen-binding subfactor produced in normal mice to constitute the whole antigen-specific TsF. Additional studies showed that the successful adoptive cell transfer of DTH-initiating T cell activity from nude mice into normal mice required cyclophosphamide treatment of the recipient. In contrast, transfer of DTH-initiating cell activity from nu/+ mice did not require cyclophosphamide treatment of the recipients. We hypothesized that nude mice lacked contrasuppressor cells. Although nude mice were able to manifest the early, initiating phase of DTH, we found that there was no suppression of early DTH-initiating T cells in nude mice, compared to nu/+. Therefore the production of DTH-initiating T cell factor could be boosted in nude mice. The ability to boost DTH-initiating cells in nude mice should facilitate the development of cell lines and clones with the ability to initiate DTH.

Animals↗

Superoxide dismutase isoenzymes in tissues and plasma from New Zealand black mice, nude mice and normal BALB/c mice.

In various types of autoimmune disease, an increased frequency of spontaneous chromosome breaks has been reported. Plasma from such patients induces chromosome breaks in normal cells. Exposure of plasma to superoxide radicals increases the breakage activity, and addition of superoxide dismutase protects against it. The New Zealand black mouse is an animal model of autoimmune disease which displays the breakage phenomenon. To test for the possibility that the breakage is related to deficient protection against superoxide radicals, the activities of superoxide dismutase isoenzymes were determined in tissues and blood from New Zealand black mice and compared with the activities of normal BALB/c mice. No differences between the strains were revealed in tissue EC-superoxide dismutase, CuZn superoxide dismutase and Mn superoxide dismutase activity. The erythrocyte superoxide dismutase activities were also equal. The plasma EC-superoxide dismutase activity was 35% lower in the New Zealand black mice than in the BALB/c mice. Between euthymic BALB/c mice and nude mice, previously reported to be deficient in tissue superoxide dismutase activity, no difference could be demonstrated.

Animals↗

Effects of opioid peptides on the cellular immunity in spleen cells from intact nude mice or nude mice bearing human ovarian carcinoma.

The present study was designed to explore the effects of opioid peptides on the lytic activity of spleen cells from intact nude mice or nude mice bearing human ovarian cancer cells (KF). When the spleen cells from intact nude mice were incubated with various concentrations of opioid peptides, the ability of the spleen cells to lyse the KF cells was significantly stimulated between 0.05 nM and 50 nM concentrations of all opioid peptides used in this study. The degree of stimulation was most marked at 5 nM opioid peptides and the most marked stimulatory effect was obtained by alpha-endorphin. On the other hand, the lytic activity of spleen cells from nude mice challenged with the KF cells was about two-fold higher than that of intact nude mice, suggesting that spleen cells from nude mice challenged with KF cells have KF-cell-specific cytotoxicity. Even if the spleen cells were incubated with any concentration of alpha-endorphin or [Met]enkephalin indicated, the lytic activity remained unchanged. In contrast, only beta-endorphin resulted in a significant increase of the lytic activity between 0.5 nM and 50 nM. These results suggest that opioid peptides play a crucial role in immune surveillance mechanisms.

Animals↗

Adoptive transfer of immunity to Nocardia asteroides in nude mice.

Nude mice on a BALB/c background were adoptively transferred with unprimed spleen cells, Nocardia-primed spleen cells, or Nocardia-primed splenic T lymphocytes from syngeneic, heterozygous (nu/+) littermates. Two days later, these recipient mice and unmanipulated (control) nude mice were infected intravenously with a 50% lethal dose of Nocardia asteroides GUH-2 from an early stationary-phase culture. Antibody titers, spleen weights, percent mortality, and organ clearance of the microorganisms were measured at 3 h to 28 days after infection. Adoptively transferred nude mice had larger spleens and greater titers of anti-nocardial antibody 7 to 28 days after infection as compared with control nude mice. Adoptive transfer with either primed spleen cells or primed splenic T lymphocytes enhanced both the survival of recipient nude mice and their ability to eliminate N. asteroides from the liver and spleen. These data indicate that adoptive immunity to infection with N. asteroides can be transferred with either specifically primed spleen cells or splenic T lymphocytes. Thus, it appears that cell-mediated immunity and T lymphocytes are of uppermost importance in host resistance to nocardial infection.

Animals↗

Lupus-like syndrome in some strains of nude mice.

Nude mice (strains ORL, C57BL, BALB/C), as well as neonatally thymectomized mice, develop spontaneous antinuclear antibodies (ANab) and antidouble-stranded DNA antibodies (dsDNAab). Later, these animals develop a lupus-like syndrome in which immunoglobulin (Ig) deposits appear, first in the kidney glomeruli, then at the dermoepidermal junction and in the choroid plexus. In the beginning, these Ig are IgM and IgG2; later, IgG1 and IgA deposit in the kidneys. The classes of the Ig of the deposits correspond to those of the circulating ANab-Ig, except for IgA. Acid eluates from kidneys and skin, contain anti-DNA histone ab. An increased C1q binding activity is observed in 8- to 12-wk-old ORL nude mice with ANab, but is not observed in age-matched ORL nude mice without ANab. These data indicate the participation of ANab in the constitution of immune complexes and of tissular Ig deposits in nude mice. The antinuclear autoimmunization process, in nude as well as in thymectomized mice, might be interpreted as a defect of T suppressor cells, which normally control autoimmune clones. However, in contrast with the preceding strains of nude mice, nude mice from the IFFA centre, which have a different genetic background, develop neither ANab, nor dsDNAab, nor glomerular lesions. Three hypotheses can be proposed to explain these particularities of IFFA nude mice. They either have an immune response regulating system, independent of the thymus which is defective or absent in the other strains, or they are deprived of lymphocytes able to produce ANab and dsDNAab, or there are not enough free nuclear antigens to stimulate an immune response. Preliminary results obtained in our laboratory favour the first hypothesis.

Animals↗

Differential effects of human interferon alpha and interferon gamma on xenografted human thyroid tissue in severe combined immunodeficient mice and nude mice.

We have studied the in vivo effects of human interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) administration on human thyroid tissue xenografted into two mouse strains: severe combined immunodeficient (SCID) mice and nude mice. Human lymphocytes survive in SCID mice but are lysed in nude mice. Thyroid tissues from Graves' disease or Hashimoto's thyroiditis, or paranodular [normal, (N)] tissue was xenografted into SCID mice (0.8 g/mouse) pretreated with anti-asialo GM-1 antiserum and radiation and also into nude mice. One week after xenografting, SCID and nude mice were divided into three groups. Group A was treated with IFN-alpha intraperitoneally (2,000 units/mouse) three times weekly; group B was treated with IFN-gamma similarly; group C was treated with phosphate buffered saline (PBS) only (control). Autologous human peripheral blood mononuclear cells (PBMCs) were added to mice receiving N xenografts. Blood was taken every 2 weeks for levels of IgG and thyroid antibodies (TAb). After 6 weeks of treatment, mice were sacrificed, and xenograft thyrocyte histocompatibility leukocyte antigen (HLA-DR) and intercellular adhesion molecule (ICAM-1) expression were measured. In addition, thyrocyte cultures were stimulated in vitro with 200 units/ml of either IFN-alpha or IFN-gamma or PBS (control). SCID mice xenografted with autoimmune thyroid disease (AITD) in group A showed a significantly higher TAb production than group C, whereas in group B, TAb production was not statistically increased compared to control (group C). SCID mice xenografted with N did not produce TAb in any group, nor did nude mice xenografted with AITD. Thyrocyte HLA-DR expression was markedly increased in group A and B in SCID mice xenografted with Graves' disease, Hashimoto's thyroiditis, and N tissue compared to group C. In contrast, only group B (IFN-gamma) showed an increase in thyrocyte HLA-DR in nude mice. In the in vitro studies, only IFN-gamma (not IFN-alpha) stimulated thyrocyte HLA-DR and ICAM-1 expression in Graves' disease, Hashimoto's thyroiditis, and N tissues. We concluded that in SCID mice, IFN-alpha causes TAB production in AITD xenografts but not in N xenografts, while increasing thyrocyte HLA-DR expression in both. Also, IFN-gamma does not cause a statistically increased TAb in AITD xenografts in SCID mice, despite a sharp rise in thyrocyte HLA-DR expression. In addition, because IFN-alpha has no effect in nude mice or in vitro on thyrocyte HLA-DR expression, its effects in SCID mice must be mediated via local infiltrating lymphocytes. Finally, IFN-gamma has a direct effect on thyrocytes to increase HLA-DR expression (and, in vitro, ICAM-1 expression) but may not stimulate TAb production.

Adolescent↗

Hair growth pattern in nude mice.

Nude mice are not bald but instead show an 'abortive' reduced hair growth on different sites of the integument. An albino (NMRI-nu) and a pigmented (C57BL/6-nu) strain of nude mice were examined as to whether the regional distribution pattern of this anagen hair proliferation is subject to the same ontogenetic development as in hairy mice. Hairy mice of both strains served as a comparison. Hair distribution was documented macroscopically by drawing and photography in a total of 415 mice of both sexes up to 421 days of age. Because of the pigmentation of the growing anagen hair follicles, the growth areas in the pigmented nude mice were distinctly visible whereas in the albino mice they were roughly recognisable from the boundaries of hair covering. The regional distribution of the 'abortive' anagen hair pattern in both nude strains corresponded to the wave-like course of the adult hair generations of hairy mice. As in older hairy mice, the hair cycle duration in nude mice was prolonged from an age of 121-180 days, the hair growth areas appeared reduced and less symmetrically orientated. Differences of up to 33% in body mass between the lighter nude and +/nu mice made ontogenetic comparison impossible so that all information is based on direct pattern or age comparison. The significance of experiments on the skin and hair follicles of nude mice is further increased if litters are examined comparatively and the temporal and spatial dimension of the follicle proliferation is considered more carefully than has been the case until now.

Animals↗

Virus carrier state suppresses tumorigenicity of tumor cells in athymic (nude) mice.

Nude mice injected subcutaneously with normal uninfected BHK 21 cells or HeLa cells regularly develop large, rapidly-growing tumours at the subcutaneous site of inoculation. However, these same tumour cell lines when persistently infected with VSV or other enveloped RNA viruses are either rejected or form small nodules in nude mice. This rejection phenomenon probably involves some type of immunocyte since heavily-irradiated nude mice (500 rads) cannot reject persistently infected cells but develop large, rapidly-growing tumours which shed virus and defective interfering virus (DI) and which do not exhibit the lymphocytic infiltration observed in the nodules of unirradiated mice given persistently infected cells. Finally, it was possible to select a subline of BHK 21-VSV carrier cells which regularly produces large rapidly-growing tumours in normal unirradiated nude mice, although all these carrier cells express virus antigen and shed large amounts of mature infectious virus and DI both in vivo and in vitro.

Animals↗

Heterotransplantation of a human prostatic adenocarcinoma cell line in nude mice.

Nude mice of NIH/Swiss background were utilized for the heterotransplantation of a tissue culture cell line derived from a human prostate adenocarcinoma metastatic to the brain. These cells, which had been grown in vitro for 13 passages, formed solid tumors when injected s.c. into nude mice. The cell line DU 145 has been passaged 60 times in vitro over a period of 18 months. Tumors removed from the mice were serially transplanted to additional mice and reestablished in vitro. Light-microscopic analysis of the tumor grown in nude mice revealed a strong similarity to the patient's metastatic tumor. The ultrastructure of the tumor cells propagated in nude mice was compared to that of the original human tumor cells and to the tissue culture cells, both before and after passage in nude mouse. No major differences were detected. Karyotypic analysis of the tumor cells grown in vitro before mouse passage, grown in nude mouse, and grown in vitro after mouse passage indicated chromosomal identity and consistent marker chromosomes: three large acrocentric chromosomes and metacentric minute chromosomes.

Adenocarcinoma↗

Triple paraneoplastic syndrome of hypercalcemia, leukocytosis and cachexia in two human tumor xenografts in nude mice.

Nude mice bearing the human oral cavity carcinoma cell line OCC-1, and the lung cancer cell line LC-1, developed a triple paraneoplastic syndrome consisting of hypercalcemia, cachexia and leukocytosis. All of these abnormalities disappeared rapidly after surgical resection of the tumors, suggesting their ectopic humoral nature. Search for the factors responsible for the respective abnormalities revealed that the production of parathyroid hormone-related protein and colony-stimulating factors (CSFs), mainly granulocyte-CSF, by the tumors could explain the hypercalcemia and leukocytosis, respectively. With regard to the severe cachexia, the production of two cachexia-associated cytokines, interleukin-6 and leukemia inhibitory factor, was able to explain the syndrome in OCC-1 bearing nude mice; however, the factor responsible in LC-1 bearing nude mice could not be identified. The triple paraneoplastic syndrome that developed in these two animal models could be explained partly by concomitant production of the peptide hormone and cytokines by cancer cells. These animal models may be very useful for the evaluation of diagnostic and therapeutic modalities for humoral abnormalities.

Animals↗

[Effects of 8 antitumor drugs against the growth of human lung adenocarcinoma (LAX-83) transplanted under the kidney capsule of nude mice].

Nude mice, inoculated with LAX 83 in bilateral subrenal capsules, were used in experimental therapy with 8 antitumor drugs. Treatment was initiated 2 d after tumor inoculation. All the drugs were ip to the nude mice daily for 7 d. At the daily doses VCR 0.4, MMC 2, CCNU 16, cis-DDP 2, AdM 2.5, 5-Fu 30, CTX 40 and MTX 2-6 mg/kg, the inhibition of the tumor growth were 100, 95.8, 91.3, 79.2, 65.2, 60.7, 62.3 and 0%, respectively. The results indicated that the effects of the drugs on nude mice inoculated with LAX-83 in subrenal capsule not only exhibited a good correlation to those in sc, but also shortened the period of experiment from 22 to 11 d. Furthermore, when LAX-83 was inoculated into the subrenal capsule of Swiss +/+ mice, the tumor tissues degenerated and disintegrated 2 d after the inoculation and replaced by inflammatory granuloma tissues 6 d later.

Adenocarcinoma↗

Nature of the thymus dependency of mucosal mast cells. III. Mucosal mast cells in nude mice and nude rats, in B rats and in a child with the Di George syndrome.

Mucosal mast cells have been examined in the small intestinal mucosae of nude mice and nude rats, B rats and a child with the DiGeorge syndrome. In all three species, mast cells were present in normal numbers despite the athymic status of the nude mice and nude rats, the vestigial nature of the thymus in the child, and the functionally T lymphocyte-deprived status of the B rats. Connective tissue mast cells were also plentiful in skins and tongues of the nude mice and the child with thymic aplasia. It is concluded that normally neither population of mast cells has a obligatory dependence on the thymus or T lymphocytes for its differentiation, but that mucosal mast cells, under certain conditions of rapid hyperplasia, require an inductive influence provided by T lymphocytes.

Animals↗

Abnormal development of the thymus in "nude" mice.

Nude mice bearing grafts of normal thymus reject skin grafts and have low, but higher than usual, lymphocyte counts. Nude bone marrow can successfully repopulate the thymus and thymus-derived areas of lethelly irradiated recipient mice. Attempts to reconstitute nude mice with normal fetal liver failed. The so-called thymic rudiment of nude mice when grafted to normal mice did not develop thymocytes. These experiments show that nude mice suffer from a defect of the epithelial portion of the thymus rather than of the precursors of thymocytes.

Animals↗

[The persistence and proliferation of tumor-xenografts implanted under the renal capsule of immunocompetent mice, cyclosporin A-treated mice and nude mice].

The subrenal capsule assay for cancer chemotherapy was performed, using tumor-specimens of 19 patients' cancers. Twelve tumor-specimens were implanted simultaneously under the renal space of immunocompetent CDF1 mice, cyclosporin A (CsA) 60 mg/kg treated mice, and BALB/c-nu/nu (nude) mice. The persistence and growth of implanted tumor-xenografts of each mouse, was evaluated, on day 6 and 9 after inoculation. The tumor-xenografts implanted under the renal space of immunocompetent mice, grew larger on days 6 in 9 cases, but histological evaluation showed tumor tissues were in various degree replaced by host reactive tissues. Host reaction in CsA-treated mice or nude mice was suppressed almost completely, but the persistence and proliferation of tumor-xenografts of both mice was varied, depending on the nature of original tumors. The judgment for cancer chemotherapy on our modified SRC assay was almost similar between CsA-treated mice and nude mice, but there were some cases in which macroscopical judgment didn't correspond with histological effect. The DNA synthesis of tumor-xenografts of 7 patients, was examined by using sequential changes of BrdU labeling index (LI) in the renal space of CsA-treated mice. It was showed LI rather indicated the nature of original tumors itself.

Animals↗

Effect of retinyl palmitate and 13-cis retinoic acid on immune functions in immunodeficient, nude mice.

Nude mice are deficient in thymus gland development and hence lacking functional, mature T-lymphocytes. Weanling nude mice were given various deficient and high retinyl palmitate (RP) or 13-cis retinoic acid (CRA) diets. The high RP (vitamin A) diets stimulated phagocytosis in the absence of mature T-helper cells. However, T-cell dependent mitogens did not cause significant mitogenesis in any group, while LPS, a B-cell mitogen, did. RP had no effect on mitogenesis. NK cell activity was increased only at a very high level of RP, as has been reported with conventional mice. Macrophage production of cytotoxic factors was unaffected by high levels of RP or CRA. Direct cytotoxicity in vitro of tumor cells was increased only at very high RP levels. Thus, mature T cells may be needed for RP to produce normal activation of macrophage, except at very high RP levels.

Animals↗

Comparison of leukocytes obtained from the intestinal lumen of Giardia-infected immunocompetent mice and nude mice.

Previous studies have suggested that Giardia infections are cleared immunologically, but have not defined the mechanism of clearance. The aim of the present work was to compare subpopulations of leukocytes harvested from the intestinal lumen of immunocompetent BALB/c mice, which clear Giardia muris infection rapidly, with those of immunodeficient nude mice, which become chronically infected with Giardia muris. Leukocytes were obtained from the intestinal lumen of Giardia-infected mice, and subpopulations of these cells were quantified after immunofluorescent staining with monoclonal antibodies. Identical numbers of leukocytes were harvested from the intestinal lumen of Giardia-infected immunocompetent mice and nude mice, but the number of these leukocytes bearing the T-lymphocyte antigen Thy-1.2 was smaller in nude mice than in immunocompetent mice. In contrast, no striking differences were observed between the numbers of luminal cytotoxic/suppressor T lymphocytes or macrophages in Giardia-infected nude versus immunocompetent mice. The findings suggest that clearance of Giardia muris infection is not mediated by cytotoxic T lymphocytes or macrophages. Subsequently, T lymphocytes and T-lymphocyte subsets were quantified in cell suspensions prepared from Peyer's patches of immunocompetent BALB/c mice and nude mice. It was found that nude mice have a profound deficiency of Peyer's patch helper/inducer T lymphocytes. This deficiency may account for the inability of nude mice to clear Giardia muris infection at a normal rate.

Animals↗