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Results for “SCID mouse”

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PubMed2001

Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model.

We used Bcl-2 antisense oligonucleotides (G3139) to chemosensitize human gastric cancer by downregulation of Bcl-2 expression in vivo. Oligonucleotides and cisplatin were administered systemically in a human gastric cancer SCID mouse model, and Bcl-2 expression, apoptosis, tumor size, and survival were assessed. Used alone, G3139 treatment led to downregulation of Bcl-2 and moderate tumor reduction compared to saline control. G3139 combined with cisplatin treatment markedly enhanced the antitumor effect of cisplatin (70% tumor size reduction vs. cisplatin alone), associated with increased apoptosis measured in tumor biopsy specimens. Combined treatment with G3139 and cisplatin prolonged survival of the tumor-bearing SCID mice by more than 50% without adding significant drug-related toxicity. Treatment with Bcl-2 antisense oligonucleotides is thus a promising novel approach to enhance antitumor activity of cisplatin or other drugs used in gastric cancer therapy and warrants further evaluation in clinical trials.

Animals↗

PubMed1998

Ganglioside composition of a mouse brain tumor grown in the severe combined immunodeficiency (SCID) mouse.

The content and composition of gangliosides were examined in an experimental mouse brain tumor, EPEN, that was grown subcutaneously in the flank of the syngeneic C57BL/6J (B6) host and in the B6 severe combined immunodeficiency (SCID) host. SCID mice lack functional T- and B-lymphocytes, but have a normal complement of macrophages. The content and distribution of the brain tumor gangliosides were similar whether the tumor was grown in the immunocompetent B6 host or in the B6-SCID host. N-acetylneuraminic acid- (NeuAc) containing GM3 was the major ganglioside in the subcutaneous tumors and in the cultured EPEN cells. Significant amounts of N-glycolylneuraminic acid- (NeuGc) containing gangliosides were found in the tumor grown in both mouse hosts. NeuGc-containing gangliosides are not expressed in normal mouse brain, but are present in macrophages and serum. An extremely complex pattern of minor gangliosides was found in the subcutaneous tumors on two-dimensional, high-performance thin-layer chromatograms. Most of the minor gangliosides comigrated with those found in mouse macrophages. The results show that the absence of functional T- and B-lymphocytes does not markedly affect brain tumor ganglioside composition and suggest that NeuGc-containing gangliosides in the EPEN can be derived from tumor infiltrating host cells (mostly macrophages) and from the extracellular milieu (serum).

Animals↗

PubMed2000

Brief communication: heat-induced accumulation of p53 and hsp72 is suppressed in lung fibroblasts from the SCID mouse.

PURPOSE: To investigate how DNA-dependent protein kinase (DNA-PK) contributes to p53-dependent signal transduction after heat shock, thermosensitivity and accumulation of p53 and hsp72 after heat shock in lung fibroblasts derived from the SCID mouse were analysed. MATERIALS AND METHODS: Thermosensitivity at 44 degrees C in colony-forming units and Western blot analysis of p53 and hsp72 were analysed. RESULTS: The results indicated that (1) the thermosensitivity at 44 degrees C of SCID cells was higher than that of parental cells and (2) heat-induced accumulation of p53 and hsp72 was abolished and suppressed in SCID cells as compared with that in parental cells respectively. CONCLUSIONS: The findings suggest that the catalytic subunit of DNA-PK may play an important role upstream of p53 and hsp72, which are possible determinants of cellular thermosensitivity.

Animals↗

PubMed1993

Rudimentary thymus of SCID mouse plays an important role in the development of retrovirus-induced neurologic disorders.

The role of the thymus in neurologic disorders induced by the murine retrovirus, ts1, a neuropathogenic and lymphocytopathic mutant of the Moloney murine leukemia virus-TB, was examined using severe combined immune deficiency (SCID) mice. Athymic nude mice are resistant to ts1-induced neurologic disease. All SCID mice inoculated neonatally with ts1 developed neurologic disorders similar to those of inoculated BALB/c mice, albeit after a longer latency period. In some experiments, instead of inoculating ts1 directly, purified thymocytes, CD4+, or CD8+ T cells from ts1-infected BALB/c mice were transferred to neonatal H-2 compatible SCID mice. We found that SCID mice that received infected thymocytes developed the disease faster than those that received infected CD4+ T cells. SCID mice that received infected CD8+ T cells did not develop any disease. Thus, the (rudimentary) thymus of SCID mouse plays a key role in ts1-induced neurologic disease. In addition, flow cytometric analysis of the reconstituted SCID mice showed that CD8+ T cells migrate and preferentially colonize the thymus while CD4+ T cells were found in the spleen and to a lesser extent in the thymus. However, the significance of this organ specific movements of transferred cells in relation to the virus infection remains unclear. In view of the involvement of the thymus and the CD4+ T cells in human immunodeficiency virus infection, which also infects the central nervous system (CNS) in most cases, our findings in this murine model may help us better understand how the thymus may contribute to the damage of the CNS in retrovirus infections.

Animals↗

PubMed1999

Low-dose-dependent carcinogenic potential of 2-amino-3-methylimidazo[4,5-f]quinoline in the immunodeficient (SCID) mouse colon.

The carcinogenic potential of 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), one of the most potent mutagenic heterocyclic aromatic amines in food, for the colon was assessed in mice with severe combined immunodeficiency (SCID). In Experiment I, 60 male animals, 7-8 weeks old, were administered 300, 100, or 0 ppm IQ in the diet for 20 weeks. The incidence of aberrant crypt foci (ACF), preneoplastic lesions, was 100% in the two IQ-administered groups, whereas no ACF were found in the controls. Larger lesions, at least four aberrant crypts per focus, were noted in the colons of both treated groups. Most ACF were located in the proximal colon, and the bromodeoxyuridine-labeling indexes were elevated in a dose-dependent manner, especially in this region. In Experiment II, IQ was administered in the diet at 50, 10, 2, or 0 ppm to 60 female and male 7- to 8-week-old SCID mice for 30 and 23 weeks, respectively. The incidence of ACF was dose dependent in both sexes: 100%, 100%, and 63% in the females administered 50, 10, and 2 ppm, respectively, and 100%, 83%, and 38%, respectively, in the males. Lesions of at least four aberrant crypts per focus were again evident with the 50-ppm dose. The long-term or higher dose administration of IQ in the diet might thus be applied to elucidate colon carcinogenesis in the SCID mouse.

Animals↗

PubMedDate not supplied

[Induction of bone tissue on different matrices: an in vitro and a in vivo pilot study in the SCID mouse].

AIM: Three resorbable biomaterials were evaluated regarding proliferation and osteogenic differentiation of human bone marrow stromal cells (BMSC) in vitro. In a second step, the new biomaterial, calcium-deficient hydroxyapatite (CDHA), was tested in a pilot in vivo study by subcutaneous implantation in the severe combined immunodeficiency (SCID) mouse. METHODS: CDHA, beta-tricalcium phosphate (beta-TCP), and demineralized bone matrix (DBM) were seeded with human BMSC and cultured in osteogenic supplements for 3 weeks. In the pilot in vivo study, CDHA was seeded with BMSC and kept in osteogenic media for 2 weeks (group A) before subcutaneous implantation in 8 SCID mice for 3 and 8 weeks. In addition, CDHA seeded with BMSC without prior osteogenic induction (group B) and empty ceramics were implanted in each mouse. RESULTS: Total protein content and the values for specific alkaline phosphatase (ALP) increased significantly in vitro on all matrices, but no significant difference between the groups was noted. In the pilot in vivo study all ceramics were well penetrated by cells. After 8 weeks 2 of 4 samples in group B and 1 of 4 samples in group A revealed cells resembling hypertrophic chondrocytes. Specific ALP was higher in the group B (p = 0.012, Z = - 2.5) compared to empty ceramics. There were no significant differences between groups A and B. Differences between group A and the empty control did not become significant (p = 0.069, Z = - 1.8). CONCLUSION: All three matrices promoted BMSC proliferation and differentiation to osteogenic cells in vitro. Human BMSC on CDHA showed signs of osteogenic differentiation after subcutaneous implantation into SCID mice.

Adolescent↗

PubMed2004

Orthotopically implanted SCID mouse model of human lung cancer suitable for investigating metastatic potential and anticancer drug effects.

To evaluate the effects of drugs in clinical settings, an animal model of lung cancer similar to clinical cancer is necessary. Our previous studies described an SCID mouse model using orthotopic implantation of the human lung cancer cell line which mimicked the lymph node metastasis of patients with lung cancer. In this study, we made animal models that reflected various metastatic forms of lung cancer in humans. We applied our procedure to 6 lung cancer cell lines. Suspensions of 2.0 x 10(4) cancer cells were injected into the left lung of SCID mice. We evaluated the mRNA expressions of 52 proteins related to the metabolism of and resistance to anticancer drugs of each tumor cell line and its orthotopically implanted tumor using a customized cDNA array. Three lung cancer cell lines had the potential of lymphogenous metastasis and 3 cell lines had the potential of hematogenous metastasis in this model system. The A549 line showed multiple metastases, and Ma2 line showed solitary metastasis. The expression of 52 genes in each implanted tumor was closely correlated with that in each cell lines (correlation coefficients: 0.8883-0.9533), and the gradient of the regression line was more than 0.9. This model was similar to the metastatic form in patients with lung cancer. The similar expression of proteins in each tumor cell line in vitro and implanted tumor in vivo gives an advantage in evaluating the effects of molecular-targeted drugs and the relationship between specific genes and tumor potential in preclinical studies.

Animals↗

PubMed2005

Role of natural killer T (NKT) cells lacking interleukin (IL)-4 producing abilities on the CC-chemokine ligand 2-associated herpes simplex virus type 1 infection in human severe combined immunodeficiency (SCID) mouse chimeras.

CC-chemokine ligand 2 (CCL2/monocyte chemoattractant protein 1) is known to have an important role on T helper type 2 (Th2) cell generation and described to induce interleukin (IL)-4 production by activated T cells. In the present study, an increase of CCL2 production in cultures of peripheral blood lymphocytes (PBL) from patients with severe thermal injuries was demonstrated. Severe combined immunodeficiency (SCID) mice reconstituted with PBL from healthy donors (PBL-SCID chimeras) were resistant to infection with herpes simplex virus type 1 (HSV-1). Treatment of these chimeras with recombinant human CCL2 resulted in an increased susceptibility to the same HSV-1 infection. However, human SCID mouse chimeras created by PBL depleted of natural killer T (NKT) cells (NKT(-) PBL-SCID chimeras) were resistant to HSV-1 infection, even though they were treated with CCL2. IL-4 was not detected in the sera of NKT(-) PBL-SCID chimeras treated with CCL2, while IL-4 was detected in the sera of PBL-SCID chimeras under the same CCL2 administration. NKT cells isolated from PBL were shown to be cells not responsible for CCL2-stimulated IL-4 production. However, in the presence of CCL2, IL-4 was detected in culture fluids of NKT cells co-cultured with naive T cells. This cytokine was produced in co-cultures of NKT cells pretreated with CCL2 (CCL2-NKT cells) and naive T cells. In addition, IL-4 production was demonstrated in transwell cultures of CCL2-NKT cells and naive T cells. These results suggest that NKT cells lacking IL-4 producing abilities contribute to the CCL2-associated increase in the susceptibility of thermally injured patients to HSV-1 infection through the induction of Th2 cell generation.

Animals↗

PubMed1996

Acute graft rejection of human fetal pancreas allografts using donor-specific human peripheral blood lymphocytes in the SCID mouse.

Transplantation of human fetal pancreas (HFP) is being considered as a potential treatment for insulin-dependent diabetes mellitus (IDDM). Therefore, it is necessary to have an experimental model of HFP-specific allograft rejection in order to understand all the fators that contribute to allograft rejection, and in which to test potential immunomodulatory protocols. The severe combined immunodeficient (SCID) mouse provides such a model. Previously, it has been reported that human allograft rejection can be observed in SCID mice engrafted with human lymphocytes. However, graft rejection is inconsistent and depends on both the number of lymphocytes injected and on the activation state. Here, we describe a model in which SCID mice are injected intraperitoneally with donor-specific lymphocytes generated by an in vitro culture period with irradiated donor splenocytes. Injection of the donor-sensitized PBL results in an acute rejection of HFP allografts (as early as 4 days post-transplant). This model does not require the establishment of chimerism. in the SCID mice, as demonstrated by the lack of detectable human CD45 cells in the peripheral blood of rejecting mice. Allograft rejection was due to human CD4+ and CD8+ cells, as determined by immunohistochemical analysis of graft-infiltrating cells. The advantages of this model include the potential to specifically manipulate either the phenotype of the responding cells or the mechanism in which the responding population is generated. This model can provide a rapid method to test the efficacy of immunomodulatory regimens designed to protect allografts from an acute rejection response.

Acute Disease↗

PubMed2006

[Psoriasis SCID-mouse model].

Psoriasis is characterized by a complex phenotype and pathogenesis along with polygenic determination. Several psoriasis animal models have only been able to incompletely reproduce the disease. A xenogeneic transplantation approach, grafting skin from psoriatic patients onto mice with a severe combined immunodeficiency (SCID), was the first to meet the criteria for a psoriasis model. During the last 10 years, this psoriasis SCID-mouse model not only allowed telling experiments focusing on pathogenetic aspects, but also proved being a powerful tool for drug discovery with a good predictive value.

Animals↗

PubMed1992

V(D)J recombination: broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes.

Lymphoid cells from scid mice initiate V(D)J recombination normally but have a severely reduced ability to join coding segments. Thymocytes from scid mice contain broken DNA molecules at the TCR delta locus that have coding ends, as well as molecules with signal ends, whereas in normal mice we previously detected only signal ends. Remarkably, these coding (but not signal) ends are sealed into hairpin structures. The formation of hairpins at coding ends may be a universal, early step in V(D)J recombination; this would provide a simple explanation for the origin of P nucleotides in coding joints. These findings may shed light on the mechanism of cleavage and suggest a possible role for the scid factor.

Animals↗

PubMed2006

Comparison of the human immune response to conjugate and polysaccharide pneumococcal vaccination using a reconstituted SCID mouse model.

The pneumococcal conjugate vaccine (CV), although highly immunogenic in infants and young children, does not consistently demonstrate an advantage over the pneumococcal polysaccharide vaccine (PPV) in older adults. To further elucidate the adult immune response to CV, we compared its response to PPV on a molecular level using a severe combined immunodeficient (SCID) mouse model. This model allowed us to analyze a single individual's response to two different forms of antigen and define differences in gene usage elicited by these vaccines. We reconstituted SCID mice with human lymphocytes derived from an unimmunized donor; the mice were divided into two groups and immunized with either the PPV or CV. Our results demonstrate significant differences in variable gene usage in SCID mice immunized with PPV versus CV and suggest that the nature of the immunizing agent has a significant impact on gene usage and therefore influences antibody function and vaccine efficacy.

Adult↗

PubMed1995

X-ray-induced chromosomal aberrations and cell killing in somatic and germ cells of the scid mouse.

To characterize further the radiosensitivity of severe combined immunodeficiency (scid) mice, the induction of micronuclei (MN) in polychromatic erythrocytes as well as cell killing and translocation induction in stem cell spermatogonia was studied. Scid mice turned out to be clearly hypersensitive for X-ray-induced cell killing of both bonemarrow cells and spermatogonial stem cells. The frequencies of recorded micronuclei in polychromatic erythrocytes were comparable with that reported for the normal mouse, whereas the recovery of translocations was extremely low in the scid mouse. The dose-response relationship for induced translocations was bell shaped with a maximum of about 0.5% around doses of 0.5-1.5 Gy X-rays.

Animals↗

PubMed2002

Antineoplastic activity of Solidago virgaurea on prostatic tumor cells in an SCID mouse model.

Solidago virgaurea (goldenrod) has traditionally been used as an anti-inflammatory herbal medicine for the treatment of various symptoms, including prostatic diseases. The plant has also been reported to have antibacterial, spasmolytic, and carminative properties. During the course of our screening for antineoplastic activities in various herbal plants, we found that the extract of S. virgaurea exhibits strong cytotoxic activities on various tumor cell lines. The active component mostly resides in the leaves of the plant and is soluble in water. When the extract was fractionated by a Sephadex G-100 column, the active fraction corresponded to a molecular weight of approximately 40,000. This cytotoxic activity is effective on various tumor cell lines, including human prostate (PC3), breast (MDA435), melanoma (C8161), and small cell lung carcinoma (H520). To examine the effect of the cytotoxic activity on tumor cells in vivo, we used the rat prostate cell line (AT6.1) and an SCID mouse model. AT6.1 cells were injected into the flank of SCID mice, and then the G-100 fraction of S. virgaurea was administered intraperitoneally or subcutaneously every 3 days. The size of the tumor was measured for up to 25 days. The growth of the tumor was significantly suppressed by the G-100 fraction at 5 mg/kg without any apparent side effects. Therefore, S. virgaurea is considered to be promising as an antineoplastic medicine with minimal toxicities.

Animals↗

PubMed2005

Establishment of the hu-PBL-SCID mouse model for the investigation of thyroid cancer.

New experimental models of human neoplastic diseases attempt to mimic the human environment that fostered the development of disease in cancer patients. The aim of the present study was to establish a human lymphocyte-engrafted, severe combined immunodeficient (hu-PBL-SCID) mouse model to investigate thyroid cancer and to evaluate the potential use of this model for cancer immunotherapy. Thyroid neoplastic tissues were obtained from ten patients (one follicular adenoma, five papillary, one follicular, one anaplastic and two medullary cancers). One 8 x 4 x 3 millimeter sample from each tumor was cut into two pieces of identical size and transplanted into two SCID mice. In each case, one of the two mice was injected intraperitoneally with lymphocytes from the same tumor patient for the reconstitution of the human immune system (Group A), while the other animal received no lymphocytes (Group B). The engraftment of the tumors was successful in all cases. The growth rate was highly dependent on the histological type. When histologies were compared before implantation and after the removal of the implants, the characters of the tumors proved to be unchanged, except one case where an anaplastic cancer arose from a papillary tumor. Macrophages were present in all but one papillary cancer. All differentiated thyroid cancers were infiltrated by T and B lymphocytes. Lymphocytes and macrophages disappeared from 19/20 grafts by week 16. However, in one case from group A lymphocytes were detected four months after the transplantation. In another case from group A, one papillary cancer spontaneously decreased in size and disappeared. Before implantation, HLA-DR expression was detected in every papillary cancer. HLA-DR expression in the grafts was not seen in 3/5 cases by week 16. In conclusion, an animal model has been established for the investigation of human thyroid cancer, by which the analysis of anti-tumor immunity, as a postulate of immune therapy, may be possible.

Adult↗

PubMed1996

The role of the innate immune system in the reconstituted SCID mouse model of herpetic stromal keratitis.

Herpetic stromal keratitis (HSK) has an immunopathological basis, thought primarily to involve a CD4+ T cell-mediated immune response to viral antigen. Other cell types, however, particularly those involved in nonspecific immunity, such as natural killer (NK) cells or neutrophils, may also contribute to tissue destruction in the cornea. The reconstituted SCID mouse model of HSK provides a powerful system in which to study the interactions of the innate and adaptive immune responses to herpes simplex virus type 1 corneal infection. In the present study, reconstituted SCID mice depleted of NK cells had a reduced incidence and severity of clinical and histopathological HSK. The levels of T cell cytokine protein and message in restimulated splenocytes and cytokine message in corneas did not differ between experimental groups. However, significantly fewer neutrophils were seen within the inflamed corneas of NK-depleted SCID mice. Therefore, endogenous NK cells may indirectly influence the severity of HSK in reconstituted SCID mice by affecting neutrophil migration into the cornea.

Animals↗

PubMed2007

Immunological protection against HPV16 E7-expressing human esophageal cancer cell challenge by a novel HPV16-E6/E7 fusion protein based-vaccine in a Hu-PBL-SCID mouse model.

Increasing evidence has suggested that infection with high-risk human papillomavirus (HPVs) is closely associated with esophageal squamous cell carcinoma (ESCC) in China. The E6 and E7 oncoproteins expressed in ESCC are considered as attractive tumor-specific antigen targets for immunotherapy. We have reported that the HPV16 mE6delta/mE7/TBhsp70delta fusion protein vaccination induced powerful anti-tumor immunity against TC-1 tumor cells in a C57BL/6 mouse model. In the present study, we further evaluate the protective efficacy of this fusion protein vaccine using an HPV E7-expressing human ESCC cell line (EC9706) and a Hu-PBL-SCID mouse model. We demonstrated that immunization with the fusion protein vaccine caused significant inhibition of tumor growth with the delay time to tumor detection (tests vs. controls, 16 d vs. 9 d, p<0.01) and much smaller tumor size (p<0.01) in vivo. The inhibitory rate was ca. 69.6%, and 25% of the fusion protein vaccinated-mice remained tumor free by the end of the experiment (42 d). Furthermore, the activated lymphocytes (CD8+) were capable of infiltrating into the tumor site, and much more apoptotic cells along with activation of caspase-3 were observed in the tumors from vaccinated-mice. Also, high expression levels of human IFN-gamma, TNF-alpha, granzyme B and perforin were detected in the tumors from vaccinated-mice. Therefore, we concluded that the HPV16 mE6delta/mE7/TBhsp70delta fusion protein vaccine is able to stimulate cellular-mediated immune response against E7-containing ESCC cells through CD8+-dependent CTL-induced apoptosis in Hu-PBL-SCID mice. These findings provide a scientific basis for HPV E7-expressing ESCC active immunotherapy.

Animals↗

PubMed1997

The Fas-deficient SCID mouse exhibits the development of T cells in the thymus.

The Fas Ag is a cell surface protein that mediates apoptosis and is highly expressed on thymocytes. However, the role of the Fas system in the thymus is unclear. To study the role of the Fas system in the thymus, we established a novel SCID mouse bearing the lpr (lymphoproliferation) mutation. Thymocytes from these mice differentiated into CD4+ CD8+ T cells and then underwent further differentiation into CD4+ CD8- or CD4- CD8+ single-positive T cells with a low surface expression of CD3, whereas B cell development remained unrescued. These TCR-positive T cells can proliferate in response to stimulation with PMA plus ionomycin, but not with third-party spleen cells. Furthermore, thymocytes from scid/lpr mice had a great variety of TCR Vbeta repertoires. These results suggest that the Fas system plays an essential role in regulating the development of intrathymic T cells as well as peripheral T cells.

Animals↗