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PubMed2002

A Nod Scid mouse model to study human prostate cancer.

Prostate cancer is the second cause of cancer mortality in men in Western countries. To study new therapeutic approaches such as gene therapy, animal models of human prostate cancer with metastatic behavior are mandatory. We used the Nod Scid mouse strain to develop an orthotopic animal model. Two androgen-independent cell lines (PC-3 and DU 145) were used. Local tumor growth and metastases were analyzed. The tumor take rates were close to those reported in the literature. However, a high frequency of various metastatic sites has been observed (liver, lung, spleen, adrenal, kidney, lymph node, and diaphragm). It can be concluded that the Nod Scid mouse is a relevant preclinical animal model to study human prostate cancer. Metastatic sites seem more numerous in comparison to other orthotopic mice models described.

Adenocarcinoma↗

PubMedDate not supplied

The use of the hu-PBL-SCID mouse model to study lymphocyte homing and responsiveness to recall antigens.

SCID mice were injected intraperitoneally with human peripheral blood lymphocytes (PBL) that had been previously stimulated with pokeweed mitogen (PWM) for two days to generate activated B cells. After two weeks, serum and gut washes obtained from SCID mice reconstituted with human PBL (hu-PBL-SCID mice) contained human IgA, IgG, and IgM indicating the successful survival of human lymphoid cell grafts in both mucosal and nonmucosal tissues of the SCID mice. Human IgA plasma cells could be detected by immunofluorescence microscopy in the lamina propria of the small intestine, while IgM plasma cells predominated in the spleen. The results suggested that PWM-activated plasma cell precursors homed to the spleen and the lamina propria of the SCID mouse where they differentiated into plasma cells. In vivo stimulation of hu-PBL-SCID mice with diphtheria and tetanus toxoids (DT/TT) elicited a primary (IgM) immune response pattern rather than a secondary (IgG) response. Antigen-specific antibody-secreting cells were found in the spleen and lamina propria after immunization. The microenvironment of the hu-PBL-SCID mice may select virgin B cells subsets over memory B cell clones.

Animals↗

PubMed1996

VH and VL gene complexes encoding an anti-spectrin antibody are defined by nucleotide sequencing of cDNA from a hybridoma generated from Hu-PBL-SCID mouse.

Previously we reported that human imunocompetent cells engrafted into scid mice mount a sustained and vigorous humoral immune response to murine erythrocytes. One of the dominant and consistently observed reactivity pattern of these antibodies in immunoblot analysis is with the alpha and beta isoforms of spectrin. In order to define the human xenoreactive response more completely, a hybridoma was generated (from a hu-PBL-scid mouse) whose antibody reacted with two high molecular weight species 225 to 250 kDa. We report here that this conserved antibody species reacts with both the murine and human erythrocyte proteins and cDNA nucleotide sequence analysis of the light and heavy chain genes encoding this antibody reveals that the light chain variable region gene has been previously observed in association with an autoreactive antibody. In addition to characterizing a conserved human B cell clonotype this is the first report of a human monoclonal antibody being generated from the hu-PBL-scid model using the standard hybridoma technology.

Amino Acid Sequence↗

PubMed1993

Human peripheral blood xenografts in the SCID mouse: characterization of immunologic reconstitution.

Immune reconstitutions (hu-PBL-SCID mice) resulting from adoptive transfer of human peripheral blood mononuclear cells into 1800 C.B-17 scid-/scid-mice were characterized. Over 90% of reconstitutions were successful as evidenced by human immunoglobulin production. Variability was noted with donor, cell number, and cell type. Human cells (T lymphocytes, few B cells) could be recovered by 5 days after engraftment. High levels of soluble CD8 and interleukin-2 receptors were detected in sera of hu-PBL-SCID mice. Cells recovered from 17 mice proliferated in response to antigens to which the donor had been primed; responses to nonboosted antigen also increased in some animals. After reconstitution, lymphocytes were found in the spleen and lymph nodes without full restoration of normal architecture. The hu-PBL-SCID mouse shows promise as a model system for a variety of immunologic studies. The inherent variation in the system must be minimized for appropriate use of the model.

Age Factors↗

PubMedDate not supplied

Use of a SCID mouse model to select for a more aggressive strain of prostate cancer.

BACKGROUND: Prostate cancer is the most common non-cutaneous malignancy to affect men and has a propensity for metastasizing to bone. To better mimic the biology of metastatic prostate cancer, we have developed a model that utilizes both human prostate cancer and human bone in the SCID mouse. MATERIALS AND METHODS: Injection of a xenograft of human prostate cancer, LAPC-4, near a human bone core that was previously implanted within the hindlimb of a SCID mouse allowed for the selection of a more aggressive subset of cells, known as LAPC-4(2) (read as "LAPC-4 squared"). RESULTS: As compared to LAPC-4 cells, these "bone-selected" LAPC-4(2) cells form tumors more rapidly, develop PSA-positive serum at an earlier time-point as well as with higher levels, develop androgen independence, and metastasize to human bone after orthotopic injection. CONCLUSION: The selection of a more aggressive subset of prostate cancer cells that have developed androgen independence and the propensity to metastasize is of paramount importance as these are the cellular characteristics that are clinically linked to morbidity. Analysis of these "bone-selected" cells may lead to a better understanding of the molecular basis behind the conversion of low-grade prostate carcinoma to its more deadly, metastatic form.

Adult↗

PubMed1997

Limitation of Hu-PBL-scid mouse model in direct application to immunotoxicity assessment.

Hu-PBL-scid mice were directly introduced to the methods of immunotoxicity assessments. Human IgG and IgM was detected 1 week after transplantation. Cyclosporin A (CsA) and cyclophosphamide (CP), which were injected i.p. 4 weeks after transplantation, decreased the serum concentration of IgM after 2-4 days of treatment but not that of IgG. Lymphocyte proliferation induced by various mitogens and primary T-dependent antibody responses to sheep red blood cells could not be measured by using splenocytes of hu-PBL-scid mice. These results were correlated with the fact that human cells were not detected in the spleen, thymus, or blood of hu-PBL-scid mouse but were detected in lymph nodes of the intestine, which were observed by flow cytometric and immunohistochemical examinations. The present results suggest using hu-PBL-scid mice in routine immunotoxicity investigations: lymph nodes of intestines could be used as the lymphocyte source. In addition, the determination of serum Ig concentration might be used as a experimental item.

Animals↗

PubMedDate not supplied

The SCID mouse--a novel experimental model for gene therapy in human rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by a progressive destruction of joints accompanied by synovial hyperplasia, inflammation and autoimmune phenomena. RA is a common disease, but current animal models resemble human RA only to a limited extent. As recent experimental approaches support the concept that T-cell-independent pathways may play a major role in RA, we developed a severe combined immunodeficient (SCID) mouse model to study the molecular and cellular interaction between RA synovium and cartilage. Both RA synovium as well as isolated RA synovial fibroblasts were able to invade and degrade normal human cartilage when coimplanted under the renal capsule of the SCID mice. Subsequently, we used this model to study the effects of retrovirus-based gene transfer of potentially inhibitory molecules into human RA synovial fibroblasts. Overexpression of interleukin (IL)-1 receptor antagonist reduced perichondrocytic cartilage degradation, but did not affect the invasiveness of RA synovial fibroblasts. Overexpression of tumor necrosis factor (TNF)-alpha receptor p55 revealed only a marginal effect. However, overexpression of IL-10 showed a most remarkable inhibition of cartilage destruction mediated by synovial fibroblasts. The SCID mouse model is a most useful tool not only to study the molecular basis of cartilage destruction, but also to evaluate novel approaches of gene therapy.

Journal Article↗

PubMed1995

Cardiotoxicity in the SCID mouse following administration of doxorubicin and cyclosporin A.

Multiple myeloma is a plasma cell malignancy which is generally incurable in spite of a high initial response to chemotherapy. Relapsing disease commonly heralds an increase in the incidence of drug resistance which is often mediated by the product of the MDR-1 gene, P-glycoprotein (Pgp). One approach to modulating drug resistance due to Pgp overexpression has involved the use of agents known as chemomodulators which inhibit its function. We have developed a human xenograft model of multiple myeloma using the SCID mouse to evaluate the efficacy and toxicities of new MDR-1 chemomodulators. Cyclosporin A (CsA) is a widely used immunosuppressant which has been demonstrated to be a potent inhibitor of Pgp in vitro at concentrations which are clinically achievable. Preliminary studies revealed an acute toxicity in our SCID model which was associated with the combination of CsA and doxorubicin, and which was not observed with either drug alone, nor with cremaphor, the vehicle for CsA. In the current study, non-tumor bearing SCID mice were dosed with doxorubicin or the combination of doxorubicin with cremaphor, verapamil or CsA. Animals were sacrificed and tissues harvested for morphologic examination and for HPLC analysis of doxorubicin levels. In all tissues examined, there was a marked increase in tissue levels of doxorubicin when combined with CsA. Results also revealed a higher incidence and severity of myocardial damage in those animals receiving the combination of doxorubicin and CsA than in those receiving other combinations. The elevations in tissue levels observed with doxorubicin and CsA may contribute to the acute toxicities observed in the SCID mouse model.

Animals↗

PubMed1999

Development of rat CD45+ 13-day-old fetal liver cells in SCID mouse fetal thymic organ cultures.

A phenotypic analysis of the lympho-hemopoietic cells which occur in the liver of 13-day-old fetal rats was achieved by flow cytometry in an attempt to further characterize the rat lymphoid progenitor cells. A small fraction of rat 13-day-old fetal liver (r13FL) cells, which weakly expressed the leukocyte common antigen CD45, constituted a homogeneous Thy-1(hi), CD71(-), CD44(+), MHC class I+, CD43(+) cell subpopulation negative for CD45RC, CD3, TCRalphabeta, TCRgammadelta, CD2, CD5, CD4, CD8, CD25, CD28, NKR-P1a and sIg. On the contrary, the CD45(-) cells were a heterogeneous cell subset which expressed Thy-1, CD71 and CD44 at distinct levels. After MACS separation, the CD45(+) r13FL cells, but not the CD45(-) cell subset, in vitro repopulated 14-day-old SCID mouse fetal thymic lobes providing rat T cells, both TCRalphabeta and TCRgammadelta, NK cells, and thymic dendritic cells but not B lymphocytes. Interestingly, NKR-P1a(lo) TCRalphabeta+ or TCRgammadelta+ cells developed in the xenogeneic cultures, and a rare CD4(+)CD8(+) double-positive subpopulation among the TCRgammadelta-expressing cells accumulated in the oldest cultures. These results are discussed from the double perspective of the nature of the precursor cells which colonize the fetal thymus and the relevance of the xenogeneic SCID mouse fetal thymic microenvironment for supporting rat lymphopoiesis.

Animals↗

PubMed1992

A severe combined immunodeficient (SCID) mouse model for infection with Entamoeba histolytica.

We used severe combined immunodeficient (SCID) mice to study resistance to invasive infection with Entamoeba histolytica. Seven of seven SCID mice developed liver abscesses when challenged intrahepatically with virulent HM1:IMSS strain E. histolytica trophozoites. Only one of seven similarly challenged immunocompetent congenic C.B-17 mice developed an abscess. Adoptive transfer of polyclonal rabbit anti-E. histolytica antiserum, but not preimmune rabbit serum, completely protected 7 of 12 SCID mice from intrahepatic challenge with ameba. These results demonstrate that lymphocyte-based immunity is important in protection against amebic liver abscess, and that anti-E. histolytica antibody can protect against amebic infection in this system. The SCID mouse may provide a powerful model for studying the components of protective immunity to invasive amebiasis.

Animals↗

PubMed1995

Use of the Bo-RBC-SCID mouse model for isolation of a Babesia parasite from grazing calves in Japan.

SCID mice with circulating bovine red blood cells (Bo-RBC-SCID mice) were used to isolate Babesia parasites from grazing calves in Japan. Although the initial blood samples obtained from the calves contained both Babesia and Theileria parasites, we were able to isolate only the Babesia parasites by repeated blood passages in Bo-RBC-SCID mice, taking advantage of the much more rapid growth of Babesia than of Theileria. The parasites isolated had characteristics of large-type Babesia, showing typical paired pyriform morphology. The Bo-RBC-SCID mice infected with the Babesia parasites developed a high level of parasitemia, showing severe clinical symptoms characterized by hemoglobinuria, jaundice, and hemolytic anemia. In addition, some mice exhibited nervous symptoms, particularly paralysis of both posterior limbs. The results demonstrated that the Bo-RBC-SCID mouse model was useful not only for isolating Babesia from cattle but also for studying the disease caused by the Babesia infection.

Agriculture↗

PubMed1996

p53 is required for both radiation-induced differentiation and rescue of V(D)J rearrangement in scid mouse thymocytes.

The murine scid mutation affects both V(D)J recombination and DNA repair. This mutation has been mapped to the gene encoding the catalytic subunit of the DNA-dependent protein kinase (DNA-PK), which is activated by DNA damage in normal cells. In scid mice, antigen receptor gene rearrangements are initiated normally, but impaired joining of coding ends prevents assembly of functional receptor genes, resulting in arrest of B- and T-cell development. Others have shown that exposure of scid mice to genotoxic agents such as gamma-irradiation rescues rearrangement at the T-cell receptor (TCR) beta locus and promotes thymocyte development. Here we demonstrate that irradiation rescues rearrangements at multiple TCR loci, suggesting a general effect on the recombination mechanism. Furthermore, our data show that p53 is required for irradiation-mediated rescue of both thymocyte development and V(D)J recombination. We also find that thymocyte proliferation and differentiation in the absence of DNA damage do not require p53 and are not sufficient to rescue V(D)J recombination. These results suggest that exposure to ionizing radiation facilitates a partial bypass of the scid defect, perhaps by inducing p53-dependent DNA damage response pathways.

Animals↗

PubMed1994

Complementation of V(D)J recombination defect and X-ray sensitivity of scid mouse cells by human chromosome 8.

Cells derived from mice homozygous for the severe combined immune deficiency (scid) mutation exhibit hypersensitivity to ionizing radiation, and defects in DNA double-strand break repair and V(D)J recombination. Using the technique of microcell-mediated chromosome transfer, we have introduced a number of dominantly marked human chromosomes into scid cells to localize the human homolog of the murine scid gene. Analysis of human-scid hybrid clones revealed that the presence of human chromosome 8 partially restored accurate V(D)J recombination and radioresistance to scid cells. Subsequent loss of the human chromosome 8 from human-scid hybrid clones rendered these cells sensitive to gamma-radiation and impaired their ability to catalyse V(D)J recombination. Introduction of chromosomes 2, 14, 16 and 19 that encode other repair genes did not result in the correction of these two scid defects. These observations demonstrate that the human homolog of the mouse scid gene resides on human chromosome 8.

Animals↗

PubMed1995

Evaluation of maduramicin and alborixin in a SCID mouse model of chronic cryptosporidiosis.

Two polyether ionophores, maduramicin and alborixin, were evaluated for anticryptosporidial activity in a severe combined immune deficient (SCID) mouse model of cryptosporidiosis. Groups of SCID mice were inoculated with 10(6) oocysts of bovine origin by oral gavage. Maduramicin or alborixin was administered beginning 4 weeks postinfection at 3 mg/kg of body weight per day. Maduramicin treatment resulted in a 96% reduction in fecal parasite load over the 3-week treatment period (P < 0.003). This reduction correlated with decreases in tissue parasite loads observed in histological sections of the small intestine (P < 0.000002) and the colon (P < 0.000006). A significant decrease in oocyst shedding was also observed after a 3-week treatment with alborixin (71% reduction, P < 0.01). Maduramicin was also evaluated in a relapsing model of cryptosporidiosis in which the infection was observed to recur after treatments were discontinued. Some toxicity, as demonstrated by weight loss, was observed with both maduramicin and alborixin. Both drugs exhibited significant anticryptosporidial activities with concomitant moderate toxicity. These polyether ionophores should be valuable as positive controls in compound evaluation studies and as lead compounds for chemical optimization (modification).

Animals↗

PubMed1995

Establishment of a SCID mouse model having circulating human red blood cells and a possible growth of Plasmodium falciparum in the mouse.

Our previous study has demonstrated that repeated transfusions of bovine red blood cells (RBCs) into SCID mice resulted in a complete substitution of their circulating RBCs. Identical experiments with human (Hu) RBCs, however, gave rise to a poor RBC-substitution because of the rapid elimination of Hu-RBCs from the circulation of SCID mice. Search for substances to decelerate the Hu-RBC clearance picked up some effective polysaccharides, such as sulfated chitin and mannan, but they were not effective enough to achieve a high level of Hu-RBC-substitution. In the present study, we found that Hu-serum significantly extended the lifetime of Hu-RBC in SCID mice and that repeated transfusions of the mice with Hu-RBCs, in combination with Hu-serum administration, resulted in an almost complete substitution of their circulating RBCs. An Hu-RBC-substituted SCID mouse inoculated with Plasmodium falciparum had a parasitemia persisting for two weeks, indicating a possible growth of this parasite in the mouse. Thus, this report gave the first demonstration of a complete substitution of the circulating RBCs in SCID mice with Hu-RBCs and of a successful P. falciparum infection in the mice.

Animals↗

PubMed1993

Preservation of functioning human thyroid organoids in the scid mouse: II. Biased use of intrathyroidal T cell receptor V genes.

The severe combined immunodeficiency (scid) mouse, which lacks functional B cells and T cells, has proven a useful model for exploring the survival of transplanted human lymphocytes and thyrocytes. In order to further characterize T cell infiltrates in reconstituted sc human thyroid organoids, we examined for the presence of 18 human T cell receptor (hTcR) V alpha and 21 hTcR V beta gene families using polymerase chain reaction (PCR) analysis. Human TcR V gene activity was confirmed by Southern blot analysis of the PCR fragments from all but one of the thyroid organoids, confirming the continued survival of human T cells within the thyroid organoids. However, only 3.5 out of 18 V alpha and 5.9 out of 21 V beta gene families were detected in these human thyroid organoids indicating a marked bias in T cell survival. Sequencing of the V-D-J regions of the amplified TcR fragments showed that approximately 60% of the sequences were representative of clonally expanded T cells. Hence, these passenger T cells exhibited highly biased use of particular TcR V gene families similar to that observed previously in thyroid tissue and intrathyroidal T cell cultures. Furthermore, variations in the V-D-J regions of sequences from similar V gene families indicated that the V gene region was important in T cell selection rather than the CD3 region.

Animals↗

PubMed1995

A novel SCID mouse model for studying spontaneous metastasis of human lung cancer to human tissue.

We established a novel severe combined immunodeficient (SCID) mouse model for the study of human lung cancer metastasis to human lung. Implantation of both human fetal and adult lung tissue into mammary fat pads of SCID mice showed a 100% rate of engraftment, but only fetal lung implants revealed normal morphology of human lung tissue. Using these chimeric mice, we analyzed human lung cancer metastasis to both mouse and human lungs by subcutaneous inoculation of human squamous cell carcinoma and adenocarcinoma cell lines into the mice. In 60 to 70% of SCID mice injected with human-lung squamous-cell carcinoma, RERF-LC-AI, cancer cells were found to have metastasized to both mouse lungs and human fetal lung implants but not to human adult lung implants 80 days after cancer inoculation. Furthermore, human-lung adenocarcinoma cells, RERF-LC-KJ, metastasized to the human lung implants within 90 days in about 40% of SCID mice, whereas there were no metastases to the lungs of the mice. These results demonstrate the potential of this model for the in vivo study of human lung cancer metastasis.

Adenocarcinoma↗

PubMed1994

The C.B.17 scid mouse strain as a model for human disseminated leukaemia and myeloma in vivo.

Using the C.B.17 scid mouse strain, we have developed a model of disseminated leukaemia and myeloma using five human cell lines, CCRF-Cem, Molt-4, Raji, IM9 and HS-Sultan. Introduction of any of these cell lines by either an intravenous or an intraperitoneal route eventually kills the mouse due to leukaemia or myeloma cell load. Neoplastic cells can be found in the blood, liver and bone marrow. Intraperitoneal transfer produces a local solid tumour whereas intravenous transfer produces foci of neoplastic cells in the spine and brain. A single dose of melphalan is able to increase survival time from infection of a lethal dose of the T-cell leukaemia cell line, CCRF-Cem.

Animals↗