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PubMed1996

Genetically programmed development of salivary gland abnormalities in the NOD (nonobese diabetic)-scid mouse in the absence of detectable lymphocytic infiltration: a potential trigger for sialoadenitis of NOD mice.

NOD (nonobese diabetic) mice develop chronic lymphocytic infiltrates of the salivary glands (sialoadenitis) that correlate with a temporal decline in saliva production. To differentiate autoimmune and nonautoimmune components in this decline, we evaluated glandular function in NOD-scid mice. Although saliva volumes and protein concentrations appeared normal, amylase and EGF activities declined 50 and 20%, respectively, in NOD-scid mice between 10 and 25 weeks of age. Salivary protein profiles on SDS-polyacrylamide gels showed a profound decline in two prominent proteins of 32 and 20 kDa, and the emergence of a new 27-kDa protein. All three proteins exhibited amino acid sequence homology to parotid secretory protein (PSP) and reacted with PSP-specific antibody, suggesting an age-dependent alteration in PSP. In addition, there was an induced expression of proline-rich protein in the salivary glands and saliva of NOD and NOD-scid mice that was not detectable in mouse strains lacking autoimmune disease. Submandibular gland histology revealed selective loss of acinar tissue despite an absence of sialoadenitis. These changes in salivary protein composition and histology in the absence of detectable lymphocytic infiltration suggest that glandular defects in the NOD genetic background may contribute to the triggering of the autoimmune response in the salivary glands.

Amino Acid Sequence↗
PubMed1998

Evaluation of in vivo therapeutic efficacy of a new benzoxazinorifamycin, KRM-1648, in SCID mouse model for disseminated Mycobacterium avium complex infection.

In this study, profiles of infection due to Mycobacterium avium complex (MAC) in CB-17 SCID mice deficient in T and B cell functions were examined, when mice were given or not given a new benzoxazinorifamycin, KRM-1648 (KRM), during the course of infection. When mice were infected intravenously with MAC, the bacterial loads in their visceral organs were larger than those of their co-isogenic CB-17 counterparts. The incidence and the degree of gross lung lesions were less in SCID mice compared to CB-17 mice. Athymic BALB/c nude mice showed similar profiles of the infection. Beige mice showed more severe gross lesions and larger bacterial loads in the lungs than did SCID and athymic BALB/c nude mice. When MAC was infected subcutaneously into the hind footpads of mice, disseminated growth of organisms in the footpads, blood, and visceral organs was seen in SCID mice, but not in CB-17 or BALB/c mice. KRM exhibited the same level of therapeutic effect on SCID mice infected with MAC via the intravenous route in terms of inhibiting bacterial growth in the lungs and kidneys, as in cases of CB-17 and BALB/c mice with normal T-cell functions. In beige mice, the degree of growth inhibition of MAC due to KRM treatment was significantly greater than that achieved in SCID mice.

Animals↗
PubMed1993

Effect of immunomodulators in the hu-PBL-SCID mouse model.

The effects of two immunomodulators were investigated in severe combined immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID mice). Both immunomodulators, maleic anhydride divinyl ether (MVE-2) and 4-imino-1,3-diazobicyclo-(3.1.0)-hexan-2- one (imexon), have been previously studied by us in retrovirus-infected mice. To determine the effects of these compounds as they may function in humans, 24 SCID mice were each reconstituted with 20 x 10(6) ficoll-purified lymphocytes from a single donor. Five weeks after reconstitution, the mice received 16 mg/kg/day of MVE-2 intraperitoneally (i.p.) on days 0, 7, and 14 or 110 mg/kg/day of imexon i.p. daily for 14 days. Spleens were removed and splenocytes labeled with monoclonal antibodies for T- and B-cell enumeration as determined by flow cytometry 24 h after final treatment. Imexon-treated mice demonstrated a slight increase in total T cells and T cell subsets compared to control mice. T helper/T suppressor cell ratios in imexon-treated mice were brought to a normal 3:2 ratio compared to placebo-treated mice. Human immunoglobulin levels were markedly increased in imexon-treated mice. MVE-2-treated hu-PBL-SCID mice had significantly reduced numbers of total T cells compared to controls. The T-cell population results using human cells in SCID mice were similar to the effects of these immunomodulators on murine cells in immunologically competent mice.

Adjuvants, Immunologic↗
PubMed1999

Tumour necrosis factor-alpha (TNF-alpha) transcription and translation in the CD4+ T cell-transplanted scid mouse model of colitis.

The adoptive transfer of activated CD4+ alpha/beta T cell blasts from the spleens of immunocompetent C.B-17+/+ or BALB/cdm2 mice into C.B-17scid/scid (scid) mice induces a colitis in the scid recipient within 8 weeks, which progresses to severe disease within 16 weeks. T cells isolated from recipient colon show a Th1 cytokine phenotype. We have examined the relationship between the phenotype of the cellular infiltrate and the transcription and translation of the proinflammatory cytokine TNF-alpha. The techniques of double indirect immunohistology and in situ hybridization using digoxigenin-labelled riboprobes were used. The prominent myeloid cell infiltrate in diseased tissues comprised F4/80+, Mac-l+ macrophages, neutrophils, dendritic cells and activated macrophages. TNF-alpha transcription and translation were associated with activated macrophages in the lamina propria. Activated macrophages transcribing and translating TNF-alpha were clustered in areas of tissue destruction. Crypt epithelium of inflamed tissues transcribed TNF-alpha at a very early stage of the disease process, but translation of TNF-alpha protein could only be found in advanced epithelial dysplasia. This indicates differential post-transcriptional control of TNF-alpha in activated macrophages and the epithelium.

Adoptive Transfer↗
PubMed1997

U937-SCID mouse xenografts: a new model for acute in vivo HIV-1 infection suitable to test antiviral strategies.

In this study we attempted to develop a new xenochimeric model for HIV infection in SCID mice, characterized by an easy engraftment of target cells, high levels of viremia and long-lasting HIV-1 infection. SCID mice were injected subcutaneously with uninfected human U937 cells and cell-free HIV-1 (IIIB strain) or HIV-1-infected human peripheral blood lymphocytes (PBL). Mice were evaluated for tumor growth, viral infection at the tumor level (DNA-polymerase chain reaction (PCR), RNA-PCR) and immunostaining for the p55/p18 HIV protein) and p24 antigenemia or serum HIV-1 RNA copies. Pretreatment of mice with antibodies to either mouse-IFN alpha/beta or granulocytes resulted in a tumor take and levels of p24 antigenemia higher than in control mice. In mice treated with these antibody preparations, there was a long-lasting HIV infection with the presence of high levels of circulating infectious virus (serum p24 values up to 4000 pg/ml and serum RNA copies up to 5 x 10(7)/ml over 3 months, with the majority of the cells expressing HIV-antigens at the tumor site). Intraperitoneal treatment of SCID mice with AZT (480 mg/kg per day) resulted in a complete inhibition of both p24 and RNA HIV-1 copies in the serum, together with a marked reduction in the number of infected cells and the levels of virus expression at the tumor site. We conclude that some specific features of this model (i.e. easy establishment, high reproducibility, well defined kinetics of virus infection, massive and long persistent viremia) underline the special advantages of its use for testing new antiviral therapies.

Animals↗
PubMed2006

Analysis of the young and elderly variable gene repertoire in response to pneumococcal polysaccharides using a reconstituted SCID mouse model.

Significant changes in anti-pneumococcal polysaccharide (PPS) variable gene usage occur with aging and may be influenced by changes in cytokine environment. Severe combined immunodeficient (SCID) mice were engrafted with B cells obtained from young and elderly donors, supplemented with human cytokines and immunized with the pneumococcal polysaccharide vaccine. B cells specific for PPS serotypes 4 and 14 were isolated from mice and immunized donors, and variable region sequences analyzed. Significant differences in variable heavy and light chain gene usage were observed between young and elderly adults despite a more constant cytokine environment. Due to the limitations of the hu-PBL-SCID model, the use of alternative systems would be beneficial in the elucidation of mechanisms underlying the reduced vaccine efficacy in the elderly.

Adult↗
PubMed2002

Temporary restoration of immune response against Toxoplasma gondii in HIV-infected individuals after HAART, as studied in the hu-PBMC-SCID mouse model.

We studied immune reconstitution against the parasite T. gondii in HIV-infected patients treated for 1 years with highly active antiretroviral therapy (HAART). We used SCID mice, humanized with peripheral blood mononuclear cells (PBMC) from patients, which were then infected with T. gondii cysts. Mice humanized with PBMC from patients before the start of HAART were highly susceptible to infection. In contrast, mice humanized with PBMC from patients who had received HAART for 6 months displayed higher survival rates, correlating with lower intracerebral parasite loads. However, this resistance was lost during follow up because mice humanized with PBMC from patients treated with HAART for 12 months survived for no longer than mice that had not been humanized. Specific lymphocyte proliferation assays showed that the increase in proliferative response depended on treatment duration and that HAART induced changes in IFN-gamma secretion in the presence of Toxoplasma antigens. Thus, our results indicate partial immune reconstitution against T. gondii in HIV-infected patients following HAART, possibly due to changes in the patterns of specific IFN-gamma production and redistribution of functional memory CD4+ cells.

Animals↗
PubMed2002

SCID mouse models to study human cancer pathogenesis and approaches to therapy: potential, limitations, and future directions.

The successful engraftment of human tumors and human immunocompetent cells into severe combined immunodeficient (SCID) mice has led to the generation of a wide array of different experimental designs that have proven useful in studying the cell biology of human cancer, and for evaluating novel therapeutic approaches to the treatment of cancer. In this review five of the most frequently used embodiments of the SCID model are presented. The goals of this review are to discuss how each model has been utilized to study human cancer and its response to many different novel therapies, to provide an assessment of the strengths and limitations of each model, and to outline future directions with a focus on what is needed to overcome some of the current limitations and pitfalls of the SCID models.

Animals↗
PubMed1991

Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man.

When human peripheral blood lymphocytes (PBLs) from Epstein-Barr virus (EBV)-seropositive donors are injected intraperitoneally into SCID mice, EBV+ B cell tumors develop within weeks. A preliminary report (Mosier, D. E., R. J. Gulizia, S. M. Baird, D. D. Richman, D. B. Wilson, R. I. Fox, and T. J. Kipps, 1989. Blood. 74(Suppl. 1):52a) has suggested that such tumors resemble the EBV-positive malignancy, Burkitt's lymphoma. The present work shows that generally the human (hu) PBL-SCID tumors are distinct from Burkitt's lymphoma and instead resemble lymphoblastoid cell lines (LCLs) generated by EBV-infection of normal B cells in vitro in terms of: (a) their cell surface phenotype, with expression of B cell activation antigens and adhesion molecules, (b) normal karyotype, and (c) viral phenotype, with expression of all the transformation-associated EBV latent proteins and, in a minority of cells, productive cycle antigens. Indeed, in vitro-transformed LCLs also grow when inoculated into SCID mice, the frequency of tumor outgrowth correlating with the in vitro growth phenotype of the LCL which is itself determined by the identity of the transforming virus (i.e., type 1 or type 2 EBV). Histologically the PBL-derived hu-SCID tumors resemble the EBV+ large cell lymphomas that develop in immuno-suppressed patients and, like the human tumors, often present at multiple sites as individual monoclonal or oligoclonal foci. The remarkable efficiency of tumor development in the hu-SCID model suggests that lymphomagenesis involves direct outgrowth of EBV-transformed B cells without requirement for secondary genetic changes, and that selection on the basis of cell growth rate alone is sufficient to explain the monoclonal/oligoclonal nature of tumor foci. EBV+ large cell lymphoma of the immunosuppressed may arise in a similar way.

Animals↗
PubMed2006

Chronic cocaine exposure in the SCID mouse model of HIV encephalitis.

Clinical and preclinical evidence suggests that cocaine exposure hastens progression of the HIV disease process. An established active, euphoric dose of cocaine (20 mg/kg) was administered to SCID mice according to a regimen consistent with exposure to the drug by cocaine-abusing HIV-infected patients to determine the effects of cocaine on four previously established pathological characteristics of HIV encephalitis: cognitive deficits, fatigue, astrogliosis, and microgliosis. Mice were intracranially inoculated with either HIV-infected, or uninfected macrophages and then injected with either cocaine or saline in a 2 (Infection)x2 (Cocaine) factorial design. Cognition was assessed by acquisition and retention of a spatially cued learning task. Fatigue was assessed by monitoring motor activity following a 2 min forced swim. Mice were then sacrificed to determine the extent of astrogliosis and microgliosis in the four groups. Results indicated that in comparison to uninfected controls, HIV positive mice had increased astrogliosis and microgliosis, cognitive deficits, and recovered more slowly from fatigue. However, despite evidence that the cocaine exposure regimen activated the central nervous system and had long-term CNS effects, the drug did not alter the behavioral or the neuropathological deficits noted in HIV-infected SCID mice.

AIDS Dementia Complex↗
PubMed1993

Scid mouse Pre-B cells with intracellular mu chains: analysis of recombinase activity and IgH gene rearrangements.

Four Pre-B cell clones with intracellular mu chains were recovered from individual leaky scid mice by transformation of bone marrow or peritoneal cells with Abelson murine leukemia virus. Three clones were derived from independent bone marrow cell cultures. These express the defective scid recombinase activity and contain truncated mu chains resulting from abnormal and/or incomplete (D to J only) gene rearrangements. A fourth clone was obtained from a peritoneal cell culture and may represent a revertant. It expresses a recombinase activity indistinguishable from that of wild-type cells; one of its rearranged IgH alleles (VDJ+) encodes a normal size mu chain, the other is non-productively rearranged (VDJ-).

Alleles↗