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PubMed1994

A murine nephritogenic monoclonal antibody binds to both single-stranded deoxyribonucleic acid and glomerulus.

BACKGROUND: Autoantibodies such as anti-DNA and antimyeloperoxidase (MPO) antibodies have been shown to cause glomerulonephritis in experimental animal models. To analyze pathogenic autoantibodies, we developed hybridomas from spleen cells of nontreated FGS mice, in which focal segmental glomerular sclerosis develops spontaneously. EXPERIMENTAL DESIGN: Reactivity and specificity of a monoclonal antibody (FG1H5) were examined using enzyme-linked immunosorbent assay and cryosections of mouse organs as substrates. Immunoprecipitation was performed to analyze reactive antigens. Hybridoma cells were injected ip into severe combined immunodeficiency (SCID) mice to examine their nephritogenicity in vivo. RESULTS: The binding of FG1H5 to single-stranded DNA (ssDNA) was inhibited by ssDNA and also MPO. The binding of FG1H5 to MPO was weak, not inhibited by MPO, and markedly enhanced by the presence of ssDNA. This marked enhancement of the binding to MPO was abolished by DNase I-treatment of the mixture of FG1H5 and ssDNA. When MPO was introduced into ssDNA-coated wells, the binding of FG1H5 to ssDNA was inhibited. On the other hand, when ssDNA was introduced into MPO-coated wells, the binding of FG1H5 to MPO was markedly enhanced. Inhibition tests using double-stranded DNA revealed that FG1H5 is specific for ssDNA. Histologic examination of FG1H5-reactive antigen using SCID mouse kidney showed positive stainings in the nucleus and glomerulus (mainly the mesangium). These positive stainings were abolished after the incubation of FG1H5 with ssDNA. The DNase I treatment of kidney sections markedly reduced the nuclear staining, but the staining of the glomerulus was preserved. Immunoprecipitation of a soluble fraction of SCID mouse kidney with FG1H5 revealed that FG1H5-reactive antigen in the glomerulus is an approximately 28-kilodalton molecule. When FG1H5 hybridoma cells were injected ip into SCID mice, the mice showed glomerulonephritis with the increases in mesangial cells and matrix as well as immunoglobulin M deposition mainly in the mesangium. CONCLUSIONS: Data demonstrate that FG1H5 binds strongly and specifically to ssDNA (but weakly and nonspecifically to MPO), and that ssDNA and MPO bind to each other. One monoclonal antibody reacts with both the nucleus and glomerulus (mainly the mesangium), and glomerular staining is not caused by nonspecific DNA binding. FG1H5, which binds to ssDNA, can induce glomerulonephritis, probably because of a direct crossreactivity to glomerular components.

Animals↗
PubMed2003

[Biologic characteristics of intraperitoneal transplantation model of human ovarian carcinoma in severe combined immunodeficiency mice].

OBJECTIVE: To develop a human ovarian carcinoma SKOV3 model in severe combined immunodeficiency (SCID) mouse and to study its biologic characteristics. METHODS: Human ovarian carcinoma SKOV3 cells were injected intraperitoneally into female SCID mouse to establish a transplantation model of human ovarian carcinoma. The biological characteristics, metastasis and morphology of transplanted tumors were studied. RESULT: All tumors grew progressively with no sign of regression. The tumor cells spread around the peritoneal cavity and mainly on the diaphragm, mesentery, peritoneum and around the liver, which was confirmed by histopathology. The morphology, growth pattern and CA125 secretion of primary culture of transplanted cells remained as same as those of ovarian carcinoma cell line SKOV3. CONCLUSION: An intraperitoneal transplantation model of human ovarian carcinoma SKOV3 in SCID mice has been developed successfully, which can simulate the biological behavior of peritoneal metastasis of human ovarian carcinoma.

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PubMed1994

Myogenesis in thymic transplants in the severe combined immunodeficient mouse model of myasthenia gravis. Differentiation of thymic myoid cells into striated muscle cells.

Thymic myoid cells (TMCs) bearing acetylcholine receptors (AchR) on their surface have a central role in the concept of intrathymic autosensitization in the pathogenesis of myasthenia gravis. In a SCID mouse model of myasthenia gravis, solid pieces of thymuses with lymphofollicular hyperplasia were transplanted into SCID mice. The chimeric mice displayed long-term secretion of anti-AchR antibodies. Here, we traced the fate of TMCs contained in transplanted myasthenia gravis thymuses. Unexpectedly, the number of thymic TMCs in transplanted tissue was slightly higher than in untransplanted thymus. More strikingly, the transplanted TMCs were more highly differentiated than their nontransplanted counterparts. This was demonstrated by a more than 10-fold increase of AchR-main immunogenic region epitopes recognized by monoclonal antibody 198. Some TMCs had even differentiated into striated muscle cells. The abundance of AchRs in human thymic transplants in the SCID mouse model of myasthenia gravis may help to study the mechanisms of autosensitization against the AchR in vivo.

Animals↗
PubMed1998

Distinct in vivo engraftment and growth patterns of t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL+ human leukemia cells in SCID mice.

The SCID mouse represents a valuable tool for assessing growth characteristics and drug sensitivity of human leukemic cells. We have examined differences in the engraftment patterns in SCID mice of primary human leukemic cells isolated from children (< 21 years old) with either t(1;19)+/E2A-PBX1+ or t(9;22)+/BCR-ABL+ acute lymphoblastic leukemia. Leukemic cells from 13/24 t(1;19)+/E2A-PBX1+ patients caused overt leukemia in SCID mice. Macroscopic lesions were evident in 6/13 cases, with multiple sites involved in some mice: hepatomegaly,(3) splenomegaly(4), thymic enlargement; liver tumors(1), kidney tumors(1), abdominal tumors(1). Microscopic lesions in SCID mouse organs were present in all 13 cases and involved the bone marrow, brain, heart, gut, liver, kidney, lung, ovary, pancreas, skeletal muscle, spleen, and thymus. Leukemic cells from 5/20 t(9;22)+/BCR-ABL+ patients caused overt leukemia in SCID mice. Notably, macroscopic lesions (splenomegaly; leukemic bones; hepatic tumors) were observed in only 1 case. In all 5 cases, microscopic lesions were found in the mouse bone marrow. Additional microscopic lesions were restricted to skeletal muscle, spleen, and mesentery (1 case) or thymus (1 case). These findings differ markedly from those of t(1;19)+/E2A-PBX1+ leukemic cells due to the lack of involvement of major organs such as liver, pancreas, kidney, skin, or brain. These data illustrate the biological heterogeneity of childhood ALL and suggest that the differential risks associated with t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL ALL might arise from unique engraftment and proliferation capabilities of the respective leukemic cell populations.

Adolescent↗
PubMed2005

The influence of host sex on the L3 to L4 molt of Brugia malayi.

Immunocompetent male mice are more susceptible to experimental infection with Brugia spp. than are females. Because permissive male SCID mice (severe combined immunodeficient mice), which lack T and B cells, also possess higher worm burdens, the mechanism is not solely immune mediated. Recovery of fewer adult worms from the female SCID mouse suggests that females do not provide sufficient nutrients for larval growth. This study assessed the potential of the female SCID mouse to support the L3 to L4 molt of Brugia malayi. Unexpectedly, worms grown in females molted at earlier time points of recovery than those harvested from males. This suggests that the early stage of development of B. malayi is delayed in the male murine host. To determine whether the effect of host sex on molting may be similar in humans, worms were cultured in media supplemented with serum from male or female donors. Worms grown in serum obtained from female donors exhibited a significantly higher percentage of complete molts over those cultured with serum from males. Host-derived molecules required for the L3 to L4 molt may be more abundant in the female, perhaps allowing the worms to survive a vulnerable developmental stage in a less permissive environment.

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PubMed1998

Diphtheria toxin A gene-mediated HIV-1 protection of cord blood-derived T cells in the SCID-hu mouse model.

The reconstitutive potential of CD34+-derived cord blood (CB) cells, transduced with a regulated diphtheria toxin A (DT-A) chain gene, was examined in SCID-hu mice harboring a conjoint organ composed of human thymus and liver (thy/liv). The DT-A-transduced cells, injected directly into the thy/liv organ, showed the same engraftment potential as control CB cells transduced with the non-DT-A parental vector. CB cells, distinguishable from the thy/liv cells by the HLA marker B7, were preferentially maintained in ex vivo culture. In the thy/liv organ, the engrafted CB cells represented >80% of the total cells. A majority of cells (>70%) in the thy/liv organ were also CD4+CD8+, as would be expected of maturing thymocytes. The incidence of double-positive cells was highest at 44 days (compared with 30 days and 80 days) after injection of CB cells. This suggested that a minimum time was required to achieve optimal proliferation of cells in the thy/liv organ but that, at later times, all of the early cells had matured. Thus, the population used for engraftment contained early cells but not self-renewing cells. The double-positive cells matured rapidly into single-positive cells (either CD4+ or CD8+) when placed in ex vivo culture. Marked cells (neo+) could readily be detected in the thy/liv-derived cells. The cells transduced with DT-A showed long-term protection in ex vivo culture against HIV T lymphotropic isolate NL4-3. This study shows that DT-A-transduced cells had no apparent disadvantage in engraftment of the thy/liv organ and did not have any toxic effects in vivo. Such cells were protected against HIV infection even when challenged more than 2 months after transduction and after a 44-day engraftment period in the thy/liv mice. These data support the feasibility of toxin gene therapy as a strategy for HIV infection.

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PubMed1991

Obtention of a human primary humoral response against schistosome protective antigens in severe combined immunodeficiency mice after the transfer of human peripheral blood mononuclear cells.

Peripheral blood mononuclear cells (PBMC) from healthy donors were injected into C.B.-17 severe combined immunodeficiency (scid) mice which were subsequently immunized with crude Schistosoma mansoni adult worm antigenic preparation (SWAP) or with recombinant S. mansoni 28-kDa glutathione transferase (r-Sm-28-GST) antigen. PBMC from a S. mansoni-infected patient were also transferred. The specific human anti-SWAP and anti-Sm-28-GST antibody responses were monitored. The presence in both cases of human specific antibodies in scid mouse sera was determined by enzyme-linked immunosorbent assay and Western blotting techniques using anti-human immunoglobulin reagents. No antibodies were detected in these sera using anti-mouse immunoglobulin antisera. These antibodies were functional since a cytotoxic activity against schistosomula was observed when monocytes were incubated with scid mouse sera positive for anti-Sm-28-GST antibodies.

Animals↗
PubMed1998

GM-CSF receptor targeted treatment of primary AML in SCID mice using Diphtheria toxin fused to huGM-CSF.

The severe combined immunodeficient (SCID) mouse model may be used to evaluate new approaches for the treatment of acute myeloid leukemia (AML). We have previously demonstrated the killing of SCID mouse leukemia initiating cells by in vitro incubation with human GM-CSF fused to Diphtheria toxin (DT-huGM-CSF). In this report, we show that in vivo treatment with DT-huGM-CSF eliminates AML growth in SCID mice. Seven cases of AML were studied. SCID mice were treated intraperitoneally with the maximally tolerated dose of 75 microg/kg/day for 7 days. Antileukemic efficacy was determined at days 40 and 80 after transplantation, by enumerating the percentages of human cells in SCID bone marrow using flow cytometry and short tandem repeat polymerase chain reaction (STR-PCR) analysis. Four out of seven AML cases were sensitive to in vivo treatment with DT-huGM-CSF at both evaluation time points. In three of these cases, elimination of human cells was demonstrated by flow cytometry and STR-PCR. One AML case showed moderate sensitivity for DT-huGM-CSF, and growth of the two remaining AML cases was not influenced by DT-huGM-CSF. Sensitivity was correlated with GM-CSFR expression. Our data show that DT-huGM-CSF can be used in vivo to reduce growth of AML and warrant further development of DT-huGM-CSF for the treatment of human AML.

Animals↗
PubMed1998

Host-mediated antibody-dependent cellular cytotoxicity contributes to the in vivo therapeutic efficacy of an anti-CD7-saporin immunotoxin in a severe combined immunodeficient mouse model of human T-cell acute lymphoblastic leukemia.

We have investigated the anti-leukemia effect that is exerted by the murine anti-CD7 antibody HB2 in a severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukemia (T-ALL) and determined the contribution that this antibody effect makes to the therapeutic potency of a saporin immunotoxin (IT) constructed with the same antibody. The anti-leukemia effect is not exerted through complement-mediated lysis or through direct growth-inhibitory signaling after binding of antibody to the CD7 molecule on the T-ALL cell surface but rather through antibody-dependent cellular cytotoxicity (ADCC). Thus, the in vivo depletion of SCID mice of their natural killer cells almost completely abolishes the therapeutic effect of native HB2 anti-CD7 antibody and moreover significantly reduces the in vivo therapeutic performance of the anti-CD7 HB2-SAPORIN IT. Furthermore, an IT constructed with the F(ab')2 fragment of the same anti-CD7 antibody (HB2-F(ab')2-SAPORIN), which is incapable of recruiting natural killer cells, performed significantly less well therapeutically than HB2-SAPORIN IT. There was also a significant improvement in the therapeutic performance of the HB2-F(ab')2-SAPORIN IT in SCID-HSB-2 mice when used in combination with intact HB2 antibody, presumably through restoration of an ADCC attack on the target HSB-2 cell. These combined data indicate that ADCC in the SCID mouse does contribute additively together with toxin to the in vivo therapeutic potency of the HB2-SAPORIN IT directed against this human T-ALL cell line and that this has potentially important implications for the utility of this and other related classes of immunotherapeutic in human therapy.

Animals↗
PubMed1998

Hepatitis C virus persistence in human hematopoietic cells injected into SCID mice.

The issue of infection of peripheral blood mononuclear cells (PBMC) by the hepatitis C virus (HCV) has potentially important implications, but is still debated. We have used the severe combined immunodeficiency (SCID) mouse model to test for the persistence of HCV in PBMC. Hematopoietic cells isolated from 14 subjects infected by HCV were inoculated intraperitoneally into SCID mice. Serum and blood cell samples from these mice were obtained with a mean follow-up of 8 weeks. As controls, human fibroblasts and sheep PBMC, preincubated with a human HCV-positive serum, were inoculated concomitantly into mice and analyzed. HCV-RNA positive strands were detected in 7 of 26 serum samples and 8 of 26 cell fractions from SCID mice inoculated with HCV-positive PBMC, after 8 weeks of follow-up. In contrast, no HCV RNA was detectable in the 10 control mice. HCV-RNA negative strands were detected in only 2 of 10 tested samples from 2 mice, and both positive mice had been inoculated with PBMC from HCV-positive subjects with malignant hematopoietic syndrome. Our study offers strong evidence for the persistence of HCV infection in mononuclear cells. Our results are also consistent with a low rate of HCV multiplication. This SCID mouse model might therefore be useful in analyzing the mechanisms of HCV persistence in mononuclear cells.

Animals↗
PubMed2003

Breaking the species barrier: use of SCID mouse-human chimeras for the study of human infectious diseases.

Mouse-human chimeras have become a novel way to model the interactions between microbial pathogens and human cells, tissues or organs. Diseases studied with human xenografts in severe combined immunodeficient (SCID) mice include Pseudomonas aeruginosa infection in cystic fibrosis, group A streptococci and impetigo, bacillary and amoebic dysentery, and AIDS. In many cases, disease in the human xenograft appears to accurately reproduce the disease in humans, providing a powerful model for identifying virulence factors, host responses to infection and the effects of specific interventions on disease. In this review, we summarize recent studies that have used mouse-human chimeras to understand the pathophysiology of specific bacterial and protozoan infections.

Animals↗
PubMed2003

An in vivo model of autoimmune post-coxsackievirus B3 myocarditis in severe combined immunodeficiency mouse.

OBJECTIVE: Severe combined immunodeficiency (SCID) mice possess neither T nor B lymphocytes and are thus suitable recipients for adoptively transferred lymphocytes. Because autoimmune mechanisms may be involved in the pathogenesis of coxsackievirus B3 (CB3) myocarditis, we attempted to assess the in vitro cellular damage caused by antigen-sensitized lymphocytes and to determine whether splenic lymphocytes from BALB/c mice with chronic CB3 myocarditis could cause myocarditis into SCID mice. METHODS AND RESULTS: Cytotoxic cellular damage against non-myocytes and myocytes was demonstrated using 51Cr-release assay by lymphocytes cultured from myocarditis specimens or splenocytes from mice with chronic CB3 myocarditis. Severe T lymphocyte infiltration with myocardial necrosis was found in adoptively splenocyte-transferred SCID mice, but myocardial necrosis was not defected in wild-type mice by the same procedure. CONCLUSIONS: Autoimmune mechanisms might operate in mice with post-CB3 myocarditis and could be transferred in to SCID mice by the antigen-sensitized lymphocytes. An in vivo model of autoimmune post-viral myocarditis in SCID mouse was demonstrated.

Animals↗
PubMed1993

Human cytomegalovirus in a SCID-hu mouse: thymic epithelial cells are prominent targets of viral replication.

Animal models of human cytomegalovirus (CMV) infections have not been available to study pathogenesis or to evaluate antiviral drugs. Severe combined immunodeficient mice implanted with human fetal tissues (SCID-hu) were found to support CMV replication and may provide a model for this species-specific virus. When conjoint implants of human fetal thymus and liver were inoculated with a low-passage-number isolate of CMV, strain Toledo, consistent high-level viral replication was detected 5, 12, 15, 28, and 35 days after inoculation and virus replication continued for up to 9 months. Other human tissue implants, including lung and colon, were also found to support viral growth but with greater variability in levels and for a shorter duration. As expected, the species specificity of human CMV was preserved in this model such that virus was detected in the human conjoint thymus/liver implant but not in surrounding mouse tissues. The majority of virus-infected cells were localized in the thymic medulla rather than cortical region of the implant and immunofluorescence analysis identified epithelial cells rather than any hematopoietic cell population as the principal hosts for viral replication. Finally, treatment of infected animals with ganciclovir reduced viral replication, thereby demonstrating the value of this system for evaluating antiviral therapies. This animal model opens the way for a range of investigations not previously possible with human CMV.

Animals↗
PubMed1996

Analysis of the colonization of unirradiated and irradiated SCID mice by human lymphoma and non-malignant lymphoid cells.

We have evaluated the severe combined immunodeficient (SCID) mouse as an in-vivo model for the study of non-Hodgkin's lymphomas (NHL). Characterization of the immune system of the animals in our SCID mouse colony was carried out to assess the numbers of lymphoid cells present, to determine natural killer (NK) cell activity as a function of age and to examine the histology of the lymphoid organs. In this study four human NHL established cell lines (Daudi, Namalwa, U937, MC116), lymphoma cells from four fresh NHL biopsies and normal peripheral blood mononuclear cells (PBMC) and bone marrow cells were investigated, after intraperitoneal injection into the mice. The presence of the human NHL cells in the peritoneum and spleen was assessed by FACS analysis. The colonization potential was investigated in a range of tissues by polymerase chain reaction (PCR) amplification of human repetitive sequences. These studies revealed clear differences in the abilities of the NHL cell types to colonize the SCID mice. Namalwa, Daudi and U937 cells demonstrated the highest efficiency of colonization and readily formed tumours, whereas MC116, the NHL biopsy cell populations and the non-malignant lymphoid cells showed little ability to survive and colonize other tissues in the SCID mice. Whole body irradiation of the SCID mice appeared to improve the survival of human PBMC, NHL biopsy cells and MC116 cells in the peritoneum, but had little effect on their colonization potential. The significance of these studies is discussed.

Animals↗
PubMed2005

The HPV xenograft severe combined immunodeficiency mouse model.

The permissive propagation of papillomaviruses outside their natural hosts has not been possible, which is an important restriction to the study of human papillomavirus (HPV) infections and associated diseases. Since the mid-1980s, several models have been described that rely on the growth of HPV in susceptible human xenografts implanted in immunodeficient mice. The severe combined immunodeficiency (SCID) mouse has been particularly suited to this approach, and to reproduce reliably the macroscopic, microscopic, and molecular features of naturally occurring lesions. We describe two common methods that permit growth and propagation of HPV in subcutaneous (heterotopic) or cutaneous (orthotopic) human skin grafts implanted in the SCID mouse.

Animals↗
PubMed2000

Interferon-gamma downregulates ion transport in murine small intestine cultured in vitro.

Effects of IFN-gamma on mammalian small intestinal ion transport were studied in vitro using incubated sheets of murine small intestine in Ussing chambers. In oxygenated standard culture medium containing hydrocortisone and antibiotics, they maintained their short-circuit current (I(sc)) responses to glucose and theophylline for 48 h. Histological examination revealed a 50% diminution of villus height over 36 h but no change in crypts. Height was better maintained during a 36-h incubation of small intestine from SCID mice, suggesting a role for B or T lymphocytes in villus atrophy. Exposure of small intestine to 100 U/ml IFN-gamma for 36 h decreased basal I(sc) by 40% and I(sc) responses to glucose and theophylline by approximately 70%; at 1,000 U/ml for 36 h, IFN-gamma inhibited these I(sc) responses by 90%. An inhibitor of inducible NO synthase did not reverse these effects, suggesting that they are not mediated by NO. Tissue resistance, mucosal K(+) content, and epithelial morphology were not affected. Ouabain-sensitive ATPase activity in homogenates was inhibited 60% by IFN-gamma (100 U/ml for 36 h). IFN-gamma inhibition of I(sc) responses to glucose and theophylline also occurred in SCID mouse small intestine. Thus murine small intestinal sheets can be maintained viable in vitro for at least 48 h, although villus blunting develops (but less so in SCID mouse small intestine). Also, prolonged exposure to IFN-gamma downregulates Na(+)-coupled glucose absorption, active Cl(-) secretion, and Na(+)-K(+)-ATPase activity, effects unlikely to be mediated by enhanced NO.

Animals↗
PubMed2003

Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in rheumatoid arthritis.

The aim of the study was to investigate the relationship between invasion and proliferation in rheumatoid arthritis synovial fibroblasts (RASFs). In vitro, RASFs, normal synovial fibroblasts (NSFs), and RASFs transformed with SV40 T-antigen (RASF(SV40)) were analyzed for the expression of cell surface markers (Thy1, VCAM-1, ICAM-1, CD40, CD44) and their proliferation by flow cytometry. Furthermore, colony-forming unit assays were performed and the expression of matrix metalloproteinases (MMP)-14 and cathepsin K mRNA were determined by real-time polymerase chain reaction. In vivo, in the severe combined immunodeficiency (SCID) mouse co-implantation model, RASFs, NSFs, and RASF(SV40) were tested for cartilage invasion, cellular density, and for their expression of the cell cycle-associated protein Ki67. In the SCID mouse co-implantation model, RASFs invaded significantly stronger into the cartilage than NSFs and RASF(SV40). Of note, RASF(SV40) cells formed tumor-like tissues, and the cellular density adjacent to the cartilage was significantly higher than in RASFs or NSFs. In turn, the proliferation marker Ki67 was strongly expressed in the SV40-transformed synoviocytes in SCID mice, but not in RASFs, and specifically not at sites of cartilage invasion. Using the colony-forming unit assay, RASFs and NSFs did not form colonies, whereas RASF(SV40) lost contact inhibition. In vitro, the proliferative rate of RASFs was low (4.3% S phase) in contrast to RASF(SV40) (24.4%). Expression of VCAM-1 was significantly higher, whereas of ICAM-1 was significantly lower, in RASFs than in RASF(SV40). CD40 was significantly stronger expressed in RASF(SV40), whereas CD44 and AS02 were present at the same degree in almost all synoviocytes. Expression of cathepsin K and matrix metalloproteinase-14 mRNA was significantly higher in RASFs than in the RASF(SV40). Our data demonstrate clearly that invasion of cartilage is mediated by activated RASFs characterized by increased expression of adhesion molecules, matrix-degrading enzymes, but does not depend on cellular proliferation, suggesting the dissociation of invasion and proliferation in RASFs.

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