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PubMed2004

Tolerance induction by veto CTLs in the TCR transgenic 2C mouse model. I. Relative reactivity of different veto cells.

Several bone marrow cells and lymphocyte subpopulations, known as veto cells, were shown to induce transplantation tolerance across major histocompatibility Ags. Due to the low frequency of the effector T cells against which the veto cells inhibitory activity is aimed, the fate of the effector cells was traditionally followed indirectly by functional limiting dilution assays, which are cumbersome and depend on numerous parameters. In the present study the fate of the effector T cells was monitored directly by FACS, using TCR transgenic mouse CD8(+) T cells in which the transgene is directed against H-2(d) (the 2C model). This assay is validated by demonstrating the potency, selectivity, radiation sensitivity, and contact dependency of anti-third-party CTLs previously demonstrated by the limiting dilution assay. In contrast to veto CTLs, nonactivated CD8(+) T cells lack veto activity. Comparison by FACS in the 2C model revealed a hierarchy of veto cells, in the order of veto CTLs activated NK cells, activated CD4(+) T cells, and activated B cells. The latter cells as well as nonactivated CD4(+) or NK cells were shown to be completely devoid of veto activity.

Animals↗
PubMed2001

Transgenic mice with overexpression of human scavenger receptor A on endothelial cells.

OBJECTIVES: To establish a new transgenic mouse model for determining the function and role of human scavenger receptor A (SR-A) in atherosclerosis in vivo. METHODS: Human scavenger receptor minigene-driven mouse tie-1 promoter was constructed and confirmed by endonuclease digestion and sequence analysis. Transgenic mice were generated via the microinjection method. PCR and Southern blot were used to screen the positive transgenic mice. RT-PCR and immunohistochemical analysis were used to detect the level and location of human SR-AI expression in transgenic mice. The activity of human SR-AI was determined by morphologic observation of aortic endothelial cells of transgenic mice under transmission electron microscopy. RESULTS: The electrophoresis assay showed the expected 4 fragments of 0.9 kb, 1.1 kb, 1.2 kb and 4.2 kb in the Sma I digest and 2 fragments of 0.8 kb and 6.7 kb in Bgl II digest of plasmids pTie-1/hSR-A. The fragment sequence of tie-1 promoter and human SR-A cDNA in plasmids pTie-1/hSR-A was correct and no ATG before the translation initiation sites of human SR-A was found by sequence analysis. 561 injected and surviving embryos with the purified human SR-A minigene were implanted into the oviducts of 19 ICR pseudopregnant mice. Among the 54 surviving pups from 13 foster mothers, 7 were identified by PCR and Southern blot analysis. The results of RT-PCR and immunohistochemical analysis showed human SR-A was specifically expressed on vascular endothelial cells of the aorta and renal artery, as well as hepatic sinusoidal endothelial cells in transgenic mice. Transmission electron microscope (TEM) of aorta of transgenic mice showed that a large number of vesicles, multivesicle bodies and swollen mitochondria filled the plasma of endothelial cells. CONCLUSIONS: A transgenic mouse model with overexpression of human SR-A in endothelial cells was successfully established. The transgene was integrated and transmitted into the chromosome of transgenic mice. Tie-1 promoter controlled the transgene to express in endothelial cells in mice. Pinocytic activity of aortic endothelial cells in transgenic mice was higher than that of C57BL/6J mice. Our studies will provide a new transgenic model for investigation of atherosclerosis and functions of human SR-A.

Animals↗
PubMed2004

Mammary tumor heterogeneity in wt-ErbB-2 transgenic mice.

Phenotypic and biological heterogeneity was studied in a single transgenic mouse model to determine the level of biological variance. We analyzed 1,258 tumors from 417 MMTV-wt-ErbB-2 transgenic mice, subdivided by casein or soy-based dietary randomization and hormonal treatment. Variance in tumor histologic features, growth pattern, invasion, metastases, and multi-focality were detected in untreated and treated mice. Ninety-three percent (1,174/1,258) of tumors had the solid growth pattern widely reported in this model. However, among the solid tumors, a spectrum of growth patterns, from well-circumscribed tumors with a pseudocapsule to locally invasive or highly aggressive, metastatic subtype, was observed. Of the non-solid tumors, glandular features were prominent in 84 (7%). Adenocarcinomas included papillary, acinar/glandular, and adenosquamous subtypes. Adenosquamous tumors were exclusively observed in the group of mice treated on a short-term basis with estrogen. In contrast to the reported literature for this transgenic mouse model, mammary tumors were multifocal in the majority of cases (303 of 417 mice, or 73%). Results of this extensive study of a single transgenic model of mammary tumorigenesis indicate phenotypic and biological heterogeneity not previously associated with this transgenic mouse. These data support a complex, multistep process of carcinogenesis and clonal evolution, with biological and phenotypic variance similar to that observed in human mammary cancer development.

Adenocarcinoma↗
PubMed2004

Small intestinal glucose absorption in cystic fibrosis: a study in human and transgenic DeltaF508 cystic fibrosis mouse tissues.

Intestinal transport is disturbed in cystic fibrosis (CF), with both defective Cl- secretion and changes in absorption being reported. We have examined the effects of the disease on Na(+)-dependent glucose absorption by the small intestine. Active glucose absorption was monitored as changes in short-circuit current (SCC) in intact and stripped intestinal sheets from normal (Swiss) and transgenic CF (Cftr(tm1Eur) and Cftr(tm2Cam)) mice with the DeltaF508 mutation, and in jejunal biopsies from children with CF and normal controls. Na(+)-dependent glucose uptake at the luminal membrane was measured in brush-border membrane vesicles (BBMVs). Intact and stripped sheets of jejunum and midintestine from Swiss mice exhibited a concentration-dependent increase in SCC with glucose. Apparent Km values were similar in the two preparations, but the apparent Vmax was greater in stripped sheets. This difference was not due to a loss of neural activity in stripped sheets as tetrodotoxin did not influence the glucose-induced SCC in intact sheets. Similar results were observed in stripped sheets of jejunum and mid-intestine from wild-type Cftr(tm1Eur) mice, but in tissues from CF mice the apparent Vmax value was reduced significantly. A lower Vmax was also obtained in intact sheets of mid-intestine from CF (Cftr(tm2Cam)) mice. Jejunal biopsies from CF patients however, exhibited an enhanced glucose-dependent rise in SCC. Na(+)-dependent uptake by BBMVs from CF (Cftr(tm1Eur)) mice was not reduced compared with wild-type and Swiss BBMVs. It was concluded that, in contrast to human intestine, intestinal glucose absorption was reduced in transgenic mouse models of CF with the DeltaF508 mutation, but that this could not be detected in an isolated preparation of brush-border membranes. Transgenic mouse models of CF may not accurately reflect all aspects of intestinal dysfunction in the human disease.

Animals↗
PubMed2004

Animal models of tumor immunity, immunotherapy and cancer vaccines.

Reliable animal models are critical for evaluating immunotherapies and for defining tumor immunology paradigms. Tumor immunologists are moving away from traditional transplantation tumor systems because they do not adequately model human malignancies. Transgenic mouse models in which tumors arise spontaneously have been developed for most cancers. The models use one of three technologies: tissue-specific promoters to drive expression of SV40 large T antigen or tissue-specific oncogenes; deletion of tumor suppressor genes by gene targeting; or, conditional deletion of tumor suppressor genes or activation of oncogenes via Cre-lox technology. Knockin mice expressing human tumor antigens and gene-targeted mice with deletions for immunologically relevant molecules have been integral to advancing knowledge of the tumor-host relationship. Although animal models are becoming more sophisticated, additional improvements are needed so that more realistic models can be developed.

Animals↗
PubMed2002

Coenzyme Q10 as a possible treatment for neurodegenerative diseases.

Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.

Animals↗
PubMed2002

Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate.

We investigated the potential of genistein, the primary isoflavone of soy, to protect against breast and prostate cancers in animal models. For mammary cancer studies, Sprague-Dawley rats were fed AIN-76A diet plus minus 250 mg genistein/kg diet. Dimethylbenz[a]anthracene was administered by gavage at d 50 postpartum to induce mammary tumors. Mammary cancer chemoprevention was demonstrated after prepubertal and combined prepubertal and adult genistein treatments but not after prenatal- or adult-only treatments, demonstrating that the timing of exposure to genistein is important for mammary cancer chemoprevention. The cellular mechanism of action was found to be mammary gland and cell differentiation, as shown by whole-mount analysis and beta-casein expression. An imprinting effect was shown for epidermal growth factor receptor expression in mammary terminal end buds. For prostate cancer studies, we used two models. The first was a chemically (N-methylnitrosourea) induced prostate cancer rat model. Genistein in the diet inhibited the development of invasive adenocarcinomas in a dose-dependent manner. The second model was a transgenic mouse model that resulted in spontaneously developing adenocarcinoma tumor of the prostate. Genistein in the diet reduced the incidence of poorly differentiated prostatic adenocarcinomas in a dose-dependent manner and down-regulated androgen receptor, estrogen receptor-alpha, progesterone receptor, epidermal growth factor receptor, insulin-like growth factor-I, and extracellular signal-regulated kinase-1 but not estrogen receptor-beta and transforming growth factor-alpha mRNA expressions. We conclude that dietary genistein protects against mammary and prostate cancers by regulating specific sex steroid receptors and growth factor signaling pathways.

Adenocarcinoma↗
PubMed1997

[Efficacy of interferon alpha in primary prevention of preneoplastic lesions in a transgenic murine model of hepatocellular carcinoma related to the interaction between woodchuck hepatitis viruses and c-myc oncogene].

OBJECTIVES: C-myc oncogene overexpression by near insertion of hepatitis B virus is important in woodchuck hepatocarcinogenesis. This DNA fragment was transferred in mice who developed hepatocellular carcinoma via preneoplastic lesions. In the present study, we tested the preventive effect of alpha interferon on the incidence of hepatocyte dysplasia. METHODS: Human recombinant alpha interferon hybrid B/D was continuously administered at increasing doses (0 to 10,000 IU/g) in a transgenic mouse model. One cohort was treated from day 21 to day 80. A histological liver examination was performed and the transgene expression was assessed by hybridization with or without previous genic amplification, and by indirect immunofluorescence. RESULTS: At day 15, histological liver examination was normal. Interferon treatment decreased the expression of viral sequences, but not of c-myc. At day 80, interferon treatment resulted in a reduction of the incidence and severity of dysplasic lesions, and a marked decrease in c-myc overexpression. CONCLUSION: In this transgenic mouse model, alpha interferon treatment decreased the incidence and severity of precancerous lesions, due to a reduction in c-myc overexpression. This prophylaxis could be of interest in human hepatocarcinogenesis where c-myc overexpression is frequent.

Animals↗
PubMed2000

Experimental prostate carcinogenesis - rodent models.

A number of rodent models of prostate carcinoma development have been established to study mechanisms and modifying potential. All except for transgenic mouse models need long experimental periods for generation of a high yield of cancers. Spontaneous prostate tumor models, while not practical in terms of time and tumor incidences, allow the natural course of multistep neoplasia to be followed without a need for chemical exposure. Carcinogens, especially in combination with testosterone, can induce prostate carcinomas in rats, but none are prostate-specific, so that tumor development in other organs is a complicating factor. Induction of invasive prostate carcinomas in the rat frequently requires long-term administration of a pharmacological dose of testosterone with or without application of a chemical carcinogen. While there are several transgenic mouse models, each also has strong and weak points, and it is therefore necessary to select the best model for the purpose of any experimental study.

Aminobiphenyl Compounds↗
PubMed1997

Extramedullary expansion of hematopoietic progenitor cells in interleukin (IL)-6-sIL-6R double transgenic mice.

Soluble cytokine receptors modulate the activity of their cognate ligands. Interleukin (IL)-6 in association with the soluble IL-6 receptor (sIL-6R) can activate cells expressing the gp130 signal transducer lacking the specific IL-6R. To investigate the function of the IL-6-sIL-6R complex in vivo and to discriminate the function of the IL-6-sIL-6R complex from the function of IL-6 alone, we have established a transgenic mouse model. Double-transgenic mice coexpressing IL-6 and sIL-6R were generated and compared with IL-6 and sIL-6R single-transgenic mice. The main phenotype found in IL-6-sIL-6R mice was a dramatic increase of extramedullary hematopoietic progenitor cells in liver and spleen but not in the bone marrow. In IL-6 single-transgenic mice and sIL-6R single-transgenic mice no such effects were observed. The high numbers of hematopoietic progenitor cells were reflected by a strong increase of peripheral blood cell numbers. Therefore, activators of the gp130 signal transducer like the IL-6-IL-6R complex may represent most powerful stimulators for extramedullary hematopoietic progenitor cells. gp130 activators may become important for the expansion of hematopoietic progenitor cells in vivo and in vitro.

Animals↗
PubMed2001

Peripheral T-cell tolerance defined through transgenic mouse studies.

Selection in the thymus restricted by MHC and self-peptide shapes the diverse reactivities of the T-cell population which subsequently seeds into the peripheral tissues, in anticipation of the universe of pathogen antigens to which the organism may be exposed. A necessary corollary is the potential for T-cell self-reactivity (autoimmunity) in the periphery. Transgenic mouse models in which transgene expression in the thymus is prevented or excluded, have been particularly useful for determining the immunological outcome when T-cells encounter transgene-encoded 'self' antigen in peripheral tissues. Data suggest that non-mutually exclusive mechanisms of T-cells 'ignoring' self-antigen, T-cell deletion, T-cell anergy and T-cell immunoregulation have evolved to prevent self-reactivity while maintaining T-cell diversity. The peripheral T-cell repertoire, far from being static following maturation through the thymus, is in a dynamic stated determined by these peripheral selective and immunoregulatory influences. This article reviews the evidence with particular reference to CD8+ive T-cells.

Animals↗
PubMed2000

CD45 opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase.

Reactive microglia have been suggested to play a role in the Alzheimer's disease (AD) process, and previous studies have shown that expression of CD45, a membrane-bound protein-tyrosine phosphatase (PTP), is elevated in microglia in AD brain compared with controls. To investigate the possible role of CD45 in microglial responsiveness to beta-amyloid (Abeta) peptides, we first co-treated primary cultured microglia with a tyrosine phosphatase inhibitor [potassium bisperoxo (1,10-phenanthroline) oxovanadate (phen), 5 micrometer] and freshly solubilized Abeta peptides (1000 nm). Data show synergistic induction of microglial activation as evidenced by tumor necrosis factor alpha (TNF-alpha) production and nitric oxide (NO) release, both of which we show to be dependent on activation of p44/42 mitogen-activated protein kinase (MAPK). Furthermore, co-treatment with phen and Abeta peptides results in microglia-induced neuronal cell injury. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibits these effects via inhibition of p44/42 MAPK, suggesting that CD45 is a negative regulator of microglial activation. Accordingly, primary cultured microglia from CD45-deficient mice demonstrate hyper-responsiveness to Abeta, as evidenced by TNF-alpha release, NO production, and neuronal injury after stimulation with Abeta peptides. As a validation of these findings in vivo, brains from a transgenic mouse model of AD [transgenic Swedish APP-overexpressing (Tg APP(sw)) mice] deficient for CD45 demonstrate markedly increased production of TNF-alpha compared with Tg APP(sw) mice. Taken together, these results suggest that therapeutic agents that stimulate the CD45 PTP signaling pathway may be effective in suppressing microglial activation associated with AD.

Alzheimer Disease↗
PubMed2005

Altered immunity accompanies disease progression in a mouse model of prostate dysplasia.

Increasing evidence suggests that altered immune function accompanies, and indeed may facilitate, cancer progression. In this study, we sought to determine the nature of, and cellular mechanisms underlying, changes in immune status during disease progression in a transgenic mouse model of prostate dysplasia. Immune cells in the tumor microenvironment, as well as in the secondary lymphoid tissues, displayed altered phenotypes. Although evidence of antitumor immunity was detected, there was a paradoxical decrease in the ability of T cells to proliferate in vitro at later stages of disease progression. Detailed analysis of the draining lumbar lymph nodes revealed an increased frequency and number of CD4(+)CD25(+) T cells and an enhanced production of inhibitory cytokines, which correlated with impaired T-cell function. Functional studies confirmed a role for CD4(+)CD25(+) regulatory T cells in suppressing T-cell proliferation as well as regulating the growth of transplanted prostate tumor cells. In addition, our studies show for the first time that anti-CD25 antibody treatment reduces, but does not prevent, tumor growth in a transgenic mouse model of prostate dysplasia. Taken together, this work provides compelling evidence that prostate tumor progression is accompanied by altered immune function and, moreover, that regulatory T cells play an important role in this process. These studies thus provide the impetus for development of specific and effective strategies to deplete regulatory T cells, or suppress their function, as an alternative or adjunct strategy for reducing tumor growth.

Animals↗
PubMed1999

Using transgenic models to study the pathogenesis of keratin-based inherited skin diseases.

In the past decade, the production of transgenic animals whose genome is modified to contain DNA transgenes of interest has significantly contributed to expand our understanding of the molecular etiology and pathobiology of several inherited skin diseases. This technology has led to the discovery that mutations affecting specific keratin genes are responsible for a wide spectrum of inherited bullous diseases, which are collectively characterized by blistering after minor trauma. Type I and type II keratin proteins are restricted to, and very abundant in, epithelial cells, where they occur as a pancytoplasmic network of cytoskeletal filaments. Although it had long been suspected that a primary function of keratin filaments may be to contribute to the physical strength of epithelial sheets, a formal demonstration came from studies of transgenic mouse models and patients suffering from keratin-based blistering diseases. Here we review the basic characteristics of keratin gene and their proteins and relate them to the molecular pathogenesis of relevant inherited skin blistering diseases. A particular emphasis is placed on the role of transgenic mouse models in the past, current, and future studies of these genodermatoses.

Animals↗
PubMed1994

Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene.

A transgenic mouse model for prostate and mammary cancer has been developed in mice containing a recombinant gene expressing the simian virus 40 early-region transforming sequences under the regulatory control of the rat prostatic steroid binding protein [C3(1)] gene. Male transgenic mice develop prostatic hyperplasia in early life that progresses to adenoma or adenocarcinoma in most animals surviving to longer than 7 months of age. Prostate cancer metastases to lung have been observed. Female animals from the same founder lines generally develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age in 100% of the animals. The development of tumors correlates with the expression of the transgene as determined by Northern blot and immunohistochemical analyses. The results of these experiments demonstrate that the C3(1) regulatory region used in these experiments is useful for targeting expression to the prostate and mammary gland. To our knowledge, this experimental system is the first reported transgenic mouse model for prostate cancer. These transgenic animals offer the opportunity to study hormone response elements in vivo and the multistage progression from normal tissue to carcinoma in the prostate and mammary glands.

Adenocarcinoma↗
PubMed2004

Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington's disease transgenic mice.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion coding for an expanded polyglutamine tract in the huntingtin protein. Dendritic abnormalities occur in human HD patients and in several transgenic mouse models of the disease. In this study, we examine, for the first time, dendrite and spine pathology in the R6/1 mouse model of HD, which mimics neurodegeneration seen in human HD. Enriching the environment of HD transgenic mice delays the onset of symptoms, so we also examine the effects of enrichment on dendrite pathology. Golgi-impregnated tissue from symptomatic R6/1 HD mice reveals a decrease in dendritic spine density and dendritic spine length in striatal medium spiny neurons and cortical pyramidal neurons. HD also causes a specific reduction in the proportion of bifurcated dendritic spines on basal dendrites of cortical pyramidal neurons. No differences in soma size, recurving distal dendrites, or dendritic branching were observed. Although home-cage environmental enrichment from 1 to 8 months of age increases spine density in wild-type mice, it has no effect on the spine pathology in HD mice. These results show that dendritic spine pathology in R6/1 HD mice resembles degenerative changes seen in human HD and in other transgenic mouse models of the disease. We thus provide further evidence that the HD mutation disrupts the connectivity in both neostriatum and cerebral cortex, which will contribute to motor and cognitive disease symptoms. Furthermore, we demonstrate that Huntington's disease pathology interferes with the normal plastic response of dendritic spines to environmental enrichment.

Animals↗
PubMed1998

Targeting tumor cells with bispecific antibodies and T cells.

It has been known for some time that mammalian immune systems are capable of eliminating large tumor burdens. Redirecting the immune response of a patient to an established tumor has now become the focus of various therapeutic strategies. In this report, two projects toward this goal are described. The first project involves the development of a transgenic mouse model for T cell directed therapeutics. These mice express specific T cell receptor alpha and beta transgenes on a background in which the recombinational-activating-gene-1 (RAG) has been knocked out. The mice express cytotoxic T cells but not either T helper cells or B cells. Despite these deficiencies, the animals are capable of eliminating tumors that express the appropriate peptide/major histocompatibility complex ligand that is recognized by the alphabeta transgenic T cell receptor. Human tumors grow as transplants in these mice, thereby allowing various agents that redirect the endogenous T cells against human tumors to be tested. The second project involves a description of such agents: bispecific antibodies that simultaneously bind to an immune effector cell and a tumor cell. The bispecific antibody described here consists of folate attached to anti-T cell receptor antibodies, or their fragments. A single-chain Fv coupled with folate can redirect the lysis of human tumor cells that bear the high affinity folate receptor. Preliminary in vivo data showed that the folate/antibody conjugates were also capable of mediating rejection of the human tumor. This transgenic mouse model should now allow the evaluation and optimization of bispecific agents that can redirect a patient's own T cell response.

Amino Acid Sequence↗
PubMed2006

Conditional transgenic models define how MYC initiates and maintains tumorigenesis.

MYC is one of the most commonly overexpressed oncogenes in human cancer. The targeted inactivation of MYC is a possible therapy for neoplasia. Conditional transgenic mouse model systems are tractable methods to precisely dissect how and when the inactivation of MYC might be effective in the treatment for human cancer. From these model systems, several general principles emerge. MYC inactivation stereotypically results in the proliferative arrest, differentiation and/or apoptosis of tumor cells. The specific consequences of MYC inactivation appear to depend both on the type of cancer as well as the constellation of genetic events unique to a given tumor. Tumors can escape from dependence upon MYC by acquiring compensatory genetic events. MYC inactivation can uncover the stem cell properties of tumor cells that differentiate into normal appearing cells. In some cases, these differentiated cells are actually dormant tumor cells that recover their neoplastic properties upon MYC reactivation. In other cases, even brief MYC inactivation is sufficient to induce sustained tumor regression. Insights from conditional transgenic mouse models will be useful in the development of therapies that target MYC for the treatment of cancer.

Animals↗