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PubMed2004

Interferon-beta gene therapy improves survival in an immunocompetent mouse model of carcinomatosis.

BACKGROUND: Interferon-beta (IFNbeta) has multiple antitumor effects; however, its use has been limited by its short half-life in vivo. This limitation may be overcome by IFNbeta gene therapy. We evaluated adenovirus-IFNbeta therapy in an immunocompetent mouse model of carcinomatosis. METHODS: Mice that were treated intraperitoneally 5 days after tumor (mouse ovarian teratoma) inoculation with an adenoviral vector that contains the mouse IFNbeta gene (Ad-IFNbeta), control adenoviral vector or saline solution. Mice were monitored for multiple outcome measures and toxicity. To determine the mechanism of antitumor effect, flow cytometry of ascites fluid was performed to differentiate immune cell populations. Nitric oxide in ascites fluid was measured with an electrochemical microsensor. RESULTS: Tumor burden was decreased and survival was prolonged (P<.001) in the Ad-IFNbeta group after a single treatment of 3.3 x 10(8) plaque-forming units, with acceptable toxicity. By flow cytometry, an increase in the proportion of natural killer cells (from less than 2% of the gated population to more than 8%; P=.024) and an increase in macrophages were seen in the treated animals. Although there was a trend toward increased levels of nitric oxide in Ad-IFNbeta treatment groups, it was not statistically significant. CONCLUSION: IFNbeta gene therapy results in decreased tumor burden and improved survival in an aggressive, immunocompetent mouse model of carcinomatosis. This therapy warrants further evaluation as a treatment for disseminated peritoneal cancer.

Adenoviridae↗
PubMed2003

Introduction of estrogen receptor-alpha into the tTA/TAg conditional mouse model precipitates the development of estrogen-responsive mammary adenocarcinoma.

Conditional expression of estrogen receptor (ER)-alpha) was introduced into tetracycline-responsive MMTV-tTA/tetop-TAg mice to develop a mouse model of estrogen-responsive ER-alpha-positive mammary adenocarcinoma. Mammary adenocarcinomas developed in the mice with a mean latency of 11 months. Precursor lesions including ductal hyperplasia and hyperplastic alveolar nodules were present by the age of 4 months. The mammary adenocarcinomas exhibited histological features similar to human breast cancers. ER steroid-binding studies conducted on adenocarcinoma lysates demonstrated binding to estradiol. Tumor explant studies in the presence and absence of estradiol in ovariectomized athymic nude mice revealed that growth of mammary tumors was stimulated by estrogen. In addition, the presence of ER-alpha altered the tumor spectrum in other MMTV-targeted tissues in the tTA/TAg female mice. Lymphomas, which develop in 40% of tTA/TAg female mice, were found in only 4% of tTA/TAg/ER-alpha mice (P = 0.014, chi-square test). These experiments demonstrate that the introduction of an ER-alpha transgene targeted to mammary epithelial cells can be used to develop mouse models of ER-alpha-responsive mammary cancer.

Adenocarcinoma↗
PubMed2006

A critical role for the inflammatory response in a mouse model of preneoplastic progression.

The tumor microenvironment, which includes inflammatory cells, vasculature, extracellular matrix, and fibroblasts, is a critical mediator of neoplastic progression and metastasis. Using an inducible transgenic mouse model of preneoplastic progression in the mammary gland, we discovered that activation of inducible fibroblast growth factor receptor-1 (iFGFR1) in the mammary epithelium rapidly increased the expression of several genes involved in the inflammatory response. Further analysis revealed that iFGFR1 activation induced recruitment of macrophages to the epithelium and continued association with the alveolar hyperplasias that developed following long-term activation. Studies using HC-11 mammary epithelial cells showed that iFGFR1-induced expression of the macrophage chemoattractant osteopontin was required for macrophage recruitment in vitro. Finally, conditional depletion of macrophages inhibited iFGFR1-mediated epithelial cell proliferation and lateral budding. These findings show that inflammatory cells, specifically macrophages, are critical for mediating early events in an inducible transgenic mouse model of preneoplastic progression.

Animals↗
PubMed1996

The Helicobacter felis mouse model in assessing anti-Helicobacter therapies and gastric mucosal prostaglandin E2 levels.

BACKGROUND: The aims of the present study were to assess the usefulness of the Helicobacter felis mouse model in the evaluation of antimicrobial therapies and the effect of Helicobacter infection on gastric mucosal prostaglandin E2 release. METHODS: Barrier-maintained BALB/c mice were infected with H. felis and treated with different antibacterial therapies. H. felis status was determined by bacterial culture, urease test, and bacterial and histologic stainings. Release of prostaglandin E2 from the gastric mucosa was measured by radioimmunoassay. RESULTS: All triple-treated mice were cleared of bacteria both 24 h and 1 month after treatment. However, tinidazole alone also resulted in 100% eradication. Monotherapies with erythromycin acistrate, tetracycline, colloidal bismuth subcitrate, and nitecapone failed to eradicate the bacteria. The release of gastric prostaglandin E2 was doubled in the infected mice (554 +/- 39, mean +/- SE) compared with the noninfected mice (270 +/- 35) (p < 0.01). CONCLUSIONS: The H. felis mouse model proved satisfactory for assessing both anti-Helicobacter therapies and the prostaglandin E2 release. The reliability of this method was improved when several methods to assess the H. felis status were used in parallel.

Amoxicillin↗
PubMed2002

Neuroimmunophilin ligand V-10,367 is neuroprotective after 24-hour delayed administration in a mouse model of diffuse traumatic brain injury.

The authors present two studies that investigate the biochemical and histologic effects of the nonimmunosuppressive neuroimmunophilin (NIMM) ligand V-10,367 in a mouse model of traumatic brain injury (TBI). In study 1, the authors examined the effect of V-10,367 (50 mg/kg x 2 per day, by mouth) on neurofilament M (NFM) protein levels and on alpha-spectrin breakdown products (SBDPs) when dosed for 2 days, starting 24 hours after TBI and killed on day 3. In study 2, V-10,367 was given for 10 days, starting 24 hours after TBI and the mice killed 6 weeks after TBI, to measure the extent of neurodegeneration (amino CuAg stain). The results in study 1 revealed that V-10,367-treatment significantly increased NFM protein levels in both sham and TBI mice. In addition, V-10,367 attenuated SBDP 150 levels in the cortex, striatum, and hippocampus. The results of study 2 indicated that TBI mice treated with V-10,367 demonstrated significantly less neurodegeneration compared to injured, vehicle-treated mice. In summary, these results suggest that NIMMs may be neuroprotective indirectly through inhibition of calpain-mediated cytoskeletal damage and perhaps via maintenance of neuronal plasticity. In the context of this mouse model of TBI, the therapeutic window for V-10,367's positive effects is at least 24 hours after injury, which, in the case of TBI models, is largely unprecedented for a neuroprotective compound.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Development of a new mouse model of acute pancreatitis induced by administration of L-arginine.

The pathogenesis of acute pancreatitis is not fully understood. Experimental animal models that mimic human disease are essential to better understand the pathophysiology of the disease and to evaluate potential therapeutic agents. Given that the mouse genome is known completely and that a large number of strains with various genetic deletions are available, it is advantageous to have multiple reliable mouse models of acute pancreatitis. Presently, there is only one predominant model of acute pancreatitis in mice, in which hyperstimulatory doses of cholecystokinin or its analog caerulein are administered. Therefore, the aim of this study was to develop another mouse model of acute pancreatitis. In this study, C57BL/6 mice were injected intraperitoneally with L-arginine in two doses of 4 g/kg each, 1 h apart. Serum amylase, myeloperoxidase, and histopathology were examined at varying time points after injection to assess injury to the pancreas and lung. We found that injection of L-arginine was followed by significant increases in plasma amylase and pancreatic myeloperoxidase accompanied by marked histopathological changes. The injury to the pancreas was slow to develop and peaked at 72 h. Subsequent to peak injury, the damaged areas contained collagen fibers as assessed by increased Sirius red staining. In contrast, D-arginine or other amino acids did not cause injury to the pancreas. In addition, acute inflammation in the pancreas was associated with lung injury. Our results indicate that administration of L-arginine to mice results in severe acute pancreatitis. This model should help in elucidating the pathophysiology of pancreatitis.

Acute Disease↗
PubMed2002

Conditional over-expression of estrogen receptor alpha in a transgenic mouse model.

Attempts to delineate the mechanisms of estrogen action have promoted the creation of several estrogen receptor alpha (ERalpha) mouse models in the past decade. These traditional models are limited by the fact that the receptors are either absent or present throughout all stages of development. The purpose of this work was to develop a conditional transgenic model that would provide an in vivo method of controlling the spatial and temporal regulation of ERalpha expression. The tetracycline responsive system was utilized. Three lines of transgenic mice carrying a transgene composed of the coding sequence for murine ERalpha placed under the regulatory control of a tet operator promoter (tet-op) were generated. These three lines of tet-op-mERa mice were each mated to an established line of transgenic mice expressing a tetracycline-dependent transactivator protein (tTA) from the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). Double transgenic MMTV-tTA/tet-op-mERalpha mice were produced. All three lines demonstrated dominant gain of ERalpha shown by RT-PCR, immunoprecipitation, and immunohistochemistry. Transgene-specific ERalpha was expressed in numerous tissues including the mammary gland, salivary gland, testis, seminal vesicle, and epididymis. Expression was silenced by administration of doxycycline in the drinking water. This model can be utilized to evaluate the consequences of ERalpha dominant gain in targeted tissues at specific times during development. In this study dominant gain of ERalpha was associated with a reduction in epididymal/vas deferens and seminal vesicle weights consistent with the proposed action of ERalpha on fluid transport in the male reproductive tract. Combining this model with other dominant gain and gene knockout mouse models will be useful for testing effects of ERalpha action in combination with specific gene products and to evaluate if developmental and stage-specific expression of ERalpha can rescue identified phenotypes in gene knockout mice.

Animals↗
PubMed2006

Prenatal viral exposure followed by adult stress produces glucose intolerance in a mouse model.

AIMS/HYPOTHESIS: It has been suggested that the uterine environment may influence metabolic disease occurring later in adult life, and that adult stress may promote disease outcome. Using a mouse model, we tested whether in utero exposure to Ljungan virus (LV) followed by adult exposure to stress produces diabetes. The influence of the timing of viral exposure over the course of pregnancy was also tested. MATERIALS AND METHODS: Pregnant CD-1 mice were exposed i.p. to LV on pregnancy days 4, 8, 12 or 17. Adult male mice from these pregnancies were stressed by being kept in shared cages. Stress only, LV exposure in utero only, and no-stress/no virus exposure groups were also followed. Outcome variables included bodyweight, epididymal fat weight, baseline glucose, glucose tolerance tests (60 and 120 min) and serum insulin. RESULTS: We demonstrated that male mice developed a type 2-like diabetes, including obesity, as adults if infected during pregnancy with LV. Diabetes at the age of 11 weeks was more severe in mice whose mothers were infected earlier than in those whose mothers were infected later in pregnancy. Only animals infected in utero and kept under stress developed diabetes; infection or stress alone did not cause disease. CONCLUSIONS/INTERPRETATION: This work demonstrates that a type 2 diabetes-like disease can be virus-induced in a mouse model. Early in utero viral insults can set the stage for disease occurring during adult life, but the final manifestation of diabetes is dependent on the combination of early viral exposure and stress in adult life.

Animals↗
PubMedDate not supplied

Developing mouse models of aging: a consideration of strain differences in age-related behavioral and neural parameters.

Increased interest is emerging for using mouse models to assess the genetics of brain aging and age-related neurodegenerative diseases. Despite this demand, relatively little information is available on aging in behavioral or neuromorphological parameters in various mouse strains that are being used to create transgenic and null mutant mice. We review several issues regarding selection of appropriate strains as follows: (1) Does the behavioral parameter exhibit a significant age by strain interaction? (2) Do the strains differ in lifespan? (3) Are there potential intervening variables, such as strain-specific performance strategies or disease, in the behavioral task being investigated that would confound the desired conclusions? (4) Does the behavioral difference have an underlying neural correlate? In this context we present a conceptual model pertaining to the selection of mouse strains and behavioral parameters for genetic analyses. We also review the importance of applying stereological techniques for determining age-related structural changes in the mouse brain as well as the potential value of a database that would catalog this information. Thus, our intention is to underscore the growing importance of mouse models of brain aging and the concomitant need for additional information about mouse aging in general.

Aging↗
PubMed1983

Immunobiological aspects of the nude mouse model relative to human cancer chemosensitivity tests.

The nude mouse model (NMM) has been proposed for testing chemosensitivity of human cancer cells with encouraging results. However, nude mice cannot be considered as unreactive "test tube" recipients of allogeneic or xenogeneic tissues, since a variety of immunological functions are fully represented in these hosts. In general, graft resistance against tumour cells can be classified as: (a) elicitable responses (ER), thymus-dependent, evoked by tumour-associated antigens; (b) natural resistance (NR), T-independent, not requiring previous exposure to transplantation antigens. Graft resistance may therefore play a substantial role even in the absence of a functional T-cell system. This has been demonstrated in irradiated euthymic mice capable of rejecting Hh-incompatible lymphomas, and in nude mice, where NR-type responses are particularly efficient, either in vitro or in vivo. It is reasonable to assume that these responses could interfere with tumour responsiveness to the chemotherapeutic effects of drugs. In fact, marked synergistic effects have been observed in conventional hosts combining chemotherapy with limited ER, or with Hh-type NR present in lethally irradiated mice. Similar combined effects could occur in nude mice bearing NR-susceptible human tumours in the course of chemosensitivity assays. These considerations have led to the search for privileged sites associated with low levels of NR; previous results show that these responses appear to be substantially absent in the brains of conventional mice and extremely low in the same organ of congenitally athymic hosts. It follows that the brain of the nude mouse appears to be a suitable site for human tumour cell growth, unaffected by or minimally subjected to NR.

Animals↗
PubMed2001

HLA-DR modulates autoantibody repertoire, but not mortality, in a humanized mouse model of systemic lupus erythematosus.

To evaluate the disease-modulating role of HLA-DR2 and DR3 molecules, which have been associated with systemic lupus erythematosus, a humanized mouse model was examined. HLA-DR2 (DRB1*1502)- and DR3 (DRB1*0301)-transgenic mice were backcrossed to the New Zealand Mixed 2410 (NZM 2410, H2(z)) strain. Seventh generation DR2 and DR3 transgene-positive animals along with their transgene-negative littermates and the parental strain NZM2410 were monitored for proteinuria, azotemia, autoantibody production, development of nephritis, and mortality. The results showed no significant differences in proteinuria, azotemia, or mortality between the backcrosses with and without HLA-DR2 or HLA-DR3. However, the genetic analysis of different backcrosses showed that heterozygosity at the endogenous H2-E locus (E(z)/E(b)) was strongly linked with acceleration of lupus nephritis in both HLA-DR2 and HLA-DR3 transgenics. More importantly, the presence of the HLA-DR2, but not the HLA-DR3, transgene significantly enhanced the production of anti-dsDNA, but not anti-ssDNA, anti-histone-dsDNA complex, or anti-histone, Abs. In contrast, neither HLA-DR2 nor HLA-DR3 influenced the development of glomerulonephritis or the degree of immune complex deposition. Moreover, nephritic kidneys from mice with and without HLA-DR2 or HLA-DR3 transgenes showed similar patterns of cytokine expression. Collectively, these findings provide molecular evidence that the association of HLA-DR2 or HLA-DR3 with lupus susceptibility is related to the type of autoantibody rather than to disease mortality. The use of a humanized mouse model provides a way of dissecting the roles of human MHC genes in systemic lupus erythematosus pathogenesis.

Animals↗
PubMed1998

Mycophenolate mofetil suppresses autoimmunity and mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus.

OBJECTIVE: To examine the effects of the immunosuppressant, mycophenolate mofetil (MM), on autoimmunity, glomerulonephritis, and mortality in the female NZB x NZW F1 (B/W) mouse model of systemic lupus erythematosus (SLE). METHODS: The development of murine lupus was assessed during the lifespan of 10 female B/W mice given 200 mg/kg/day of MM compared to 10 female B/W mice given vehicle. At 6 week intervals, mice were examined for weight change, albuminuria, antibodies to DNA, and IgG immunoglobulin levels. Morbidity and mortality were assessed daily. In a parallel study, MM treated and control B/W mice were examined at 18 weeks of age for splenocyte phenotype and adhesion molecule expression, as well as antibody titers and in vitro cytokine production in response to immunization with dinitrophenyl-keyhole limpet hemocyanin (DNP-KLH). RESULTS: The administration of MM was well tolerated without apparent side effects. Weight gain in MM treated and control mice was identical through 36 weeks of age. In the treatment group, MM suppressed the development of albuminuria and anti-DNA antibodies compared to the control animals. There were no significant differences between groups in serum concentrations of total IgG. At 60 weeks of age survival in the MM treated group was 100% compared to 10% in the control group. MM did not alter the percentages of CD4, CD8, or IgM positive splenocytes; however, the percentage of CD4+ T lymphocytes expressing very late antigen 4 and intercellular adhesion molecule 1 was reduced. MM inhibited the antibody response to DNP-KLH immunization in vivo; however, in vitro cytokine production in response to KLH was not suppressed. CONCLUSION: MM suppressed the development of autoimmunity and prolonged lifespan in the female B/W mouse model of SLE. Suppression of autoimmunity was achieved without obvious side effects or altered CD4:CD8 T cell ratios. MM may be a useful primary or adjunctive therapy in human SLE.

Albuminuria↗
PubMed2006

Cloning of pig parotid secretory protein gene upstream promoter and the establishment of a transgenic mouse model expressing bacterial phytase for agricultural phosphorus pollution control.

This study examined the feasibility of using the promoter of the pig parotid secretory protein (PSP) gene for expression of the phytase transgene in mouse models. The pig parotid secretory protein gene is specifically expressed at high levels in the salivary glands. The 10-kb upstream promoter region of the gene necessary for tissue-specific expression has been identified. We have constructed phytase transgenes composed of the appA phytase gene from Escherichia coli driven by the upstream promoter region of the pig PSP gene with a 3' tail of either bovine growth hormone or the pig PSP gene polyadenylation signal. Transgenic mouse models with the construct showed that the upstream region of the pig PSP gene is sufficient for directing the expression of phytase transgenes in the saliva. Expression of salivary phytase reduced fecal phytate by 8.5 and 12.5% in 2 transgenic mouse lines, respectively. These results suggest that the expression of phytase in salivary glands of monogastric animals offers a promising biological approach to relieve the requirement for dietary phosphate supplements and to reduce phosphorus pollution from animal agriculture.

6-Phytase↗
PubMed1998

Spontaneous autoimmune gastritis in C3H/He mice: a new mouse model for gastric autoimmunity.

Autoimmune gastritis is the underlying pathological lesion of pernicious anemia in humans. The lesion is characterized by a chronic inflammatory infiltrate in the gastric mucosa with loss of parietal and zymogenic cells. It is associated with circulating autoantibodies to the gastric H/K-ATPase, the enzyme responsible for acidification of gastric juice. Experimental models of autoimmune gastritis have previously been produced in mice after a variety of manipulations, including thymectomy. Here we report for the first time a spontaneous mouse model of autoimmune gastritis in C3H/He mice. The spontaneous gastritis is also accompanied by circulating autoantibodies to the gastric H/K-ATPase. The spontaneous mouse model should be useful for studies directed toward the immunopathogenesis and treatment of autoimmune gastritis.

Animals↗
PubMed2002

Transgenic animal models for type 1 diabetes: linking a tetracycline-inducible promoter with a virus-inducible mouse model.

Autoimmunity is thought to emerge as a consequence of genetic predispositions and environmental tiggering factors. Often the etiology and the mechanisms involved in the autoaggressive destruction of self-components are rather complex and in many cases poorly understood. Chemokines and cytokines are central mediators of inflammatory processes that are involved in initiation and progression of autoimmunity. Many animal models for human autoimmune diseases use transgenic technology to express chemokines and/or cytokines in an organ or tissue specific manner. However, most of these model systems express the transgene irreversibly without considering the time of expression as a very important parameter. Here, we review experiences that were made from using a tetracycline-inducible promotor system (tTA-system) to express TNFalpha at various times during an ongoing autoimmune process, such as the destruction of pancreatic beta-cells in a mouse model for human type 1 diabetes.

Animals↗
PubMed2005

Apoptosis through targeted activation of caspase 8 ("ATTAC-mice"): novel mouse models of inducible and reversible tissue ablation.

Recent studies identifying obesity as a significant and increasingly more common cause of morbidity and mortality have intensified research efforts aimed at increasing our understanding of adipose tissue biology. These efforts have culminated in the discovery of several adipokines, or adipose tissue-derived hormones, that have been implicated in the regulation of multiple physiological functions, as well as the realization that adipose tissue dysfunction plays an important role in the pathogenesis of diseases such as obesity and diabetes. To better understand the role of adipose tissue in these physiological/pathological events, several studies have employed transgenic strategies to eliminate adipose tissue. However, these mouse models of congenital lipoatrophy/lipodystrophy exhibit severe metabolic and somatic cell dysfunction. To circumvent this limitation, we have designed and characterized the first inducible fatless mouse. The FAT-ATTAC mouse is a transgenic model whereby expression of a myristoylated caspase 8-FKBP fusion protein enables selective ablation of adipocytes via induction of apoptosis that occurs upon treatment with a chemical dimerizer. The FAT-ATTAC mouse model not only has the advantage that adipocyte ablation be induced at any time during development, but it is also fully reversible, as adipose tissue regenerates after cessation of dimerizer treatment. The inducibility of this fatless mouse model holds potential for revealing novel physiological roles for adipose tissue as well as its contribution to the etiology and pathogenesis of various disease states. Here we describe several ongoing areas of research employing the FAT-ATTAC mouse; in addition we describe potential uses of the targeted transgenic apoptotic approach to study other cell types of interest.

Adipose Tissue↗
PubMed2006

Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the disease cystic fibrosis. We previously reported that gentamicin administration suppressed a CFTR premature stop mutation in a Cftr-/- mouse model carrying a human CFTR-G542X (hCFTR-G542X) transgene, resulting in the appearance of hCFTR protein and function. However, the high doses used in that study resulted in peak serum levels well beyond the levels typically administered to humans. To address this problem, we identified doses of both gentamicin and amikacin that resulted in peak serum levels within their accepted clinical ranges. We then asked whether these doses could suppress the hCFTR-G542X mutation in the Cftr-/- hCFTR-G542X mouse model. Our results indicate that low doses of each compound restored some hCFTR protein expression and function, as shown by immunofluorescence and short-circuit current measurements. However, we found that amikacin suppressed the hCFTR-G542X premature stop mutation more effectively than gentamicin when administered at these clinically relevant doses. Because amikacin is also less toxic than gentamicin, it may represent a superior choice for suppression therapy in patients that carry a premature stop mutation in the CFTR gene.

Amikacin↗
PubMed2004

Mouse models of mitochondrial dysfunction and heart failure.

Mitochondria in the adult mammalian heart have a tremendous capacity for oxidative metabolism, and the conversion of energy by these pathways is critical for proper cardiac function. This review describes mouse models relating mitochondrial metabolism to cardiac function through gain- or loss-of-function approaches that manipulate mitochondrial energy transduction or ATP synthetic pathways. Mouse models of mitochondrial defects are relevant to genetic and acquired forms of human cardiomyopathy. Examples include inborn errors in mitochondrial metabolism or end-stage heart failure. Conversely, chronic reliance on energy production via mitochondrial fatty acid oxidation, such as occurs in the diabetic heart, likely leads to maladaptive sequelae including cellular lipotoxicity and mitochondrial dysfunction. Collectively, these model systems have allowed us to begin to dissect the relationship between mitochondrial metabolism and the development of cardiomyopathy and to define the molecular pathways regulating cardiac mitochondrial number and function.

Animals↗