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PubMedDate not supplied

Immune reproductive failure: effect of nonspecific immunostimulation in mouse model.

There is much evidence that pregnancy loss may be immunologically mediated. Failure of the maternal immune system to actively support the pregnancy may be responsible for its demise. Potentiation of immune functions has been attempted in humans; however, the success of immunotherapy is still not clear. Thus immunotherapy experiments in mouse models are important. Nonspecific immuno-stimulation with complete Freund adjuvant (CFA) was shown in our laboratory to reverse the tendency to fetal loss in the CBA/J X DBA/2J mouse combination. CFA elevates the non-T lymphocyte population, decreases T-cell secreted lymphokines, and enhances macrophage-secreted monokines. However, a relationship between these changes and a beneficial effect of CFA on reproductive performance has to be proved. Information obtained from nonspecific immunopotentiation in the CBA/J-DBA/2J model may contribute the assessment of nonspecific immunotherapy in humans.

Animals↗
PubMed2000

Transgenic mouse models in carcinogenesis research and testing.

Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c-myc cDNA and mouse metallothionein 1 promoter-human TGF-alpha cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing both the interaction of nuclear oncogenes and growth factors in tumorigenesis. In addition, these mice provide an experimental model to test how environmental chemicals might interact with the c-myc and TGF-alpha transgenes during the neoplastic process. We show experimental evidence that co-expression of TGF-alpha and c-myc transgenes in mouse liver promotes overproduction of ROS and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-alpha/c-myc mouse model. Also, the role of mutagenesis in hepatocarcinogenesis induced by 2-amino-3,8-dimethylimidazo(4,5-f)-quinoxaline (MeIQx) was demonstrated in C57BL/lacZ (Muta Mice) and double transgenic c-myc/lacZ mice that carry the lacZ mutation reporter gene. The MeLQx hepatocarcinogenicity was associated with an increase in in vivo mutagenicity as scored by mutations in the lacZ reporter gene. These results suggest that transgenic mouse models may provide important tools for testing both the carcinogenic potential of environmental chemicals and the interaction/cooperation of these compounds with specific genes during the neoplastic process.

Animals↗
PubMed1986

Pharmacological analysis of rebound excitation in large intestine of piebald mouse model for Hirschsprung's disease.

Pharmacological agents that might influence the poststimulus rebound contractile response (PSRR) through an action on the intrinsic inhibitory innervation of the circular muscle coat were studied in the large intestine of the piebald mouse model for Hirschsprung's disease. Tetrodotoxin (0.3-3 microM) suppressed, in a dose-dependent manner, the amplitude, duration, and area under the contractile traces of the PSRR and increased the latency for the response in ganglionated segments of the large intestine of piebald and normal mice. Sensitivity to tetrodotoxin was greater in the megacolon of piebald mice than in the colon of normal mice. Norepinephrine (6-360 microM) suppressed all parameters of the PSRR in ganglionated regions of the large intestine of abnormal mice. Sensitivity to norepinephrine was greater in the megacolon than in the colon of normal mice. Norepinephrine abolished spontaneous contractile behavior in ganglionated regions of the large intestine of normal and diseased mice and in the aganglionic segment of the piebald mice. Suppression of the PSRR by phentolamine and propranolol were interpreted as nonspecific local anesthetic effects. Atropine (20-200 microM) increased the area under the contractile traces in the midcolon of the intestine of both normal and piebald mice and had no effects on the terminal segment of the large intestine of normal mice. Spontaneous contractile activity and baseline tension were increased by atropine (350 microM) in all preparations. The nicotinic agonist, DMPP (3-157 microM), suppressed the PSRR in the ganglionated regions of the bowel from both normal and abnormal mice. DMPP relaxed resting tension in ganglionated regions, but did not affect the aganglionic terminal segment of the piebald mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Mouse models and the role of nitric oxide in reproduction.

As a group, nitric oxide synthase (NOS) isoforms are localized to a wide variety of tissues. Understanding the role of NOS in reproductive physiology was facilitated by the introduction of genetically engineered mice. Specifically, "knock-out" mice with targeted disruptions in neuronal NOS, endothelial NOS and inducible NOS have been made. These models have been useful in addressing the of role of nitric oxide in areas of reproductive biology that include: hypothalamic-pituitary-ovarian axis, mating behavior, maternal blood pressure regulation and fetal development. Despite several promising observations using "knock-out" mouse models, one must exercise caution in interpreting data from individual experiments. Very often the need to draw on two mouse strains to generate the founder NOS deficient line, purity of the strain used for observing phenotypes (presence or absence of backcrossing to achieve a pure strain), and the strain used for comparison purposes (control strains are often not identical in their genetic make-up to the deficient line) make wide spread applicability of results open to criticism.

Animals↗
PubMed2005

Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy.

EphA2, a receptor tyrosine kinase, is elevated in many invasive human breast cancers, and the majority of EphA2 remains unphosphorylated. The successful attachment of ligand EphrinA1 present on the surface of adjacent cells to EphA2 initiates EphA2 phosphorylation leading to its turnover. In vivo efficacy of various approaches targeting EphA2 for breast cancer therapy is usually evaluated in nude mice bearing human breast cancer xenografts. In order to establish an immunocompetent mouse model of breast cancer for EphA2-targeted therapies, we evaluated a mouse breast cancer cell line (MT1A2) for EphA2 expression and phosphorylation. Overexpression of EphA2 was observed in MT1A2 cells and the majority of it remained unphosphorylated signifying that EphA2 in MT1A2 cells behaved similar to that of human breast cancer cells. Human adenovirus subtype 5 (HAd5) vectors expressing secretory forms of EphrinA1 were used for in vitro and in vivo targeting of MT1A2-derived EphA2. MT1A2 cells infected with HAd-EphrinA1-Fc (HAd expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) induced EphA2 activation and its turnover. This led to inhibition in MT1A2 cell colony formation in soft agar and cell viability in monolayer culture. In addition, MT1A2 cells-infected with HAd-EphrinA1-Fc failed to form tumors in syngeneic FVB/n mice at least 32 days postinoculation. Moreover, intratumoral inoculation of FVB/n mice-bearing MT1A2-induced tumors with HAd-EphrinA1-Fc slowed the tumor growth and also resulted in the development of vector-specific immune response. These results indicate that FVB/n mice-bearing MT1A2-induced tumors could serve as an immunocompetent model of breast cancer for EphA2-targeted therapeutic strategies.

Adenoviridae↗
PubMed1987

Morphometric study of the anteroventral cochlear nucleus of two mouse models of presbycusis.

The dimensions and volume of the anterior ventral cochlear nucleus (AVCN), the density and number of AVCN neurons, and the size of neuronal somata nuclei (in Nissl-stained tissue) were determined in two mouse models of age-related hearing loss: the C57BL/6J strain, which undergoes progressive chronic sensorineural hearing loss with onset during young adulthood, and the CBA/J, which demonstrates only moderate hearing loss with onset late in life. Frontal and horizontal AVCN sections, as well as cochleas, were analyzed in 4 C57 age-groups (1, 7, 12, 19+ months) and in 3 CBA groups (1, 10, 22 months). Within each strain no significant changes in AVCN dimensions or volume occur with aging. In C57 mice, packing density and cell number decrease between 1 and 7 months, but remain stable thereafter, despite chronic severe hearing impairment. CBA mice show a reduction in AVCN cell number and packing density only during the second year of life. In aging C57 mice, the size of spherical and perhaps globular cells increases, whereas the size of multipolar cells tends to decrease slightly. In CBA mice, all three AVCN cell types tend to decrease in size with aging. The early cell loss and cell size increases in C57 mice are most consistent in the dorsal (high frequency) region of the AVCN. Likewise, loss of cochlear spiral ganglion cells is most pronounced in the base of the cochlea, which provides input to this region. The data indicate that aging is associated with rather different central effects, depending on AVCN cell type, cochleotopic organization, genotype, and/or the type of peripheral hearing loss involved. The C57 and CBA AVCNs also differ in several aspects irrespective of age. The volume of AVCN and number of AVCN neurons are significantly greater in C57 mice.

Animals↗
PubMed2001

Immune responses and protection induced by mucosal and systemic immunisation with recombinant measles nucleoprotein in a mouse model of measles virus-induced encephalitis.

In this study the immunogenicity of recombinant nucleoprotein (Np) administered intranasally or intraperitoneally, and its ability to support a systemic protective anti-virus antibody response was examined, in a mouse model of measles virus (MV)-induced encephalitis. Although both intranasal and intraperitoneal routes of immunisation resulted in priming Np- and MV-specific T-cell responses, the intraperitoneal route was shown to prime for a predominantly IgG2a serum anti-MV antibody response of high avidity, which confered complete protection following intracranial challenge with a neuroadapted strain of MV. On the other hand, intranasal priming resulted in a mixed IgG1, IgG2a serum anti-MV antibody response of low avidity, and only 43% of immunised mice survived following intracranial challenge with the neuroadapted strain of MV. These findings suggest that the route of immunisation in combination with an appropriate adjuvant could influence the induction of a quality antibody response with protective capacity.

Animals↗
PubMed2000

Mouse models of lipodystrophy.

Lipodystrophies are a group of heterogeneous diseases characterized by the loss of adipose tissue and by abnormalities of carbohydrate and lipid metabolism, including insulin resistance, diabetes, and hyperlipidemia. In this review, we describe several mouse models that recapitulate various aspects of the lipodystrophy syndrome, offering insights into the etiology of this condition and potential therapeutic approaches. Studies on these mice suggest that adipose is the primary tissue affected in lipodystrophy, and that secondary leptin deficiency may be responsible for the associated insulin resistance.

Animals↗
PubMed2005

Olfactory bulb mitral cell dendritic pruning abnormalities in a mouse model of the Fragile-X mental retardation syndrome: further support for FMRP's involvement in dendritic development.

The Fragile-X mental retardation syndrome is the leading form of inherited mental retardation. Dendritic analysis in a mouse model (FraX) found abnormal pruning in somatosensory cortex. To further characterize dendritic abnormalities and assess their occurrence in other brain regions, we examined mitral cells in FraX mice olfactory bulbs. FraX mice exhibited dendritic abnormalities consistent with somatosensory cortex, suggesting that deficient pruning is found in multiple brain regions.

Animals↗
PubMed2003

Regulated expression of erythropoietin from an AAV vector safely improves the anemia of beta-thalassemia in a mouse model.

In vivo gene transfer is being considered in the systemic delivery of therapeutic proteins. This report evaluates the use of AAV vectors administered into muscle to deliver erythropoietin (Epo) for the treatment of anemia in a mouse model of beta-thalassemia. Injection of vector expressing Epo from a constitutive promoter resulted in Epo overproduction and improved erythropoiesis. However, severe and lethal polycythemia developed. In order to titrate the expression of Epo to therapeutic and non-toxic levels, vectors were constructed to allow pharmacologic control of Epo transcription. Specifically, expression of Epo was dependent on the presence of a chimeric transcription factor that is activated by the orally available small molecule drug rapamycin. beta-thalassemic mice injected with vectors containing the regulated Epo gene failed to show any effect until they were administered a regimen of rapamycin, which led to the production of Epo and an increase in hematocrit values. Epo expression and its hematologic consequences were directly dependent on the dose of rapamycin and were completely reversed when rapamycin was withdrawn. The increase in hematocrit was associated with partial improvements in the abnormalities of red blood cell morphology. This study confirms the value of pharmacologic regulation of transgene expression in the development of safe and effective gene therapies in which biologically active secreted proteins are produced.

Animals↗
PubMed2004

Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia.

Oligodendrocytes are critical for the development of the plasma membrane and cytoskeleton of the axon. In this paper, we show that fast axonal transport is also dependent on the oligodendrocyte. Using a mouse model of hereditary spastic paraplegia type 2 due to a null mutation of the myelin Plp gene, we find a progressive impairment in fast retrograde and anterograde transport. Increased levels of retrograde motor protein subunits are associated with accumulation of membranous organelles distal to nodal complexes. Using cell transplantation, we show categorically that the axonal phenotype is related to the presence of the overlying Plp null myelin. Our data demonstrate a novel role for oligodendrocytes in the local regulation of axonal function and have implications for the axonal loss associated with secondary progressive multiple sclerosis.

Alleles↗
PubMed2004

A mouse model of pemphigus vulgaris by adoptive transfer of naive splenocytes from desmoglein 3 knockout mice.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by antidesmoglein3 (anti-Dsg3) IgG autoantibodies. Recently, we developed a PV mouse model by adoptive transfer of splenocytes from recombinant Dsg3-immunized Dsg3(-/-) mice to Rag2(-/-) immunodeficient mice that expressed Dsg3. OBJECTIVES: We determined whether the adoptive transfer of naive splenocytes from nonimmunized Dsg3(-/-) mice induces the anti-Dsg3 IgG production and the PV phenoytpe in recipient mice. METHODS: We adoptively transferred naive Dsg3(-/-) splenocytes into Rag2(-/-) mice and compared their PV phenoytpe with those mice receiving immunized Dsg3(-/-) splenocytes. The numbers of splenocytes and their subpopulations required for anti-Dsg3 IgG production were examined. RESULTS: Mice that received naive Dsg3(-/-) splenocytes produced anti-Dsg3 IgG, which bound to keratinocyte cell surfaces in vivo, and developed the PV phenotype, including oral erosions with suprabasilar acantholysis. Antibody production and the appearance of the PV phenotype were delayed by approximately 2 weeks in mice that received naive splenocytes compared with mice that received immunized splenocytes. However, once the PV phenotypes developed, there were no apparent differences in disease severity between the two models. Interestingly, the anti-Dsg3 IgG titres were significantly lower in mice that received naive splenocytes than in mice that received immunized splenocytes, suggesting that the former antibodies were more potent than the latter. The frequency of anti-Dsg3 IgG production depended on the number of transferred naive splenocytes. Both CD4+ T cells and B220+ B cells from naive Dsg3(-/-) mice were essential for the production of anti-Dsg3 IgG antibodies. CONCLUSIONS: Dsg3-specific naive lymphocytes in Dsg3(-/-) mice can be primed and activated by the endogenous Dsg3 in recipient mice to produce pathogenic anti-Dsg3 IgG without active immunization. This approach using naive lymphocytes provides a unique model to dissect immunological mechanisms of tolerance against peripheral autoimmune targets.

Adoptive Transfer↗
PubMed2004

Different procarcinogenic potentials of lymphocyte subsets in a transgenic mouse model of chronic hepatitis B.

The immune response to hepatitis viruses is believed to be involved in the development of chronic hepatitis; however, its pathogenetic potential has not been clearly defined. The current study, using a transgenic mouse model of chronic hepatitis B, was designed to determine the relative contributions of the immune cell subsets to the progression of liver disease that induces hepatocellular carcinogenesis. Hepatitis B virus transgenic mice were adoptively transferred with CD4+ and CD8+ T cell-enriched or -depleted and B cell-depleted splenocytes obtained from hepatitis B surface antigen-primed, syngeneic nontransgenic donors. The resultant liver disease, hepatocyte apoptosis, regeneration, and tumor development were assessed and compared with the manifestations in mice that had received unfractionated spleen cells. Transfer of CD8(+)-enriched splenocytes caused prolonged disease kinetics, and a marked increase in the extent of hepatocyte apoptosis and regeneration. In 12 of 14 mice the transfer resulted in multiple hepatocellular carcinomas (HCCs) comparable with the manifestations seen in the mice transferred with total splenocytes. In contrast, mice that had received CD4(+)-enriched cells demonstrated lower levels of liver disease and developed fewer incidences of HCC (4 of 17). The experiment also revealed that all of the groups of mice complicated with HCC developed comparable mean numbers and sizes of tumors. B-cell depletion had no effect on disease kinetics in this model. Taken together, these results demonstrate that the pathogenetic events induced by CD8+ T-cell subset are primarily responsible for the induction of chronic liver disease that increases tumor incidence, suggesting their potential in triggering the process of hepatocarcinogenesis.

Animals↗
PubMed1999

A mouse model for Liddle's syndrome.

Liddle's syndrome (or pseudoaldosteronism) is an autosomal dominant form of salt-sensitive hypertension, due to abnormal sodium transport by the renal tubule. To study the pathophysiology of salt sensitivity, a mouse model for Liddle's syndrome has been generated by Cre/loxP-mediated recombination. Under normal salt diet, mice heterozygous (L/+) and homozygous (L/L) for Liddle mutation (L) develop normally during the first 3 mo of life. In these mice, BP is not different from wild type despite evidence for increased sodium reabsorption in distal colon and low plasma aldosterone, suggesting chronic hypervolemia. Under high salt intake, the Liddle mice develop high BP, metabolic alkalosis, and hypokalemia accompanied by cardiac and renal hypertrophy. This animal model reproduces to a large extent a human form of salt-sensitive hypertension and establishes a causal relationship between dietary salt, a gene expressed in kidney and hypertension.

Animals↗
PubMed2006

Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy.

Neurofibrillary tangles form in a specific spatial and temporal pattern in Alzheimer's disease. Although tangle formation correlates with dementia and neuronal loss, it remains unknown whether neurofibrillary pathology causes cell death. Recently, a mouse model of tauopathy was developed that reversibly expresses human tau with the dementia-associated P301L mutation. This model (rTg4510) exhibits progressive behavioral deficits that are ameliorated with transgene suppression. Using quantitative analysis of PHF1 immunostaining and neuronal counts, we estimated neuron number and accumulation of neurofibrillary pathology in five brain regions. Accumulation of PHF1-positive tau in neurons appeared between 2.5 and 7 months of age in a region-specific manner and increased with age. Neuron loss was dramatic and region-specific in these mice, reaching over 80% loss in hippocampal area CA1 and dentate gyrus by 8.5 months. We observed regional dissociation of neuronal loss and accumulation of neurofibrillary pathology, because there was loss of neurons before neurofibrillary lesions appeared in the dentate gyrus and, conversely, neurofibrillary pathology appeared without major cell loss in the striatum. Finally, suppressing the transgene prevented further neuronal loss without removing or preventing additional accumulation of neurofibrillary pathology. Together, these results imply that neurofibrillary tangles do not necessarily lead to neuronal death.

Aging↗
PubMed2001

Mouse models of altered CRH-binding protein expression.

CRH is the key physiological mediator of the endocrine, autonomic, and behavioral responses to stress. The recent characterization of urocortin, a new mammalian CRH-like ligand, adds to the complexity of the CRH system. Both CRH and urocortin mediate their endocrine and/or synaptic effects via two classes of CRH receptors. Similarly, both CRH and urocortin bind to the CRH-binding protein (CRH-BP). This secreted binding protein is smaller than the CRH receptors, but binds CRH and urocortin with an affinity equal to or greater than that of the receptors, and blocks CRH-mediated ACTH release in vitro. Several regions of CRH-BP expression colocalize with sites of CRH synthesis or release, suggesting that this binding protein may have a profound impact on the biological activity of CRH (or urocortin). While in vitro and in vivo studies have characterized the biochemical properties and regulation of the CRH-BP, animal models of altered CRH-BP expression can provide additional information on the in vivo role of this important modulatory protein. This review focuses on three mouse models of CRH-BP overexpression or deficiency. These animal models show numerous physiological changes in the HPA axis and in energy balance, with additional alterations in anxiogenic behavior. These changes are consistent with the hypothesis that CRH-BP plays an important in vivo modulatory role by regulating levels of "free" CRH and other CRH-like peptides in the pituitary and central nervous system.

Animals↗
PubMed2005

Mechanisms of memory loss in Abeta and tau mouse models.

Although memory loss is the central symptom of Alzheimer's disease, the pathophysiological mechanisms leading to dementia are poorly understood. It is difficult to answer this issue with studies in humans and impossible in cultured cells. Therefore animal models are needed to elucidate the molecular mechanisms leading to dementia. The chief neuropathological changes during Alzheimer's disease, namely neurofibrillary tangles and amyloid plaques, have helped us to determine which molecules to focus upon in the animal models, specifically Abeta (amyloid beta) and tau. This paper presents my perspective on what we have learnt about mechanisms of memory loss from Abeta and tau mouse models of Alzheimer's disease.

Alzheimer Disease↗
PubMed2005

Adipokine expression profile in adipocytes of different mouse models of obesity.

Adipose tissue produces and secretes multiple adipokines. Most studies on adipokine production/expression have been performed on whole adipose tissue. In addition, data concerning an overall of adipokine expression are scarce and can be heterogeneous depending on the obesity model studied. Our first aim was to compare the expression of adipokines involved in the interplay between obesity and insulin resistance in isolated adipocytes from different mouse models of obesity displaying different levels of weight gain and insulin sensitivity. The second aim was to determine perigonadal/subcutaneous ratio of each adipokine. Only resistin expression was decreased in obese mice without modifications in glucose and insulin blood levels. In addition to decreased levels of resistin, obesity models associated with hyperglycemia and hyperinsulinemia presented an increased expression of leptin and tumor necrosis factor-alpha (TNFalpha). Obese and diabetic mice were the only animals to exhibit high expression of plasminogen activator inhibitor type-1 and interleukin-6. All adipokines except TNFalpha were more heavily expressed in perigonadal than in subcutaneous adipocytes. Interestingly, fat-enriched diet and overweight on their own did not modify the distribution of adipokines between the two fat depots. However, severe obesity modified the distribution of proinflammatory adipokines. In conclusion, the level and number of adipokines with altered expression increased with obesity and hyperinsulinemia in mice. The physiopathological impact of depot-specific differences of adipokine expression in adipocytes remains to be clarified.

Adipocytes↗