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PubMed1999

Serum amyloid P is not present in amyloid beta deposits of a transgenic animal model.

Serum amyloid P component (SAP) is associated with amyloid beta (A beta) deposition in Alzheimer disease (AD). Since SAP is exclusively synthesized by peripheral organs, its presence in the brain of AD suggests impairment of the blood-brain barrier (BBB). We studied the association of SAP with A beta deposits in a transgenic mouse model overexpressing beta-protein precursor (betaPP). Both SAP and another extracellular matrix binding protein, basic fibroblastic growth factor bind to the heparinase sensitive sites of A beta deposits in this model. However, no endogenous SAP immunoreactivity was found in the transgenic mouse brain. These results suggest that SAP is not required for A beta deposition, and that this mouse model does not develop the same BBB abnormalities as those seen in AD.

Alzheimer Disease↗
PubMed2005

Emergence of immune escape variant of mammary tumors that has distinct proteomic profile and a reduced ability to induce "danger signals".

Breast tumors are shaped, in part, by a process termed immunoediting which selects for immunologically evasive phenotypes. In the present study we used the rat neu-transgenic mouse model of breast cancer and its congenic non-transgenic parental strain, FVB, to explore the phenotype of tumors that emerge in the presence of an immune response directed against the neu antigen. When inoculated into parental FVB mice, a neu-overexpressing mouse mammary carcinoma (MMC) cell line isolated from spontaneous breast tumors of the FVB neu (FVBN202) transgenic mouse, elicited a neu-specific immune response resulting in a tumor rejection because of the presence of the rat neu antigen. However, a neu negative variant (ANV) of MMC arose after a long latency in spite of the neu-specific immune response. We show that compared to MMC, ANV tumor cells have a significantly reduced ability to secrete pro-inflammatory cytokines and the CCL5 chemokine, to express immunostimulatory chaperones, and they have a distinct expression of proteins involved in cell motility, and metabolic and signal transduction pathways. These studies suggest that tumor escape through immunoediting can not be explained by the loss of a single tumor antigen, but rather by a selection process of a tumor variant that has a reduced ability to induce "danger signals" together with up-regulation of proteins involved in the tumor survival. Based on these findings, we propose to target novel antigens over-expressed in the escape variant of breast tumors to treat primary tumor and to prevent tumor relapse.

Animals↗
PubMed2000

Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder.

We previously created a transgenic mouse model of comorbid Tourette's syndrome and obsessive-compulsive disorder (TS+OCD), by expressing a neuropotentiating cholera toxin (CT) transgene in a subset of dopamine D1 receptor-expressing (D1+) neurons thought to induce cortical and amygdalar glutamate output. To test glutamate's role in the TS+OCD-like disorder of these transgenic mice (D1CT-7 line), the effects of glutamate receptor-binding drugs on their behavior were examined. MK-801, a non-competitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated a transgene-dependent abnormal behavior (repetitive climbing and leaping) in the D1CT-7 mice at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviors at high doses. NBQX, a seizure-inhibiting AMPA receptor antagonist, reduced only the MK-801-dependent stereotypic and limbic seizure behavior of D1CT-7 mice, but not their transgene-dependent behaviors. These data imply that TS+OCD-like behavior is mediated by cortical-limbic glutamate, but that AMPA glutamate receptors are not an essential part of this behavioral circuit. Our findings lead to the prediction that the symptoms of human Tourette's syndrome and obsessive-compulsive disorder are elicited by excessive forebrain glutamate output.

Animals↗
PubMed2000

Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis.

The neu (c-erbB-2, Her-2) protooncogene is amplified and overexpressed in 20-30% of human breast cancers. Although transgenic mouse models have illustrated the role of Neu in the induction of mammary tumors, Neu expression in these models is driven by a strong viral promoter of questionable relevance to the human disease. To ascertain whether expression of activated Neu under the control of the endogenous promoter in the mammary gland could induce mammary tumors we have generated mice that conditionally express activated Neu under the transcriptional control of the intact endogenous Neu promoter. Expression of oncogenic neu in the mammary gland resulted in accelerated lobulo-alveolar development and formation of focal mammary tumors after a long latency period. However, expression of activated Neu under the normal transcriptional control of the endogenous promoter was not sufficient for the initiation of mammary carcinogenesis. Strikingly, all mammary tumors bear amplified copies (2-22 copies) of the activated neu allele relative to the wild-type allele and express highly elevated levels of neu transcript and protein. Thus, like human erbB-2-positive breast tumors, mammary tumorigenesis in this mouse model requires the amplification and commensurate elevated expression of the neu gene.

Animals↗
PubMed2005

New target antigens for cancer immunoprevention.

Prevention of cancer through the activation of the immune system has been explored in recent years in preclinical systems thanks to the availability of several new transgenic mouse models that closely mimic the natural history of human tumors. The most thoroughly investigated model of cancer immunoprevention is the mammary carcinoma of HER-2/neu transgenic mouse. In this system it has clearly been shown that the activation of immune defences in healthy individuals can effectively prevent the subsequent onset of highly aggressive mammary carcinomas. A complete prevention was obtained using a combination of three signals (the so called "triplex" vaccine) that included the specific antigen (p185, the product of HER-2/neu) and nonspecific signals like allogeneic histocompatibility antigens and interleukin 12. The analysis of protective immune responses in models of cancer immunoprevention revealed some unexpected features, in particular the central role of antibodies in immunoprevention, at variance with conventional immuno-therapy which is firmly based on cytotoxic T cells. In the HER-2/neu system anti-p185 antibodies, in addition to immunological functions leading to tumor cell lysis, inhibit p185 dimerization and induce its internalization, resulting in the inhibition of mitogenic signaling. Most current tumor antigens appear to be unsuitable targets for cancer immunoprevention. An ideal antigen should have a crucial pathogenetic role in tumor growth to avoid the selection of antigen loss variants. Downregulation of major histocompatibility complex (MHC) expression during tumor progression frequently limits antigen recognition by MHC-restricted T cells. Thus an ideal antigen for cancer immunoprevention should be recognized both by T cells and by antibodies. Antibody binding to cell surface oncogenic determinants, in addition to complement- and cell-mediated tumor cell lysis, can block mitogenic signaling and induce internalization, resulting in tumor growth arrest. A search for new tumor antigens should be conducted among molecules that are directly involved in neoplastic transformation and are recognizable by the immune response also in MHC loss variants. Novel tumor antigens fulfilling both conditions will be crucial for the development of cancer immunoprevention and will provide new targets also for cancer immunotherapy.

Animals↗
PubMedDate not supplied

A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.

Vaccinations with amyloid-beta peptide (A beta) can dramatically reduce amyloid deposition in a transgenic mouse model of Alzheimer's disease. To determine if the vaccinations had deleterious or beneficial functional consequences, we tested eight months of A beta vaccination in a different transgenic model for Alzheimer's disease in which mice develop learning deficits as amyloid accumulates. Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice show memory deficits, the A beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia.

Aging↗
PubMed1999

Mechanisms of central and peripheral T-cell tolerance: lessons from experimental models of multiple sclerosis.

Studies of experimental autoimmune encephalomyelitis in conventional and transgenic mouse models have clarified mechanisms of central and peripheral tolerance to myelin antigens. It is now clear that myelin antigens are expressed in the thymus and their expression can influence generation of the potential autoimmune T-cell repertoire. How autoreactive T cells escape tolerance in the thymus is largely unclear. One mechanism has been revealed through the use of a transgenic mouse expressing a T-cell receptor specific for a myelin antigen. T cells specific for the N-terminal epitope of myelin basic protein escape tolerance through low avidity interaction. The affinity of antigen binding to MHC also proves to be important for induction of peripheral tolerance. Peptides may be administered in solution to adults in order to reinstate peripheral tolerance and suppress disease. Induction of antigen-specific suppression with synthetic peptides can result in either linked or bystander suppression and this appears to involve the generation of T cells secreting suppressive cytokines. The use of altered peptide ligands for induction of peripheral tolerance has been investigated. This can be achieved but the complexity of the approach argues against its use for treatment of human autoimmune diseases.

Amino Acid Sequence↗
PubMed2003

Transgenic sickle mice have vascular inflammation.

Inflammation may play an essential role in vaso-occlusion in sickle cell disease. Sickle patients have high white counts and elevated levels of serum C-reactive protein (CRP), cytokines, and adhesion molecules. In addition, circulating endothelial cells, leukocytes, and platelets are activated. We examined 4 transgenic mouse models expressing human alpha- and sickle beta-globin genes to determine if they mimic the inflammatory response seen in patients. These mouse models are designated NY-S, Berk-S(Antilles), NY-S/S(Antilles) (NY-S x Berk-S(Antilles)), and Berk-S. The mean white counts were elevated 1.4- to 2.1-fold (P </=.01) in the Berk-S(Antilles), NY-S/S(Antilles), and Berk-S mice, but not in the NY-S mice compared with controls. Serum amyloid P-component (SAP), an acute-phase response protein with 60% to 70% sequence homology to CRP, was elevated 8.5- to 12.1-fold (P </=.001) in transgenic sickle mice. Similarly, serum interleukin-6 (IL-6) was elevated 1.6- to 1.9-fold (P </=.05). Western blots, confirming immunohistochemical staining, showed vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and platelet-endothelial cell adhesion molecule (PECAM) were up-regulated 3- to 5-fold (P </=.05) in the lungs of sickle mice. Ribonuclease protection assays (RPAs) demonstrated VCAM mRNA also was elevated in sickle mice 1.2- to 1.4-fold (P </=.01). Nuclear factor kappaB (NF-kappaB), a transcription factor critical for the inflammatory response, was elevated 1.9-fold (P </=.006) in NY-S sickle mouse lungs. We conclude that transgenic sickle mice are good models to study vascular inflammation and the potential benefit of anti-inflammatory therapies to prevent vaso-occlusion in sickle cell disease.

Anemia, Sickle Cell↗
PubMed2001

Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease.

Active immunization with the amyloid beta (A beta) peptide has been shown to decrease brain A beta deposition in transgenic mouse models of Alzheimer's disease and certain peripherally administered anti-A beta antibodies were shown to mimic this effect. In exploring factors that alter A beta metabolism and clearance, we found that a monoclonal antibody (m266) directed against the central domain of A beta was able to bind and completely sequester plasma A beta. Peripheral administration of m266 to PDAPP transgenic mice, in which A beta is generated specifically within the central nervous system (CNS), results in a rapid 1,000-fold increase in plasma A beta, due, in part, to a change in A beta equilibrium between the CNS and plasma. Although peripheral administration of m266 to PDAPP mice markedly reduces A beta deposition, m266 did not bind to A beta deposits in the brain. Thus, m266 appears to reduce brain A beta burden by altering CNS and plasma A beta clearance.

Alzheimer Disease↗
PubMed1996

Local expression of human growth hormone in bone results in impaired mechanical integrity in the skeletal tissue of transgenic mice.

The effect of local production of human growth hormone on murine cortical bone was investigated using a transgenic mouse model. Femora and humeri from human growth hormone transgenic mice and littermate control mice were obtained, and the geometrical, biomechanical, compositional, and histomorphometric properties of all specimens were determined. The goals were to investigate the effects of local expression of human growth hormone on skeletal integrity, including the functional geometry of long bone and its related structural and mechanical behavior, as well as tissue composition and integrity. As expected, local production of human growth hormone by osteoblasts indeed resulted in longer femora with significantly greater mid-diaphyseal cross-sectional geometry in the transgenic mice (16% increase in cross-sectional area and 29% increase in bending moments of inertia). However, the significant increase in geometry was not associated with a proportional increase in bending stiffness and other structural properties, which suggested that the mechanical properties of the cortical bone tissue may have been inferior. Microspecimen bending tests verified this prediction, given that transgenic cortical bone tissue had significantly lower apparent elastic modulus and ultimate strength (52 and 68%, respectively, of control values). These defects in the whole bone structural and tissue mechanical properties of transgenic specimens were associated with a smaller fraction of ash, larger fractions of woven bone and cartilage islands, and greater porosity in the mid-diaphyseal cortices. These results suggest that local production of human growth hormone by osteoblasts is indeed anabolic for bone, but at the expense of bone tissue integrity.

Adaptation, Physiological↗
PubMedDate not supplied

Calpain inhibitors: a treatment for Alzheimer's disease.

Activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer's disease (AD) (Liu et al., 1999; Rapoport, 1999; Selkoe, 1994). Calpains regulate the function of many proteins by limited proteolysis and initiate the complete degradation of other proteins. In particular, they modulate processes that govern the function and metabolism of proteins key to the pathogenesis of AD, including tau and amyloid precursor protein (APP). (Xie and Johnson, 1998; Wang, 2000). We have found that overexpression of APP(K670M:N671L) and PS1(M146L) proteins in hippocampal cultures derived from transgenic mice causes an increase in the frequency of spontaneous release of neurotransmitter. We have also found that calpain immunoreactive clusters are co-localized with immunoreactivity for the vesicle-associated presynaptic marker, synaptophysin. Moreover, application of calpain inhibitor reduces the frequency of spontaneous release of neurotransmitter. Therefore, we have hypothesized that calpains might contribute to the increase in transmitter release. Based on this hypothesis, we propose to test whether it is possible to restore normal synaptic transmission between cells derived from the transgenic model of AD by using calpain inhibitors. The transgenic mouse model also shows spatial learning impairment, a phenomenon that is thought to be associated with plastic changes at synaptic level. Therefore, we will also test whether we can rescue the learning impairment through a treatment with calpain inhibitors.

Alzheimer Disease↗
PubMed1994

Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice.

Gliosis is a characteristic pathologic state in many CNS disorders. Cytokines are considered to be effectors of gliosis. In order to explore the role of IL-6 in gliosis, the temporal and spatial expression of the IL-6 gene and its consequent effects on the brain were studied in a GFAP-IL6 transgenic mouse model. In GFAP-IL6 mice, IL-6 transgene expression was detectable in the brain at 1 week postnatally and increased to maximal levels by 3 months of age before declining at 8 and 12 months. Enhanced glial fibrillary acidic protein (GFAP) (marker for astrocytes) and Mac-I (marker for microglia) mRNA expression were first prominent at 1 month, increased to maximum levels by 3 months and remained significantly elevated through 12 months of age. Western blot analysis revealed that the enhanced GFAP mRNA expression in these transgenic mice was accompanied by increased GFAP protein levels. Immunostaining for Mac-I demonstrated that in addition to an increased staining intensity, the number of cells expressing the microglial/macrophage marker was also apparently increased, particularly in the cerebellum and brain stem. Concurrent with IL-6 transgene mRNA expression and reactive gliosis, upregulation of IL-1 alpha/beta, TNF alpha, ICAM-1 and EB22/5.3 (acute-phase reactant) but not inducible nitric oxide synthase gene expression was also observed. EB22/5.3 mRNA expression was most prominent and increased progressively with age. Expression of the IL-6, GFAP and EB22/5.3 RNAs was found to have similar distribution in the brain being found predominantly in the cerebellum, brain stem and sub-cortical regions. In conclusion, the constitutive expression of IL-6 in the brain induced the development of a pronounced and lifelong reactive gliosis affecting both astrocytes and microglia. The altered state of these cells may contribute to the functional and structural CNS impairment exhibited by the GFAP-IL6 mice. Finally, in these mice, expression of the EB22/5.3 gene correlated closely with the progression of neuropathy indicating that this acute-phase response gene was a good marker for and may be involved in the pathogenesis of CNS injury mediated by the expression of IL-6.

Amino Acid Oxidoreductases↗
PubMed2001

Fasting, leptin treatment, and glucose administration differentially regulate Y(1) receptor gene expression in the hypothalamus of transgenic mice.

NPY is a potent orexigenic signal and represents a key component of targets through which leptin exerts a regulatory restraint on body adiposity. Part of the orexigenic effects of NPY are mediated by hypothalamic NPY-Y(1) receptors. Here we studied the effect of fasting, leptin, and glucose administration on Y(1) receptor gene expression using a transgenic mouse model carrying a mouse Y(1) receptor/LacZ fusion gene. Transgene expression was determined by quantitative analysis of beta-galactosidase histochemical staining in the paraventricular, arcuate, ventromedial, and dorsomedial hypothalamic nuclei and in the medial amygdala, as a control region. Food deprivation for 72 h decreased transgene expression in the paraventricular nucleus but not in the arcuate nucleus. Leptin treatment, that was per se ineffective, counteracted the decrease of transgene expression induced in the paraventricular nucleus by 72 h fasting. Supplementing the drinking water with 10% glucose increased beta-galactosidase expression both in the paraventricular nucleus and arcuate nucleus of control mice. Finally, none of the treatments altered transgene expression in the dorsomedial hyphothalamic, ventromedial, and amygdaloid nuclei. Results suggest that changes in energetic balance affect Y(1) receptor expression in the paraventricular and arcuate nuclei and that leptin regulates the NPY-Y(1) system in the paraventricular nucleus. Different regulatory signals might modulate the NPY-Y(1) transmission in the dorsomedial hyphothalamic and ventromedial hyphothalamic nuclei.

Animals↗
PubMed1999

Insulin in oral immune "tolerance": a one-amino acid change in the B chain makes the difference.

Oral administration of self-Ags can dampen or prevent autoimmune processes by induction of bystander suppression. Based on encouraging results from experiments in nonobese diabetic (NOD) mice, clinical trials have been initiated in type 1 diabetes using human insulin as an oral Ag. However, neither the precise antigenic requirements nor the mechanism of bystander suppression are currently understood in detail. Here we report that 1) a 1-aa difference in position 30 of the insulin B chain abrogated the ability of insulin to confer protection in both NOD as well as a virus-induced transgenic mouse model for type 1 diabetes. In the latter model transgenic mice express the nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) under the control of the rat insulin promotor (RIP) in the pancreatic beta cells and develop diabetes only following LCMV infection; and 2) protection could be transferred with insulin B chain-restimulated but not LCMV-restimulated splenocytes from RIP-NP transgenic mice, demonstrating that the mechanism of diabetes prevention in the RIP-NP model is mediated by insulin B chain-specific, IL-4-producing regulatory cells acting as bystander suppressors.

Administration, Oral↗
PubMedDate not supplied

A comparison of placental development and endocrine functions between the human and mouse model.

The placenta plays a key role in pregnancy, mediating exchanges between mother and fetus and maternal tolerance of fetopaternal antigens. In some species, it also produces hormones that ensure the maintenance of gestation and fetal well-being. This unique organ also has considerable potential for use as a model for various aspects of biology. Indeed, the use of transgenic mouse models has greatly improved our understanding of the genetic control of placental development in this species and has opened up new fields of investigation in developmental biology. Analogous cell types have been identified among human and murine trophoblasts: proliferative trophoblastic cells, invasive trophoblastic cells and cells differentiating into syncytium, but human and mouse placentas differ in both morphogenesis and endocrine function. Herein, the similarities and differences between the human and mouse models are reviewed, with a view to encouraging caution in the extrapolation of results from one model to the other.

Animals↗
PubMed2002

Effects of mouse strain, position of integration and tetracycline analogue on the tetracycline conditional system in transgenic mice.

The tetracycline conditional system is a very powerful method for achieving control of gene expression in transgenic mice, allowing one to turn expression both off and on in the same animal. We have used it to make a tissue-specific transgenic mouse model of Charcot-Marie-Tooth disease type 1A. This disease is most commonly caused by overexpression of peripheral myelin protein 22 (PMP22) in Schwann cells of the peripheral nervous system. Here we describe the effects of position of integration of the transgene, tetracycline analogue and mouse strain in this model. The small transgenes used to express tTA, the LacZ reporter and the pmp22 cDNA were all very dependent on the position of integration with few of the transgenic lines working successfully. In contrast, the single transgenic made with the 560 kb yeast artificial chromosome construct containing the tTA open reading frame worked well. Tetracycline was found to be cleared from mice relatively fast in comparison with doxycycline and is thus useful if one wants to switch on gene expression after extended periods of administration. Finally, the initial litters were on a mixed genetic background and the level of LacZ or pmp22 expression was very variable between mice. We found that expression became uniform between mice, and occurred in a higher proportion of cells, when the transgenes were crossed onto the CBA/Ca background in comparison with the C57BL/6J background.

Animals↗
PubMed2002

DNA vaccination breaks tolerance for a neo-self antigen in liver: a transgenic murine model of autoimmune hepatitis.

Understanding the pathogenesis of autoimmune hepatitis requires an animal model in which chronic progressive immune injury develops spontaneously or with minimal manipulations. The new transgenic mouse model proposed in this study is based on the hypothesis that infectious agents have the potential to initiate autoreactivity through molecular mimicry. A transgenic mouse expressing lymphocytic choriomeningitis virus nucleoprotein (NP) in a H-2(b) background developed liver injury when vaccinated with plasmids expressing NP as an intracellular or a secretory protein. Coinjection of plasmids coding for NP and IL-12 facilitated the induction of a Th1 phenotype as detected by a specific B lymphocyte response characterized by a predominance of IgG2 subclass anti-NP Abs. CTLs activated in peripheral lymphoid organs by DNA vaccination migrated to the periportal and lobular areas of the liver. Their presence was associated with a significant degree of cytolysis, as evidenced by elevated transaminases several weeks after immunization. As activated specific T lymphocytes proliferated in the periphery and caused cytolysis of target cells, this study suggests that autoimmune hepatitis can be triggered by molecular mimicry, and that local injury may not be essential to initiate autoreactivity in the liver.

Animals↗
PubMed2003

Hormonal and dietary modulation of mammary carcinogenesis in mouse mammary tumor virus-c-erbB-2 transgenic mice.

Exogenous and dietary estrogens have been associated with modification of breast cancer risk. Mammary cancer model systems can be used to explore interactions between specific transgenes, and hormonal and dietary factors. Transgenic mice bearing the rat wild-type erbB-2 gene were used to study the effects of short-term hormonal exposure [17beta-estradiol (E2) or tamoxifen] or a soy meal diet on mammary carcinogenesis. In mice fed a casein diet, mammary tumors developed at an earlier age after short-term E2 exposure during the early reproductive period. The median mammary tumor latency was shortest (29 weeks) for the high-dose estrogen as compared with the lowest dose of E2 treated or placebo control mice (33 and 37 weeks, respectively). The timing of short-term E2 exposure was also important, with the most significant changes observed in mice exposed to E2 between 8 and 18 weeks of age. E2 exposure was associated with the subsequent development of more aggressive tumors as determined by histologic grade, multifocal tumor development, stromal invasion, and pulmonary metastasis. In contrast, short-term tamoxifen-exposed mice generally failed to develop mammary tumors by 60 weeks of age. Mice fed a soy meal diet developed mammary tumors at a later age than casein-fed animals treated with E2 or placebo, whereas no differences were observed by diet for the tamoxifen-treated mice. Mammary tumor prevention was >80% in tamoxifen-treated mice on either diet. Novel histologic tumor types were identified, suggesting greater phenotypic diversity than described previously. Benign mammary gland morphogenesis was also significantly altered by short-term hormonal exposure or dietary factors, consistent with the modification of mammary tumor risk in specific treatment groups. Estrogenic modulation of the mammary tumor phenotype in wild-type erbB-2 transgenic mice was observed. Histologic tumor types and clinical aggressivity not reported previously in this transgenic model were noted, suggesting greater biologic heterogeneity than reported previously. In addition, dietary phytoestrogens modified mammary development and tumor latency, suggesting a need for greater stringency in dietary assignment for transgenic mouse models of mammary neoplasia.

Age Factors↗