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PubMed2005

Modulation of single-nephron GFR in the db/db mouse model of type 2 diabetes mellitus.

Hyperfiltration has been implicated in the progression toward diabetic nephropathy in type 2 diabetes mellitus (DM2). This study focuses for the first time on the in vivo modulation of single-nephron GFR (SNGFR) in the classic B6.Cg-m(+/+)Lepr(db)/J (db/db) mouse model of DM2. To obtain stable preparations, it was necessary to use a sustaining infusion of 3.3 ml.100 g body wt(-1) x h(-1), or higher. SNGFR (measured both proximally and distally) was greater in db/db vs. heterozygote (db/m) mice (P < 0.05) but not vs. the wild-type (WT) mice. The tubuloglomerular feedback (TGF) responses, determined as free-flow proximal vs. distal SNGFR differences, were significant in db/db mice (11.6 +/- 0.8 vs. 9.3 +/- 1.0 nl/min, P < 0.01), in db/m mice (8.0 +/- 0.8 vs. 7.2 +/- 0.6 nl/min, P < 0.02), and WT mice (9.9 +/- 0.6 vs. 8.9 +/- 0.7 nl/min, P < 0.05). After increasing the sustaining infusion in the db/db mice, to offset glycosuric urine losses, the SNGFR increased significantly, and the TGF response was abolished. In these volume-replete db/db mice, absolute fluid reabsorption measured both at the late proximal and distal tubular sites were significantly increased vs. db/m mice infused at 3.3 ml.100 g body wt(-1) x h(-1). After infusion of the neuronal nitric oxide synthase (nNOS) inhibitor S-methylthiocitrulline, SNGFR fell in both db/db and db/m mice. These studies show that SNGFR is elevated in this mouse model of DM2, is suppressed by nNOS inhibition, and is modulated by TGF influences that are altered by the diabetic state and responsive to changes in extracellular fluid volume.

Albuminuria↗
PubMed2005

Effects of intraperitoneal injection of Rofecoxib in a mouse model of ALS.

There is increasing evidence that inflammatory mechanisms are involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Inhibition of a key mediator of inflammation, cyclooxygenase 2 (COX-2), represents a promising therapeutic approach in ALS. Here we tested the in vivo effects of a specific COX-2 inhibitor, Rofecoxib, administered by intraperitoneal injection, in the SOD1(G93A G1H) mouse model of the familial form of ALS (fALS). Rofecoxib administration commenced at postnatal day 60 (P60), since the hallmarks of inflammation in the spinal cord were found to occur beyond this time-point in this mouse model of fALS. We found a significant but small delay in the onset of locomotor impairment in mice treated with Rofecoxib at the dose of 10 mg/kg of weight. However, survival was not effected by treatment. As prostaglandin E2 levels in spinal cord or in plasma were not reduced by Rofecoxib treatment, these results may suggest lack of sufficient bioavailability as the reason for the modest clinical changes observed.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-alpha-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity.

PURPOSE: The purpose of this study was to test the teratogenic potential of the antiepileptic drug (AED) levetiracetam (LEV), its major metabolite in humans, 2-pyrrolidone-N-butyric acid (PBA), and enantiomer, (R)-alpha-ethyl-oxo-pyrrolidine acetamide (REV), in a well-established mouse model. METHODS: All compounds were administered by intraperitoneal injections once daily to SWV/Fnn mice on gestational days 8-1/2 to 12-1/2. LEV was administered at doses of 600, 1,200, and 2,000 mg/kg/day, piracetam (PIR) and PBA, at 600 and 1,200 mg/kg/day, and REV, at 600 mg/kg/day. On gestational day 18(1/2), fetuses were examined for gross external malformations and prepared for skeletal analysis by using Alizarin Red S staining. RESULTS: No significant gross external malformations were observed in any of the study groups. Fetal weights were significantly reduced in most study groups. Resorption rates were significantly increased only in the 2,000-mg/kg/day LEV group. The overall incidence of skeletal abnormalities and specifically of hypoplastic phalanges was significantly increased in both PBA treatments and in the intermediate 1,200-mg/kg/day LEV group. In contrast to that in humans, 24-h urinary excretion analysis in mice showed that 65-100% of the LEV doses were excreted unchanged, whereas only 4% was excreted as the metabolite PBA. CONCLUSIONS: Results of this study demonstrate that both LEV and its major metabolite in humans, PBA, do not induce major structural malformations in developing SWV/Fnn embryos and suggest that they provide a margin of reproductive safety for the pregnant epileptic population when compared with other AEDs tested in this mouse model.

Animals↗
PubMed2005

Inhibition of nitric oxide synthase reverses permeability changes in a mouse model of acute peritonitis.

Acute peritonitis is the most frequent complication of peritoneal dialysis. Previous studies have suggested a major role for nitric oxide (NO) in the permeability changes and loss of ultrafiltration induced by acute peritonitis. In this study, we further investigated the potential role of NO in a mouse model of peritonitis induced by Escherichia coli Lipopolysaccharide (LPS). A 2-hour peritoneal equilibration test was performed in control and LPS-treated mice using 7% glucose dialysate supplemented or not with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The levels of NO metabolites in the dialysate were maximal 18 hours after LPS injection. At that time, acute peritonitis induced by LPS was reflected by an increased recruitment of leukocytes, an increased intraperitoneal release of interleukin-6, a significant increase in the peritoneal permeability for small solutes, a loss of sodium sieving, and a loss of ultrafiltration in comparison with controls. Addition of L-NAME in LPS-treated mice significantly reversed permeability modifications and prevented the release of NO metabolites into the dialysate. These results confirm that increased NO mediates permeability modifications during acute peritonitis, and illustrate the potential of mouse models to investigate the molecular mechanisms regulating peritoneal permeability.

Acute Disease↗
PubMed2006

Prospective contributions of transgenic mouse models to central auditory research.

Neuroscientists are increasingly embracing mice as a means to address central nervous system questions at a molecular level. Examples abound from sensory systems like olfaction and vision. The use of mice to study central auditory processing, however, has remained relatively limited. In this commentary, I draw on some of the successes from other fields to highlight directions in which mouse models may contribute valuable and otherwise unattainable insights into the neural circuitry and plasticity within central auditory stations. Efforts towards this are beginning and would benefit from increased collaboration to generate useful transgenic mouse models for such studies.

Acoustics↗
PubMed1998

Selective loss of alpha motoneurons innervating the medial gastrocnemius muscle in a mouse model of amyotrophic lateral sclerosis.

Mutations in the superoxide dismutase gene 1 (SOD-1) are found in patients with familial amyotrophic lateral sclerosis (FALS). Overexpression of a mutated human SOD-1 gene in mice results in neurodegenerative disease as result of motoneuron loss in lumbar spinal cord (10). Using this mouse model of FALS, we have established a quantitative assay utilizing the retrograde tracer Fluorogold (FG) to determine the number of motoneurons innervating one skeletal muscle in mice with ongoing disease. In adult wild-type mice, the number of alpha motoneurons retrogradely labeled by an injection of FG into medial gastrocnemius muscle is 50 +/- 7 and this number remains constant from 7 to 18 weeks of age. In mutant mice, the number of alpha motoneurons retrogradely labeled by FG is the same as in wild-type mice at 7 and 9 weeks, but then declines to 36% of that in normal mice at 18 weeks. This decline also correlates positively to severity of motor impairments in these mice as assessed by the hindlimb splay test. In contrast, the number of FG-labeled gamma motoneurons remains relatively unchanged in both wild-type and mutant mice up to 18 weeks. At 18 weeks of age, this apparent alpha motoneuron denervation is paralleled by an average of 55% reduction of MG-muscle mass and 40% weaker performance in the hindlimb splay test. These data suggest that alpha motoneurons are the most vulnerable neuronal subtype in this mouse model of ALS and it is primarily their loss that leads to functional motor deficits. This quantitative bioassay also will be valuable for evaluating novel therapeutics for ALS.

Aging↗
PubMed2006

Mechanisms of particle-induced pulmonary inflammation in a mouse model: exposure to wood dust.

Repeated airway exposure to wood dust has long been known to cause adverse respiratory effects such as asthma and chronic bronchitis and impairment of lung function. However, the mechanisms underlying the inflammatory responses of the airways after wood dust exposure are poorly known. We used a mouse model to elucidate the mechanisms of particle-induced inflammatory responses to fine wood dust particles. BALB/c mice were exposed to intranasally administered fine (more than 99% of the particles had a particle size of < or = 5 microm, with virtually identical size distribution) birch or oak dusts twice a week for 3 weeks. PBS, LPS, and titanium dioxide were used as controls. Intranasal instillation of birch or oak dusts elicited influx of inflammatory cells to the lungs in mice. Enhancement of lymphocytes and neutrophils was seen after oak dust exposure, whereas eosinophil infiltration was higher after birch dust exposure. Infiltration of inflammatory cells was associated with an increase in the mRNA levels of several cytokines, chemokines, and chemokine receptors in lung tissue. Oak dust appeared to be a more potent inducer of these inflammatory mediators than birch dust. The results from our in vivo mouse model show that repeated airway exposure to wood dust can elicit lung inflammation, which is accompanied by induction of several proinflammatory cytokines and chemokines. Oak and birch dusts exhibited quantitative and qualitative differences in the elicitation of pulmonary inflammation, suggesting that the inflammatory responses induced by the wood species may rise via different cellular mechanisms.

Animals↗
PubMed2002

Noninvasive, in vivo approaches to evaluating behavior and exercise physiology in mouse models of mitochondrial disease.

Mitochondrial diseases are a clinically heterogeneous group of disorders related to dysfunction of various components of oxidative metabolism. Common manifestations of these diseases include encephalopathy, skeletal myopathy, and cardiomyopathy, but essentially any tissue can be affected. To understand better the pathogenesis of mitochondrial disease and to potentially evaluate novel therapies, several mouse models have been reported in the literature over the past few years. In assessing genetically altered mice as potential models of human mitochondrial disease, careful behavioral and physiologic analyses are essential components of the overall phenotypic characterization. Noninvasive, in vivo approaches are useful because they assess end-organ and multiorgan function in a whole-organism context, as well as permit serial measurements of individual animals over time. This review presents various behavioral and exercise physiology protocols that can be used for the evaluation of potential mouse models of human mitochondrial disorders.

Animals↗
PubMed2001

Isolation of novel mouse genes associated with ectopic ossification by differential display method using ttw, a mouse model for ectopic ossification.

Mouse mutant ttw (tiptoe walking) is an excellent model for ectopic ossification. This mutant exhibits ossification in various soft tissues, which is histologically similar to human OPLL (ossification of posterior longitudinal ligament of the spine). We previously reported that ttw is caused by a nonsense mutation of the nucleotide pyrophosphatase (ENPP1) gene, and that a polymorphism of the human ENPP1 gene is associated with OPLL. These facts indicate that ENPP1 regulates ectopic ossification in vivo; however, the mechanism is unclear. ENPP1 is an ectoenzyme that generates phosphate (Pi) and pyrophosphate (PPi). PPi is a strong inhibitor of ossification. Abnormal Pi metabolism is observed in patients with OPLL, and diseases with abnormal Pi metabolism such as hypophosphatemic rickets are frequently complicated by ectopic ossification. These lines of evidence suggest Pi-PPi metabolism associated with ENPP1 may play an important role in regulation of ectopic ossification. To clarify the molecular mechanism of ectopic ossification in ttw, we examined the effect of dietary phosphate and calcium on the ttw phenotype and found a high dietary phosphate-accelerated ectopic ossification. Then we examined genes associated with the enhanced ossification in ttw on a high phosphate diet by a differential display method. We identified nine mouse genes; six genes were up-regulated by the high phosphate diet, and three were down-regulated. Six of the nine genes were novel and we cloned and characterized them. Two of the genes were highly specific to cartilage, suggesting their specific role in enchondral ossification. Our identification of the novel genes would give novel insight into the mechanism of ectopic ossification and etiology of OPLL.

Animals↗
PubMed2004

Increased GABAergic function in mouse models of Huntington's disease: reversal by BDNF.

Huntington's disease (HD) is characterized by loss of striatal gamma-aminobutyric acid (GABA)ergic medium-sized spiny projection neurons (MSSNs), whereas some classes of striatal interneurons are relatively spared. Striatal interneurons provide most of the inhibitory synaptic input to MSSNs and use GABA as their neurotransmitter. We reported previously alterations in glutamatergic synaptic activity in the R6/2 and R6/1 mouse models of HD. In the present study, we used whole-cell voltage clamp recordings to examine GABAergic synaptic currents in MSSNs from striatal slices in these two mouse models compared to those in age-matched control littermates. The frequency of spontaneous GABAergic synaptic currents was increased significantly in MSSNs from R6/2 transgenics starting around 5-7 weeks (when the overt behavioral phenotype begins) and continuing in 9-14-week-old mice. A similar increase was observed in 12-15-month-old R6/1 transgenics. Bath application of brain-derived neurotrophic factor, which is downregulated in HD, significantly reduced the frequency of spontaneous GABAergic synaptic currents in MSSNs from R6/2 but not control mice at 9-14 weeks. Increased GABA current densities also occurred in acutely isolated MSSNs from R6/2 animals. Immunofluorescence demonstrated increased expression of the ubiquitous alpha1 subunit of GABA(A) receptors in MSSNs from R6/2 animals. These results indicate that increases in spontaneous GABAergic synaptic currents and postsynaptic receptor function occur in parallel to progressive decreases in glutamatergic inputs to MSSNs. In conjunction, both changes will severely alter striatal outputs to target areas involved in the control of movement.

Animals↗
PubMed2004

Mouse model of membranous nephropathy induced by cationic bovine serum albumin: antigen dose-response relations and strain differences.

BACKGROUND: Few well-characterized animal models have been developed to study the pathogenesis of membranous nephropathy (MN). We have developed a mouse model of MN induced by cationic bovine serum albumin (cBSA), and examined the role of genetic background on disease induction by assessing different mouse strains. METHODS: cBSA in an optimum dose was given intravenously to 8-week-old female ICR, BALB/c and C57BL/6 mice for 4 weeks. The disease state was verified by renal histopathology as well as by serum and urine metabolic profiles. Serum concentrations of anti-cBSA immunoglobulins (Igs) and circulating immune complex (CIC) were assayed to study the mechanisms of initiation and progression. T-helper (Th) cell subsets in peripheral blood were examined using flow cytometry, and the Th1/Th2 subset distribution was determined by comparing the serum concentrations of IgG1 and IgG2a, using quantitative heterologous interpolation enzyme-linked immunosorbent assays. RESULTS: Only ICR and BALB/c mice developed the typical clinical and pathological patterns of MN in response to an optimum dose of cBSA. Disease induction was dose related and strain specific. The serum concentrations of anti-cBSA were significantly higher in the strains that developed MN, but there were no differences in CIC concentrations. This suggests that in situ immune-complex glomerulonephritis may be involved in the development of MN. The Th2 type immune response may predominate in the ICR and BALB/c mice models, as the serum concentration of IgG1 was higher than that of IgG2a; moreover Th2 type strain specificity was necessary for the development of MN. CONCLUSIONS: This improved mouse model of MN induced by cBSA more closely duplicates human MN than the other available models. Disease generation is antigen dose related and strain specific.

Animals↗
PubMed2004

[Expressions of hTERT, p53, c-erbB-2 and Bcl-2 in colonic adenocarcinoma mouse models with liver metastases: effects of classical traditional Chinese medicine prescriptions for promoting circulation and removing blood stasis].

OBJECTIVE: To observe the effects of classical traditional Chinese medicine prescriptions that function to promote blood circulation and removing blood stasis on the metastatic behavior of malignant tumors, and explore the possible mechanisms of such effects. METHODS: BALB/c mouse models of colonic adenocarcinoma with liver metastases were established by intrasplenic injection of colonic adenocarcinoma cells (CT26) to receive treatment with the three representative classical circulation-promoting and blood stasis-removing prescriptions of traditional Chinese medicine, namely Guizhifuling pills, Didang Tang and Danshenyin, respectively. The expressions of human telomerase reverse transcriptase (hTERT), p53, c-erbB-2 and Bcl-2 were detected in the mouse models with different treatments and in normal control mice. RESULTS: Tumor metastases of various degrees were observed in the mice after inoculation of the tumor cells. The expressions of hTERT, p53, c-erbB-2 and Bcl-2 in the models receiving treatment with either Didang Tang or Guizhifuling pills differed significantly from those of the untreated model group (P<0.05), whereas between Danshenyin group and the model group, only the expression of hTERT showed significant difference. CONCLUSION: Didang Tang and Guizhifuling pills can reduce the expressions of hTERT, p53, c- erbB-2 and Bcl-2, while Danshenyin can only reduce the expression of hTERT without similar effects on the other 3 oncogenes. Such inhibitory effects of the prescriptions on hTERT and the oncogenes might explain their actions to inhibit malignant tumor metastasis, which can be related to performance of the prescriptions in promoting circulation by removing blood stasis.

Adenocarcinoma↗
PubMed2005

Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.

DNA methylation is associated with malignant transformation, but limitations imposed by genetic variability, tumor heterogeneity, availability of paired normal tissues and methodologies for global assessment of DNA methylation have limited progress in understanding the extent of epigenetic events in the initiation and progression of human cancer and in identifying genes that undergo methylation during cancer. We developed a mouse model of T/natural killer acute lymphoblastic leukemia that is always preceded by polyclonal lymphocyte expansion to determine how aberrant promoter DNA methylation and consequent gene silencing might be contributing to leukemic transformation. We used restriction landmark genomic scanning with this mouse model of preleukemia reproducibly progressing to leukemia to show that specific genomic methylation is associated with only the leukemic phase and is not random. We also identified Idb4 as a putative tumor-suppressor gene that is methylated in most mouse and human leukemias but in only a minority of other human cancers.

Animals↗
PubMed2004

Mouse models of triplet repeat diseases.

Since their discovery in 1991, triplet repeat mutations have been found to be the cause of genomic fragile sites, two of which are linked to mental retardation, myotonic dystrophy, and several late-onset neurodegenerative diseases. In all cases, these mutations exhibit gametic and/or somatic instability once they have expanded into the mutant range. The mutations are located in coding and noncoding gene regions and have been found to act by dominant and recessive mechanisms. A wide range of mouse models has been generated to understand both of the mechanisms that underlie repeat instability and the molecular pathogenesis of the diseases. Mouse models have proved extremely useful in these goals and are now also being used for the preclinical testing of therapeutic compounds. This chapter reviews the successes and limitations of the approaches that have been developed.

Animals↗
PubMed2003

Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin's lymphoma severe combined immunodeficiency mouse model.

PURPOSE: Rituximab is a chimeric antibody (Ab) directed against the cluster designated (CD) 20 antigen found on normal and malignant B cells. Rituximab activity has been associated with complement-mediated cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. Recent studies performed in severe combined immunodeficiency (SCID) mouse models suggest that in vivo rituximab-associated ADCC is mediated via the FcgammaRIII receptor on effector cells. Despite low level expression of FcgammaRIII, neutrophils are also known to induce ADCC primarily via FcgammaRI receptor (CD64). The purpose of this work was to study the effect(s) of neutrophils on the in vivo antitumor activity of rituximab. EXPERIMENTAL DESIGN: To better characterize the biological activity of rituximab, we used a human non-Hodgkin's lymphoma animal model by injecting Raji cells i.v. into natural killer (NK) cell-depleted SCID mice. Disseminated disease involving liver, lung, and central nervous system developed, with subsequent death occurring approximately 3 weeks after tumor inoculation. Specifically, 6-8-week-old NK cell-depleted SCID mice were inoculated by tail vein injection with 1 x 10(6) Raji cells on day 0. The animals then were divided into three cohorts: (a) group A received placebo (PBS); (b) group B received rituximab administered via tail vein injection at 10 mg/kg on days 3, 5, 7, and 11; and (c) group C consisted of neutrophil-depleted SCID mice treated with rituximab at 10 mg/kg on the same schedule. Neutrophils were depleted by i.p. administration of 80 microg of rat antimouse Ly-6G (Gr-1) Ab (BD PharMingen, Inc.) on days -1, 4, 9, and 14. The end point of the study was survival. Differences in outcome between treatment groups were analyzed by Kaplan-Meier methodology. RESULTS: Neutrophil- and NK cell-depleted SCID mice (group C) did not respond to rituximab, and the mean survival time was not significantly different from that of control mice. NK cell-depleted SCID mice with intact neutrophil function (group B) responded to rituximab, and 66% remained alive and appeared healthy after a mean follow-up period of 246 days. Overall, NK cell-depleted SCID mice with intact neutrophil function treated with rituximab had statistically longer mean survival as compared with mice in neutrophil-depleted and control groups (161 days versus 28 days versus 22 days, P=0.003). CONCLUSIONS: In the absence of neutrophils, rituximab was less effective in controlling lymphoma cell growth or prolonging survival in our B-cell lymphoma SCID mouse model. Neutrophil-induced ADCC appears to contribute to the in vivo antitumor activity of rituximab. Strategies that improve the function of neutrophils, such as granulocyte-macrophage colony-stimulating factor or G-CSF priming, may increase the antitumor effects of rituximab. Additional in vivo animal studies are warranted.

Animals↗
PubMed2005

Mouse models of human non-small-cell lung cancer: raising the bar.

Lung cancer is a devastating disease that presents a challenge to basic research to provide new steps toward therapeutic advances. The cell-type-specific responses to oncogenic mutations that initiate and regulate lung cancer remain poorly defined. A better understanding of the relevant signaling pathways and mechanisms that control therapeutic outcome could also provide new insight. Improved conditional mouse models are now available as tools to improve the understanding of the cellular and molecular origins of adenocarcinoma. These models have already proven their utility in proof-of-principle experiments with new technologies including genomics and imaging. Integrated thinking to apply technological advances while using the appropriate mouse model is likely to facilitate discoveries that will significantly improve lung cancer detection and intervention.

Animals↗
PubMed2002

Mouse model of cerebral aneurysm: experimental induction by renal hypertension and local hemodynamic changes.

BACKGROUND AND PURPOSE: Rupture of cerebral aneurysm (CA) is the major cause of subarachnoid hemorrhage. Molecular mechanisms of this disease, however, remain unknown. To make possible genetic analysis of CA formation with genetically altered mice, we have successfully established a mouse model of saccular CA that recapitulates the essential features of human saccular CA. METHODS: In C57black/6 male mice, various stages of CAs were experimentally induced at the right anterior cerebral artery-olfactory artery bifurcations by ligations of left common carotid arteries and posterior branches of bilateral renal arteries with high salt diet. Both light and electron microscopic studies were performed with the longitudinal sections of anterior cerebral artery-olfactory artery bifurcations. RESULTS: In the treated group, various aneurysmal changes were detected in 14 of 18 mice. On the other hand, in the control group, no aneurysmal changes were found in 15 mice. In microscopic studies, aneurysmal changes were shown to include mainly fragmentation of internal elastic lamina, thinning of the smooth muscle cell layer, and degeneration of adventitial tissue, which were very similar to critical changes in human saccular CA. CONCLUSIONS: This mouse model of CA will be useful for studying the effects of complex determinants on CA formation and makes it possible to understand the pathogenesis of CA at the molecular level.

Animals↗
PubMed2007

Immunological protection against HPV16 E7-expressing human esophageal cancer cell challenge by a novel HPV16-E6/E7 fusion protein based-vaccine in a Hu-PBL-SCID mouse model.

Increasing evidence has suggested that infection with high-risk human papillomavirus (HPVs) is closely associated with esophageal squamous cell carcinoma (ESCC) in China. The E6 and E7 oncoproteins expressed in ESCC are considered as attractive tumor-specific antigen targets for immunotherapy. We have reported that the HPV16 mE6delta/mE7/TBhsp70delta fusion protein vaccination induced powerful anti-tumor immunity against TC-1 tumor cells in a C57BL/6 mouse model. In the present study, we further evaluate the protective efficacy of this fusion protein vaccine using an HPV E7-expressing human ESCC cell line (EC9706) and a Hu-PBL-SCID mouse model. We demonstrated that immunization with the fusion protein vaccine caused significant inhibition of tumor growth with the delay time to tumor detection (tests vs. controls, 16 d vs. 9 d, p<0.01) and much smaller tumor size (p<0.01) in vivo. The inhibitory rate was ca. 69.6%, and 25% of the fusion protein vaccinated-mice remained tumor free by the end of the experiment (42 d). Furthermore, the activated lymphocytes (CD8+) were capable of infiltrating into the tumor site, and much more apoptotic cells along with activation of caspase-3 were observed in the tumors from vaccinated-mice. Also, high expression levels of human IFN-gamma, TNF-alpha, granzyme B and perforin were detected in the tumors from vaccinated-mice. Therefore, we concluded that the HPV16 mE6delta/mE7/TBhsp70delta fusion protein vaccine is able to stimulate cellular-mediated immune response against E7-containing ESCC cells through CD8+-dependent CTL-induced apoptosis in Hu-PBL-SCID mice. These findings provide a scientific basis for HPV E7-expressing ESCC active immunotherapy.

Animals↗