Response In Mouse Model Research Articles

IMMUNOTHERAPY. Could microbial therapy boost cancer immunotherapy?

Intestinal microbes affect immunotherapy responses in mouse models of cancer [Also see Reports by Vétizou et al. and Sivan et al. ]

Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis

Integrin αvβ6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGFβ1). In human liver cirrhosis, αvβ6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that αvβ6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin αvβ6-dependent TGFβ1 activation. Freshly isolated αvβ6(+) liver cells demonstrate clonogenic potential and differentiate into cholangiocytes and functional hepatocytes in vitro, whereas colony formation by epithelial cell adhesion molecule-positive progenitor cells is blocked by αvβ6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti-αvβ6 antibody is recapitulated by TGFβ1 neutralization and rescued by addition of bioactive TGFβ1. Genetic disruption or selective targeting of αvβ6 with 3G9 antibody potently inhibits progenitor cell responses in mouse models of chronic biliary injury and protects from liver fibrosis and tumorigenesis, two conditions clinically associated with exacerbated ductular reaction. These results suggest that αvβ6 is a promising target for chronic fibrotic liver diseases and associated cancers.

The structural HCV genes delivered by MPG cell penetrating peptide are directed to enhance immune responses in mice model

One of the significant problems in vaccination projects is the lack of an effective vaccine against hepatitis C virus (HCV). The goal of the current study is to evaluate and compare two DNA constructs encoding HCV core and coreE1E2 genes alone or complexed with MPG peptide as a delivery system for stimulation of antibody responses and IFN-γ secretion in Balb/c mice model. Indeed, MPG cell penetrating peptide was used to improve DNA immunization in mice. Our results demonstrated that MPG forms stable non-covalent nanoparticles with pcDNA-core and pcDNA-coreE1E2 at an N/P ratio of 10:1. The in vitro transfection efficiency of core or coreE1E2 DNA using MPG and TurboFect delivery systems was confirmed by western blot analysis. The results indicated the expression of the full-length core (∼21 kDa), and coreE1E2 (∼83 kDa) proteins using an anti-His monoclonal antibody. In addition, the expression of HCV core and coreE1E2 proteins was performed in bacteria and the purified recombinant proteins were injected to mice with Montanide 720 adjuvant. Our data showed that the immunized mice with HCV core and coreE1E2 proteins generated the mixture of sera IgG1 and IgG2a isotypes considerably higher than other groups. Furthermore, DNA constructs encoding core and coreE1E2 complexed with MPG could significantly induce IFN-γ secretion in lower concentrations than the naked core and coreE1E2 DNAs. Taken together, the DNA formulations as well as protein regimens used in this study triggered high-level IFN-γ production in mice, an important feature for the development of Th1 immune responses.

Asthma Prevention: Right Bugs, Right Time?

Asthma is an increasingly prevalent chronic respiratory disease particularly affecting children. Microbial colonization during early life has emerged as a central factor influencing asthma susceptibility. A recently published prospective study links the reduction in relative abundance of 4 bacterial genera at 3 months of age to the development of asthma.

UNBIASED ASSESSMENT OF CIRCULATING MICRORNAS PROVIDES AN INDEPENDENT LINK BETWEEN THE CHOLESTEROL-REGULATING MIR-382-5P AND CORONARY ARTERY DISEASE IN HUMANS

UNBIASED ASSESSMENT OF CIRCULATING MICRORNAS PROVIDES AN INDEPENDENT LINK BETWEEN THE CHOLESTEROL-REGULATING MIR-382-5P AND CORONARY ARTERY DISEASE IN HUMANS

MUC1-2VNTR DNA Vaccine Induces Immune Responses in Mouse Model with Multiple Myeloma

To investigate the humoral and cellular immune responses induced by MUC1-2VNTR DNA vaccine in multiple myeloma (MM) tumor-bearing mice. In vitro, multiple myeloma cells were transfected by plasmid pcDNA3.1-2VNTR/myc-hisB with Lipofectamine2000. The above-mentioned mouse myeloma cells were inoculated subcutaneously into female BALB/c mice for establishing tumor-bearing animal models. These female BALB/c mice were immunized with pcDNA-2VNTR/myc-hisB or pcDNA/myc-hisB. The cytotoxic T lymphocyte (CTL) activity was detected by the LDH method and the spleen lymphocyte proliferation activity was detected by CCK-8 method. After immunization of BALB/c tumor-bearing mice with recombinant plasmid for 25 days, the tumor mass (0.5605 ± 0.2065 g) was significantly lighter than that in the empty plasmid control group (1.521 ± 0.6985 g) (P < 0.01) and the control group (1.5315 ± 0.5425 g) (P < 0.01). The difference of tumor mass was not statislically significant between empty plasmid control group (1.521 ± 0.6985 g) and the control group (1.5315 ± 0.5425 g) (P > 0.05). The CTL and NK cell activity was significantly higher in the group of intramuscular injection with recombinant plasmid than that in control group. The spleen lymphocyte proliferation was statistically significantly increased after being immunized with recombinant plasmid pcDNA3.1-2VNTR/myc-hisB, compared with empty vector (P < 0.01). The results showed that MUC1-2VNTR gene immunization could induce anti-tumor effect in MM tumor-bearing mice. MUC1-2VNTR DNA immunization can elicit both humoral and cellular tumor specific immune response to multiple myeloma in MM tumor-bearing mice. It suggested that the MUC1-2VNTR DNA vaccine may be a potential treatment measure for patients with MM.

Virus-Like Vesicle-Based Therapeutic Vaccine Vectors for Chronic Hepatitis B Virus Infection.

More than 500,000 people die each year from the liver diseases that result from chronic hepatitis B virus (HBV) infection. Therapeutic vaccines, which aim to elicit an immune response capable of controlling the virus, offer a potential new treatment strategy for chronic hepatitis B. Recently, an evolved, high-titer vaccine platform consisting of Semliki Forest virus RNA replicons that express the vesicular stomatitis virus glycoprotein (VSV G) has been described. This platform generates virus-like vesicles (VLVs) that contain VSV G but no other viral structural proteins. We report here that the evolved VLV vector engineered to additionally express the HBV middle surface envelope glycoprotein (MHBs) induces functional CD8 T cell responses in mice. These responses were greater in magnitude and broader in specificity than those obtained with other immunization strategies, including recombinant protein and DNA. Additionally, a single immunization with VLV-MHBs protected mice from HBV hydrodynamic challenge, and this protection correlated with the elicitation of a CD8 T cell recall response. In contrast to MHBs, a VLV expressing HBV core protein (HBcAg) neither induced a CD8 T cell response in mice nor protected against challenge. Finally, combining DNA and VLV-MHBs immunization led to induction of HBV-specific CD8 T cell responses in a transgenic mouse model of chronic HBV infection. The ability of VLV-MHBs to induce a multispecific T cell response capable of controlling HBV replication, and to generate immune responses in a tolerogenic model of chronic infection, indicates that VLV vaccine platforms may offer a unique strategy for HBV therapeutic vaccination. HBV infection is associated with significant morbidity and mortality. Furthermore, treatments for chronic infection are suboptimal and rarely result in complete elimination of the virus. Therapeutic vaccines represent a unique approach to HBV treatment and have the potential to induce long-term control of infection. Recently, a virus-based vector system that combines the nonstructural proteins of Semliki Forest virus with the VSV glycoprotein has been described. In this study, we used this system to construct a novel HBV vaccine and demonstrated that the vaccine is capable of inducing virus-specific immune responses in mouse models of acute and chronic HBV replication. These findings highlight the potential of this new vaccine system and support the idea that highly immunogenic vaccines, such as viral vectors, may be useful in the treatment of chronic hepatitis B.

Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia

In patients with severe eosinophilic asthma, local maturation rather than systemic recruitment of mature cells might contribute to persistent airway eosinophilia. Group 2 innate lymphoid cells (ILC2s) are a major source of type 2 cytokines (IL-5 and IL-13) and can facilitate eosinophilic inflammatory responses in mouse models of asthma in the absence of CD4+ lymphocytes. This study investigated the potential role of ILC2s in driving chronic airway eosinophilia in patients with severe asthma, despite regular high-dose oral corticosteroid therapy. In a cross-sectional study we enumerated blood and sputum ILC2s (lin(-)CD45(+)127(+)ST2(+)) and levels of intracellular IL-5 and IL-13 in patients with severe asthma (n = 25), patients with steroid-naive mild atopic asthma (n = 19), and nonatopic control subjects (n = 5). Results were compared with numbers of CD4+ lymphocytes, eosinophil lineage-committed progenitors (eosinophilopoietic progenitor cells [EoPs]), and mature eosinophils. Significantly greater numbers of total and type 2 cytokine-producing ILC2s were detected in blood and sputum of patients with severe asthma compared to mild asthmatics. In contrast, intracellular cytokine expression by CD4 cells and EoPs within the airways did not differ between the asthmatic groups. In patients with severe asthma, although sputum CD4+ cells were more abundant than ILC2s and EoPs, proportionally, ILC2s were the predominant source of type 2 cytokines. In addition, there were significantly greater numbers of sputum IL-5(+)IL-13(+) ILC2s in patients with severe asthma whose airway eosinophilia was greater than 3%, despite normal blood eosinophil numbers (<300/μL). Our findings suggest that ILC2s can promote the persistence of airway eosinophilia in patients with severe asthma through uncontrolled localized production of the type 2 cytokines IL-5 and IL-13, despite high-dose oral corticosteroid therapy.

Vaccine-induced Aβ-specific CD8+ T cells do not trigger autoimmune neuroinflammation in a murine model of Alzheimer's disease.

BackgroundActive immunization against Aβ was reported to have a therapeutic effect in murine models of Alzheimer’s disease. Clinical Aβ vaccination trial AN1792 was interrupted due to the development in 6 % of the patients of meningoencephalitis likely involving pro-inflammatory CD4+ T cells. However, the potential implication of auto-aggressive anti-Aβ CD8+ T cells has been poorly investigated.MethodsPotential MHC-I-restricted Aβ-derived epitopes were first analyzed for their capacity to recruit functional CD8+ T cell responses in mouse models. Their impact on migration of CD8+ T cells into the brain parenchyma and potential induction of meningoencephalitis and/or neuronal damage was investigated upon vaccination in the APPPS1 mouse model of AD.ResultsWe identified one nonamer peptide, Aβ33-41, which was naturally processed and presented in association with H-2-Db molecule on neurons and CD11b+ microglia. Upon optimization of anchor residues for enhanced binding to H-2-Db, immunization with the modified Aβ33-41NP peptide elicited Aβ-specific IFNγ-secreting CD8+ T cells, which are cytotoxic towards Aβ-expressing targets. Whereas T cell infiltration in the brain of APPPS1 mice is dominated by CD3+CD8− T cells and increases with disease evolution between 4 and 7 months of age, a predominance of CD3+CD8+ over CD3+CD8− cells was observed in 6- to 7-month-old APPPS1 but not in WT animals, only after vaccination with Aβ33-41NP. The number of CD11b+ mononuclear phagocytes, which significantly increases with age in the brain of APPPS1 mice, was reduced following immunization with Aβ33-41NP. Despite peripheral activation of Aβ-specific CD8+ cytotoxic effectors and enhanced infiltration of CD8+ T cells in the brain of Aβ33-41NP-immunized APPPS1 mice, no clinical signs of severe autoimmune neuroinflammation were observed.ConclusionsAltogether, these results suggest that Aβ-specific CD8+ T cells are not major contributors to meningoencephalitis in response to Aβ vaccination.

410. The Development of HLAnull K562 Cells Expressing CD1d and Co-Stimulatory Molecules as Artificial Antigen-Presenting Cells for Clinical Scale Expansion of NKT Cells With Superior In Vivo Persistence and Anti-Tumor Potential

CD1d-restricted type-I Natural Killer T cells (NKTs) have been shown to mediate antitumor responses in mouse models and are associated with improved outcome in several types of cancer. However, the therapeutic application of NKTs has been limited by low numbers and functional defects of these cells in patients with cancer. Herein we present an effective method for ex-vivo NKT-cell numeric expansion for adoptive immunotherapy. The method is based on engineered properties of K562 cells to function as artificial antigen-presenting cells (aAPC). K562 cells express a single endogenous HLA allele, HLA-Cw3, an NK-cell activating ligand which favors the expansion of NK cells that compete with NKTs in culture. We rendered K562 cells HLAnull by eliminating HLA-C gene from K562 cell genome using a HLA-C-specific zinc finger nuclease. We then transduced parental and HLAnull K562 cells with CD1d cDNA followed by single cell sorting and clonal expansion. The clones were pulsed with αGalactosylceramide and tested as irradiated aAPC for NKTs using CFSE proliferation assay. We found that in contrast to HLA-Cw3+ K562/CD1d, HLAnullK562/CD1d clones selectively expanded NKTs when added to primary PBMC, and clones with an intermediate level of CD1d expression induced the highest rate of NKT-cell proliferation. Next, a selected HLAnullCD1dmed clone was further modified to express CD86 alone or in combination with 4-1BBL and/or OX40L followed by single cell sorting and clonal expansion, producing 250 clones. One clone with the phenotype HLAnullCD1dmedCD86high4-1BBmedOX40Lmed (designated B-8-2) consistently induced the highest rate of NKT-cell expansion. B-8-2 aAPC were able to efficiently expand both primary NKTs as well as NKTs modified to express a chimeric antigen receptor (CAR) specific for CD19 antigen, a clinically validated therapeutic target for B-cell malignancies. CAR expression in NKTs rendered them highly cytotoxic against CD19+ Raji leukemia cells. Compared with CAR-NKTs expanded with autologous PBMC, those expanded with B-8-2 cells exhibited a Th-1-skewed cytokine profile, prolonged in vivo persistence, and superior therapeutic activity in Raji leukemia model. Gene expression analysis of NKTs expanded with B-8-2 cells vs. those expanded with autologous PBMC revealed a significant up-regulation of genes associated with T- and NK-cell memory (CCR7, CD45RA, KLRG1, KLRD1, IL-21R), a mixture of Th17- and Th-1-associated molecules (IL-17A, IL-17F, STAT1, IL12RB1, GZMA, GZMB GNLY) and downregulation of a particular pro-apoptotic gene from the BCL2 family, BCL2L11. Therefore, the engineered K562-derived B-8-2 cells can be used as a highly efficient aAPC for ex vivo propagation of fully functional primary as well as gene-modified NKTs amenable for cancer immunotherapy.

P0461 : Increased liver gamma delta T cells accompanied by enhanced innate immune responses in mouse model of acute hepatitis B virus (HBV) infection by hydrodynamics-based in vivo transfection of HBV-DNA

P0461 : Increased liver gamma delta T cells accompanied by enhanced innate immune responses in mouse model of acute hepatitis B virus (HBV) infection by hydrodynamics-based in vivo transfection of HBV-DNA

Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment.

CD40 stimulation on antigen-presenting cells (APC) allows direct activation of CD8(+) cytotoxic T cells, independent of CD4⁺ T-cell help. Agonistic anti-CD40 antibodies have been demonstrated to induce beneficial antitumor T-cell responses in mouse models of cancer and early clinical trials. We report here that anti-CD40 treatment induces programmed death ligand-1 (PD-L1) upregulation on tumor-infiltrating monocytes and macrophages, which was strictly dependent on T cells and IFNγ. PD-L1 expression could be counteracted by coadministration of antibodies blocking the PD-1 (programmed death-1)/PD-L1 axis as shown for T cells from tumor models and human donors. The combined treatment was highly synergistic and induced complete tumor rejection in about 50% of mice bearing MC-38 colon and EMT-6 breast tumors. Mechanistically, this was reflected by a strong increase of IFNγ and granzyme-B production in intratumoral CD8⁺ T cells. Concomitant CTLA-4 blockade further improved rejection of established tumors in mice. This study uncovers a novel mechanism of acquired resistance upon agonistic CD40 stimulation and proposes that the concomitant blockade of the PD-1/PD-L1 axis is a viable therapeutic strategy to optimize clinical outcomes.

Comparison of β-Propiolactone and Formalin Inactivation on Antigenicity and Immune Response of West Nile Virus.

West Nile Virus (WNV) is a pathogenic arbovirus that belongs to genus Flavivirus under family Flaviviridae. Till now there are no approved vaccines against WNV for human use. In this study, the effect of two alkylating agents, formaldehyde and β-PL, generally used for inactivated vaccine preparation, was assessed on the basis of antigenic and immunogenic potential of the inactivated WNV. Lineage 5 WNV isolates were inactivated by both formalin and β-PL treatments. Inactivation was confirmed by repeated passage in BHK-21 cell line and infant mice. Viruses inactivated by both the treatments showed higher antigenicity. Immune response in mice model showed serum anti-WNV antibody titre was moderately higher in formalin inactivated antigen compared to β-PL inactivated antigen. However, no significant differences were observed in neutralization antibody titre. In conclusion, we can state that both formaldehyde and β-PL inactivation processes were found to be equally efficient for inactivation of WNV. However, they need to be compared with other inactivating agents along with study on cell mediated immune response.

マウスはやはりヒト炎症性疾患のモデルになる―バイオインフォマティクス的手法によるマウスモデルの再評価―

マウスはやはりヒト炎症性疾患のモデルになる―バイオインフォマティクス的手法によるマウスモデルの再評価―

Role of coagulation‐associated processes on factor VIII immunogenicity in a mouse model of severe hemophilia A

Immune responses to therapeutic factorVIII remain a major problem, affecting 30% of patients with severe hemophiliaA. The primary factors that drive immune responses in these patients remain elusive. There have been conflicting reports on a role of coagulation (or thrombin) in anti-FVIII immune responses. To assess the importance of coagulation-associated processes for the onset of the anti-FVIII immune response. Using FVIII-deficient mice, we compared the immunogenicity of recombinant FVIII or the inactive FVIII(V) (634M) mutant. In parallel, the involvement of tissue factor (TF) activity in the anti-FVIII immune response was investigated upon injection of a neutralizing anti-TF antibody or by the use of chimeric mice that lack TF expression in myeloid cells. The development of the anti-FVIII immune response was also monitored after treatment with warfarin. The kinetics of the development of antibody responses to FVIII(V) (634M) were indistinguishable from those of wild-type FVIII. Inhibition of TF activity did not modulate immune responses to exogenous FVIII. Additionally, global inhibition of coagulation with warfarin failed to reduce the anti-FVIII immune response. Thrombin generation or coagulation-associated processes do not modulate the anti-FVIII antibody response in mouse model of severe hemophiliaA.

Abstract 2815: Induction of both OVA specific CD4+ and CD8+ T cells by using PepTivator® OVA-pulsed DCs in mouse model

Abstract Antigen specific immune response by both MHC class I-restricted CD8+ T cells and MHC class II-restricted CD4+ T cells is a key event in cancer immunotherapy. In DC vaccine therapy, the short epitope peptides (9 or 10-mer) are mainly used to load, but these short peptides are presented on MHC class I molecule and can stimulate only CD8+ T cells. Using whole protein as antigen might be better to induce both antigen specific CD8+ and CD4+ T cells. The PepTivator® is a peptide pool: consisting mainly of 15-mer sequences with 11 amino acids overlap and covering the complete sequence of target protein. In this study, we used PepTivator® derived from ovalbumin protein (PepTivator® OVA) instead of whole protein as antigen, and evaluated the inducing activity of antigen specific CD8+ and CD4+ T cell responses in mouse model. In order to examine the antigen presenting ability of PepTivator® OVA-pulsed DCs, CD8+ T cells (106 cells/mL) isolated from OT-I transgenic mouse (OT-I CD8T) or CD4+ T cells (106 cells/mL) isolated from OT-II transgenic mouse (OT-II CD4T) were cultured with PepTivator® OVA-pulsed DCs (5×104 cells/mL) for 4 days. As positive control, OT-I epitope peptide (OVA257-264aa) and OT-II epitope peptide (OVA323-339aa) were used. DCs were prepared from bone marrow cells of C57BL/6 mice after cultivation with medium containing GM-CSF, IL-4 and LPS for 10 days. In preparation of peptide-pulsed DCs, DCs were treated with each peptide at 2 µg/mL for 4 hours and washed with medium to deplete free peptide before use. During the cultivation of OT-I CD8T or OT-II CD4T cells with each peptide-pulsed DCs, the responsive T cell proliferation was measured daily by flow cytometric analysis with absolute count beads and CFSE dye dilution. In addition, cytokines (IL-2 and IFN-gamma) in culture supernatant were measured by ELISA. As a result, the proliferation of OT-I CD8T cells cocultured with PepTivator® OVA-pulsed DCs seemed to be similar to that in coculture with OT-I epitope peptide-pulsed DCs. In the case of proliferation assay using OT-II CD4T cells, PepTivator® OVA-pulsed DCs showed similar T cell expansion in comparison with OT-II epitope peptide-pulsed DCs. As for cytokines secretion, no difference was observed in concentration of IL-2 and IFN-gamma in both cases using OT-I CD8T and OT-II CD4T cells when PepTivator® OVA was compared with OT-I or OT-II epitope peptide, respectively. These results showed that PepTivator® OVA pulsed-DCs could induce both antigen specific CD8+ and CD4+ T cell responses in mouse model. It suggests that PepTivator® OVA is at least superior to short epitope peptide in inducing antigen specific T cell response. In addition, it might be big advantage that PepTivator® derived from tumor antigen could be useful in many candidate patients without their HLA restriction. It is expected that therapeutic benefit of PepTivator® pulsed-DCs will be shown in clinical. Citation Format: Kenji Miki, Koji Nagaoka, Hermann Bohnenkamp, Takayuki Yoshimoto, Takashi Kamigaki, Ryuji Maekawa. Induction of both OVA specific CD4+ and CD8+ T cells by using PepTivator® OVA-pulsed DCs in mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2815. doi:10.1158/1538-7445.AM2014-2815

MicroRNA-29b Modulates Innate and Antigen-Specific Immune Responses in Mouse Models of Autoimmunity

In addition to important regulatory roles in gene expression through RNA interference, it has recently been shown that microRNAs display immune stimulatory effects through direct interaction with receptors of innate immunity of the Toll-like receptor family, aggravating neuronal damage and tumour growth. Yet no evidence exists on consequences of microRNA immune stimulatory actions in the context of an autoimmune disease. Using microRNA analogues, we here show that pancreatic beta cell-derived microRNA sequences induce pro-inflammatory (TNFa, IFNa, IL-12, IL-6) or suppressive (IL-10) cytokine secretion by primary mouse dendritic cells in a sequence-dependent manner. For miR-29b, immune stimulation in RAW264.7 macrophages involved the endosomal Toll-like receptor-7, independently of the canonical RNA interference pathway. In vivo, the systemic delivery of miR-29b activates CD11b+B220− myeloid and CD11b-B220+ plasmacytoid dendritic cells and induces IFNa, TNFa and IL-6 production in the serum of recipient mice. Strikingly, in a murine model of adoptive transfer of autoimmune diabetes, miR-29b reduces the cytolytic activity of transferred effector CD8+ T-cells, insulitis and disease incidence in a single standalone intervention. Endogenous miR-29b, spontaneously released from beta-cells within exosomes, stimulates TNFa secretion from spleen cells isolated from diabetes-prone NOD mice in vitro. Hence, microRNA sequences modulate innate and ongoing adaptive immune responses raising the question of their potential role in the breakdown of tolerance and opening up new applications for microRNA-based immune therapy.

Genomic responses in mouse models greatly mimic human inflammatory diseases

The use of mice as animal models has long been considered essential in modern biomedical research, but the role of mouse models in research was challenged by a recent report that genomic responses in mouse models poorly mimic human inflammatory diseases. Here we reevaluated the same gene expression datasets used in the previous study by focusing on genes whose expression levels were significantly changed in both humans and mice. Contrary to the previous findings, the gene expression levels in the mouse models showed extraordinarily significant correlations with those of the human conditions (Spearman's rank correlation coefficient: 0.43-0.68; genes changed in the same direction: 77-93%; P = 6.5 × 10(-11) to 1.2 × 10(-35)). Moreover, meta-analysis of those datasets revealed a number of pathways/biogroups commonly regulated by multiple conditions in humans and mice. These findings demonstrate that gene expression patterns in mouse models closely recapitulate those in human inflammatory conditions and strongly argue for the utility of mice as animal models of human disorders.

Protumor B Cells Are Therapeutic Targets in Squamous Cell Carcinoma

Abstract B-cell depletion with anti-CD20 mAb enhances chemotherapy response in mouse models of SCC.

Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Aβ amyloidosis

Histopathological studies on the brains of tauopathy cases including cases with Alzheimer's disease (AD) demonstrate that neurons with hyperphosphorylated protein tau display granulovacuolar degeneration (GVD), as evidenced by vacuolar lesions harboring a central granule, together with markers of the activated unfolded protein response (UPR). In order to examine whether this hallmark is reproduced in animal models we studied the presence of GVD and the activated UPR in two complementary mouse models, pR5 mice with a tau pathology and APPSLxPS1mut mice with an amyloid plaque pathology. Neither GVD nor a significant activation of the UPR was found in both APPSLxPS1mut mice and in those regions in the pR5 brain where only neurons with an early stage of tau hyperphosphorylation were present. In contrast, those neurons that displayed a tau phospho-epitope signature that only appeared in old pR5 mice and also correlated with Gallyas-positive tangle staining harbored granulovacuolar lesions that were labeled with the GVD markers casein kinases 1δ and 1ε. Granulovacuolar lesions in pR5 mice were also labeled with the UPR markers phosphorylated PKR-like endoplasmic reticulum kinase, phosphorylated inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α. However, GVD was rarely observed in neurons bearing mature neurofibrillary tangles as evidenced by Congo red staining. Our results suggest that NFT-formation activates the UPR in pR5 mice and that it is the early stages of neurofibrillary tangle formation that are accompanied by GVD, in line with observations from studies on human autopsy cases.