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The phlorotannin-polycaprolactone-coated endotracheal tube (PP tube) has been developed with the aim of preventing tracheal stenosis that can result from endotracheal intubation, a factor that can lead to a serious airway obstruction. Its preventive efficacy has been assessed through both in vitro and in vivo investigations. However, there is a lack of studies concerning its biocompatibility and sub-chronic toxicity in animal models, a crucial factor to ensure the safety of its usage as a functional endotracheal tube. Thus, this study aimed to evaluate the biocompatibility and sub-chronic (13 weeks) toxicity of the PP tube through L929 cell line and diverse in vivo models. The cytotoxicity testing was performed using the extracts of PP tube on L929 cells for 72 h. Furthermore, other tests conducted on animal models, including ICR mice (acute systemic toxicity), New Zealand white rabbit (intradermal reactivity and pyrogen tests), guinea pig (maximization sensitization), and Sprague Dawley rats (sub-chronic toxicity). In both biocompatibility and sub-chronic toxicity analyses, no significant adverse effects are observed in the groups exposed to the PP tube, when compared to control group. Altogether, the findings suggested that the PP tube exhibits relative non-toxic and safety, supporting its suitability for clinical usage. However, extended periods of intubation may produce mild irritant responses, highlighting the clinical caution of limiting intubation duration to less than 13 weeks. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is currently the most common complication of pregnancy and is defined as a glucose intolerance disorder with recognition during pregnancy. GDM is considered a uniform group of patients in conventional guidelines. In recent years, evidence of the disease's heterogeneity has led to a growing understanding of the value of dividing patients into different subpopulations. Furthermore, in view of the increasing incidence of hyperglycemia outside pregnancy, it is likely that many cases diagnosed as GDM are in fact patients with undiagnosed pre-pregnancy impaired glucose tolerance (IGT). Experimental models contribute significantly to the understanding of the pathogenesis of GDM and numerous animal models have been described in the literature. The aim of this review is to provide an overview of the existing mouse models of GDM, in particular those that have been obtained by genetic manipulation. However, these commonly used models have certain limitations in the study of the pathogenesis of GDM and cannot fully describe the heterogeneous spectrum of this polygenic disease. The polygenic New Zealand obese (NZO) mouse is introduced as a recently emerged model of a subpopulation of GDM. Although this strain lacks conventional GDM, it exhibits prediabetes and an IGT both preconceptionally and during gestation. In addition, it should be emphasized that the choice of an appropriate control strain is of great importance in metabolic studies. The commonly used control strain C57BL/6N, which exhibits IGT during gestation, is discussed in this review as a potential model of GDM. [ABSTRACT FROM AUTHOR]

As a chronic autoimmune disease systemic lupus erythematosus (SLE) can also affect the central and the peripheral nervous system causing symptoms which are summed up as neuropsychiatric systemic lupus erythematosus (NPSLE). These symptoms are heterogenous including cognitive impairment, seizures, and fatigue, leading to morbidity or even mortality. At present, little is known about the pathophysiological processes involved in NPSLE. This review focuses on the current knowledge of the pathogenesis of NPSLE gained from the investigation of animal models, autoantibodies, and neuroimaging techniques. The antibodies investigated the most are anti-ribosomal P protein antibodies (Anti-rib P) and anti-N-Methyl-D-Aspartic Acid Receptor 2 antibodies (Anti-NR2), which represent a subpopulation of anti-dsDNA autoantibodies. Experimental data demonstrates that Anti-rib P and Anti-NR2 cause different neurological pathologies when applied intravenously (i.v.), intrathecally or intracerebrally in mice. Moreover, the investigation of lupus-prone mice, such as the MRL/MpJFaslpr/lpr strain (MRL/lpr) and the New Zealand black/New Zealand white mice (NZB x NZW F1) showed that circulating systemic antibodies cause different neuropsychiatric symptoms compared to intrathecally produced antibodies. Furthermore, neuroimaging techniques including magnetic resonance imaging (MRI) and positron emission tomography (PET) are commonly used tools to investigate structural and functional abnormalities in NPSLE patients. Current research suggests that the pathogenesis of NPSLE is heterogenous, complex and not yet fully understood. However, it demonstrates that further investigation is needed to develop individual therapy in NPSLE. [ABSTRACT FROM AUTHOR]

Context: Valerian extract capsule (VEC) is an effective Chinese patent medicine used for gastrointestinal (GI) diseases. Objective: To investigate the detailed pharmacological activity for VEC clinical effects in GI diseases. Materials and methods: Sprague-Dawley rats were divided into six groups: control, model, and drugtreated (VEC-L, VEC-M, VEC-H, and teprenone). Rats were orally administered VEC (124, 248, 496 mg/kg) and teprenone (21.43 mg/kg) for 3 consecutive days. After 1 h, the five groups (except the control group) were orally given ethanol (10mL/kg) for 1 h or indomethacin (80mg/kg) for 7 h. The spasmolytic activity of VEC (0.01-1 mg/mL) on ACh/BaCl2-induced New Zealand rabbit smooth muscle contraction was performed. The C57BL/6 mice carbon propelling test evaluated the effects of VEC (248-992mg/kg) on intestinal motility in normal and neostigmine/adrenaline-induced mice. Results: Compared with the model group, VEC treatment reduced the gastric lesion index and mucosal damage. Further experiments showed that the pathological ameliorative effect of VEC was accompanied by augmentation of the enzymatic antioxidant system and cytoprotective marker (COX-1, p<0.01; PGI2 p<0.05;), along with the alleviation of the levels of MPO (ethanol: 15.56 ± 0.82 vs. 12.15 ± 2.60, p<0.01; indomethacin: 9.65 ± 3.06 vs. 6.36 ± 2.43, p<0.05), MDA (ethanol: 1.66 ± 0.44 vs. 0.81 ± 0.58, p<0.01; indomethacin: 1.71 ± 0.87 vs. 1.09 ± 0.43, p<0.05), and inflammatory mediators. VEC decreased the high tone induced by ACh/BaCl2 and promoted intestinal transit in normal and neostigmine/adrenalineinduced mice. Discussion and conclusions: VEC showed a potential gastroprotective effect, suggesting that VEC is a promising phytomedicine for the treatment of GI diseases. [ABSTRACT FROM AUTHOR]

Healthcare associated infections caused by vancomycin-resistant Enterococcus faecium (VREfm) have a major impact on health outcomes. VREfm is difficult to treat because of intrinsic and acquired resistance to many clinically used antimicrobials, with daptomycin being one of the few last line therapeutic options for treating multidrug-resistant VREfm. The emergence of daptomycin-resistant VREfm is therefore of serious clinical concern. Despite this, the impact that daptomycin-resistant VREfm have on patient health outcomes is not clearly defined and knowledge on the mechanisms and genetic signatures linked with daptomycin resistance in VREfm remains incomplete. To address these knowledge gaps, phenotypic daptomycin susceptibility testing was undertaken on 324 E. faecium isolates from Australia and New Zealand. Approximately 15% of study isolates were phenotypically resistant to daptomycin. Whole genome sequencing revealed a strong association between vanA -VREfm and daptomycin resistance, with 95% of daptomycin-resistant study isolates harbouring vanA. Genomic analyses showed that daptomycin-resistant VREfm isolates were polyclonal and carried several previously characterised mutations in the liaR and liaS genes as well as several novel mutations within the rpoB, rpoC , and dltC genes. Overall, 70% of daptomycin-resistant study isolates were found to carry mutations within the liaR, rpoB, rpoC , or dltC genes. Finally, in a mouse model of VREfm bacteraemia, infection with the locally dominant daptomycin-resistant clone led to reduced daptomycin treatment efficacy in comparison to daptomycin-susceptible E. faecium. These findings have important implications for ongoing VREfm surveillance activities and the treatment of VREfm infections. [ABSTRACT FROM AUTHOR]

Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-a neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNFα, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIγ, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs. [ABSTRACT FROM AUTHOR]

B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL. [ABSTRACT FROM AUTHOR]

Most systemic autoimmune diseases occur more frequently in females than in males. This is particularly evident in Sjögren's syndrome, systemic lupus erythromatosis (SLE) and thyroid autoimmunity, where the ratio of females to males ranges from 20:1 to 8:1. Our understanding of the etiology of SLE implies important roles for genetics, environmental factors and sex hormones, but the relative significance of each remains unknown. Using the New Zealand hybrid mouse model system of SLE, we present here a new fetal liver chimera-based system in which we can segregate effects of immune system genes from that of sex hormones in vivo. We show that female hematopoietic cells express an intrinsic capacity to drive lupus-like disease in both male and female recipient mice, suggesting that this capacity is hormone independent. Particularly, only chimeric mice with a female hematopoietic system showed significantly increased numbers of germinal center B cells, memory B cells and plasma cells followed by a spontaneous loss of tolerance to nuclear components and hence elevated serum antinuclear autoantibodies. A protective effect of testosterone was noted with regard to disease onset, but not disease incidence. Thus, genetic factors encoded within the female hematopoietic system can effectively drive lupus-like disease even in male recipients. [ABSTRACT FROM AUTHOR]

The safety of four different adjuvants was assessed in lupus-prone New Zealand black/New Zealand white ( BW)F1 mice. Four groups of mice were injected intraperitoneally with incomplete Freund's adjuvant ( IFA), complete Freund's adjuvant ( CFA), squalene ( SQU) or aluminium hydroxide ( ALU). An additional group received plain phosphate-buffered saline ( PBS) ( UNT group). Mice were primed at week 9 and boosted every other week up to week 15. Proteinuria became detectable at weeks 17 ( IFA group), 24 ( CFA group), 28 ( SQU and ALU groups) and 32 ( UNT group). Different mean values were obtained among the groups from weeks 17 to 21 [week 17: one-way analysis of variance ( anova) P = 0·016; weeks 18 and 19: P = 0·048; weeks 20 and 21: P = 0·013] being higher in the IFA group than the others [ Tukey's honestly significant difference ( HSD) post-test P < 0·05]. No differences in anti- DNA antibody levels were observed among groups. Anti- RNP/ Sm antibody developed at week 19 in only one CFA-treated mouse. Mean mouse weight at week 18 was lower in the ALU group than the IFA ( Tukey's HSD post-test P = 0·04), CFA ( P = 0·01) and SQU ( P < 0·0001) groups, while the mean weight in the SQU group was higher than in the IFA ( P = 0·009), CFA ( P = 0·013) and UNT ( P = 0·005) groups. The ALU group weight decreased by almost half between weeks 29 and 31, indicating some toxic effect of ALU in the late post-immunization period. Thus, SQU was the least toxic adjuvant as it did not (i) accelerate proteinuria onset compared to IFA; (ii) induce toxicity compared to ALU or (iii) elicit anti- RNP/ Sm autoantibody, as occurred in the CFA group. [ABSTRACT FROM AUTHOR]

In several rodent strains such as the New Zealand Obese (NZO) mouse, the incidence of obesityassociated diabetes mellitus is much higher in males than in females. In the present study, we investigated the effects of ovariectomy on glucose homeostasis in female NZO mice in order to elucidate the mechanism of their diabetes resistance. NZO females were ovariectomized at the age of 4 weeks, received a high-fat diet and body weight, body fat, glucose and insulin tolerance were investigated in comparison to sham-operated mice. In a second experiment, operated mice were fed a carbohydrate-free diet up to the age of 19 weeks before they received the high-fat diet. In comparison with a shamoperated control group, ovariectomized female NZO mice exhibited similar body weights, a reduced glucose tolerance, developed signifi- cantly higher blood glucose levels, lost insulin producing β-cells, which finally resulted in a diabetes prevalence of 73 % at the age of 16 weeks vs. 25 % in controls. Similar to male NZO mice, ovariectomized females presented a more severe insulin resistance in the insulin tolerance test than sham-operated controls. Furthermore, the more severe insulin resistance in ovariectomized mice preceded the development of diabetes and pancreatic insulin depletion that was caused by a dietary regimen of carbohydrate restriction and subsequent re-exposure. In summary our data demonstrate that estrogen protects NZO females from β-cell loss and obesity-associated diabetes mellitus. This effect is due to a reduced insulin resistance and possibly also to a reduced sensitivity of β-cells to glucolipotoxic conditions. [ABSTRACT FROM AUTHOR]

L chain allelic inclusion has been proposed as a B cell tolerance mechanism in addition to clonal deletion, clonal anergy, and re-ceptor editing. It is said to rescue autoreactive B cells from elimination by diluting out the self-reactive BCR through the expression of a second innocuous L chain. In autoimmune animals, such as lupus-prone mice, allelically included B cells could be activated and produce pathogenic autoantibodies. We have previously shown that anti-DNA hybridomas from diseased New Zealand Black/New Zealand White F1 mice exhibit nearly perfect allelic exclusion. In the current study, we have analyzed single B cells from these and from nonautoimmune mice. In addition, we have cloned and expressed the Ig variable regions of several L chain-included B cells in cell culture. We find that although the number of L chain-included B cells increases as a result of receptor editing, the majority of such cells do not retain an autoreactive HxL chain combination and, therefore, allelic inclusion in itself does not serve as a B cell tolerance mechanism in these autoimmune mice. [ABSTRACT FROM AUTHOR]

Infertility, associated with oligo/anovulation, increased ovarian volume, numerous follicular cysts, and metabolic disturbances such as obesity and insulin resistance (IR) are characteristics common to polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age. Here, we show that New Zealand obese (NZO) mice display similar metabolic characteristics such as obesity, leptin insensitivity, glucose intolerance, and IR. Importantly, NZO mice are poor breeders; however, the mechanism for this has not been investigated. The aim of this study was to assess the ovarian structure/morphology and sex hormone levels in female NZO and lean C57BL/6J control mice. Twenty-five NZO and twenty female control mice were studied at three different ages (young, adult, and aged). The animals were weighed, an insulin tolerance test was carried out, and blood was collected for measurement of hormone levels. The ovaries were removed for histological analysis. As expected, NZO mice presented higher body weights (P=0.001), increased basal plasma glucose (P=0.007), and insulin levels (P=0.001) as well as IR, compared with control mice. NZO mice showed an increased ovarian volume, reduced numbers of corpora lutea, and higher total follicle numbers (P=0.0001). The number of primordial follicles increased (P=0.02) at the young stage, as well as the amount of atretic follicles (P=0.03), in NZO compared with control mice. NZO mice also displayed reduced plasma LH and increased estradiol levels. In conclusion, NZO mice show a poor breeding performance due to decreased ovulation, increased number of primordial and atretic follicles, and ovarian size. Given that NZO mice are obese, hyperinsulinemic and insulin resistant, they are suitable for investigating pathophysiological mechanisms linking metabolic alterations with reproductive defects. [ABSTRACT FROM AUTHOR]

Background: Obesity and diabetes in mice can be modified by dietary variables. Here we systematically analysed the effect of the sucrose and fat content and of the fat quality in New Zealand Obese mice, a mouse model of the metabolic syndrome. Results: Male NZO mice fed a semi-purified diet with sucrose exhibited an identical weight gain and diabetes incidence as controls without sucrose. In contrast, mice on a chow diet gained weight more slowly and developed diabetes approximately 10 weeks later than those on the semi-purified diet (energy density 3.05 vs. 3.85 kcal / g; fibre content 12.9 vs. 4.7 % ). In a second experimental series, neither the fat content (10 vs. 40 % of the total energy) nor the quality of the fat (lard, safflower oil, or fish oil) of semipurified diets modified weight gain. However, diabetes started approximately 2 weeks earlier and appeared more severe (blood glucose 30 vs. 20 mmol / l at week 13) in the high-fat diet group (energy density 4.58 kcal / g; fibre content 5.7 % ). Conclusions: Obesity in NZO mice develops independent of the dietary sucrose or fat content, and of the fat quality. However, the dietary fat content accelerates the onset of diabetes without enhancing adiposity. In contrast, chow diet exerts an anti-adipogenic / anti-diabetogenic effect that appears to be due to its lower caloric density and / or its higher fibre content. [ABSTRACT FROM AUTHOR]

Molecular markers and morphological characters can help infer the colonization history of organisms. A combination of mitochondrial (mt) d -loop DNA sequences, nuclear DNA data, external measurements and skull characteristics shows that house mice (Mus musculus) in New Zealand and its outlying islands are descended from very diverse sources. The predominant genome is Mus musculus domesticus (from western Europe), but Mus musculus musculus (from central Europe) and Mus musculus castaneus (from southern Asia) are also represented genetically. These subspecies have hybridized to produce combinations of musculus and domesticus nuclear DNA coupled with domesticus mtDNA, and castaneus or musculus mtDNA with domesticus nuclear DNA. The majority of the mice with domesticus mtDNA that we sampled had d -loop sequences identical to two haplotypes common in Britain. This is consistent with long-term British–New Zealand cultural linkages. The origins of the castaneus mtDNA sequences widespread in New Zealand are less easy to identify. [ABSTRACT FROM AUTHOR]

Abstract: Chronic hyperbaric oxygen (HBO) therapy significantly attenuates atherosclerosis in New Zealand white rabbits as well as the apoE knockout (KO) mice, independent of plasma lipid concentrations and lipoprotein profiles. Because atherosclerosis has many features of a chronic inflammatory disease, in which both cell-mediated and humoral immune responses participate, we examined the effect of HBO treatment on various aspects of the immune response. We now demonstrate that in apoE KO mice, HBO treatment significantly reduces the circulating levels of antibodies to MDALDL, both in the IgG and IgM class, as well as the delayed-type hypersensitivity (DTH) response to oxLDL challenge. Furthermore, HBO treatment results in a profound attenuation in the production of pro-inflammatory cytokines in response to an inflammatory stimulus (LPS), which is accompanied by a marked increase in the constitutive production of the anti-inflammatory cytokine IL-10 by spleen cells, independent of antigen specificity, as indicated by polyclonal activation of T cells. Our results demonstrate that HBO treatment results in the dampening of T and B cell-mediated responses to oxLDL or inflammatory stimuli. [Copyright &y& Elsevier]

Background: Immunosuppressive agents may induce severe changes on bone metabolism and may impair the osseointegration process during the implant healing. No data are available concerning the influence of cyclosporin A on dental implants previously integrated to the bone. The aim of this study was to evaluate the influence of cyclosporin A administration on the mechanical retention of bone previously integrated to dental implants. Methods: Eighteen female New Zealand rabbits were submitted to an implant surgery. Each animal received one commercial dental implant of 10 x 3.75 mm. After 12 weeks of an undisturbed healing period, six animals were randomly sacrificed and the removal torque test was performed (group A). In addition, six animals were submitted to a daily injection of cyclosporin A in a dosage of 10 mg/kg (group C), and six animals received saline solution as a control (group B). After 12 weeks of cyclosporin A administration, groups B and C were sacrificed and submitted to a removal torque test in which higher values can be interpreted as higher mechanical bone retention to the implant surface or higher osseointegration. Results: The removal torque results were 305 (±9.8) Ncm for group A, 50.17 (±17.5) Ncm for group B, and 26 (±7.8) Ncm for group C. The statistical analysis showed significant differences between groups A and B (P<0.05) and groups B and C (P<0.01). Conclusion: Cyclosporin A administration may impair the mechanical retention of dental implants previously integrated to the bone. [ABSTRACT FROM AUTHOR]

Immunoglobulin E (IgE) plays a critical role in both resistance to parasitic infection and allergy to environmental antigens. The IgE response is in turn regulated by the B-cell co-receptor CD23, and CD23- deficient mice show exaggerated IgE responses and airway hyper-responsiveness. In this report, we show that New Zealand black (NZB) mice express a variant CD23 allele, with mutations in both the C-lectin-binding domain and stalk region, which fails to bind IgE at high affinity and has reduced expression on the cell surface. Expression of the variant CD23 chain interferes with trimerisation of the receptor and has a dominant-negative effect leading to reduced IgE binding in crosses between NZB and other strains. Genetic mapping shows that the variant CD23 leads to an exaggerated primary IgE response, which is independent of other strain-specific effects. These results suggest that NZB mice or mice carrying the variant allele will be useful models for studying both allergy and quantitative traits associated with atopy. The exaggerated IgE response provides an explanation for the natural resistance of NZB mice to parasitic infection by Leishmania. [ABSTRACT FROM AUTHOR]

The New Zealand obese (NZO) mouse strain shares with the related New Zealand black (NZB) strain a number of immunophenotypic traits. Among these is a high proportion of B-1 B lymphocytes, a subset associated with autoantibody production. Approximately 50 % of NZO/HILt males develop a chronic insulin-resistant type 2 diabetes syndrome associated with 2 unusual features: the presence of B lymphocyte-enriched pen-insular infiltrates and the development of anti-insulin receptor autoantibodies (AIRAs). to establish the potential pathogenic contributions of H lymphocytes and AIRAs in this model, a disrupted immunoglobuhn heavy chain gene (Igz-6) congenic on the NZB/BIJ background was backcrossed 4 generations into the NZO/HILt background and was then intercrossed to produce mice that initially segregated for wild-type versus the mutant Igh-6 allele and thus permitted comparison of syndrome development. A new flow cytometric assay (AIRA binding to transfected Chinese hamster ovary cells stably expressing mouse insulin receptor) showed IgM and IgG subclass AIRAs in serum from Igh-6 intact males, but not in Igh-6null male serum. However, the absence of B lymphocytes and antibodies distinguishing mutant from wild-type males failed to significantly affect diabetes-free survival. The Igh-6null males gained weight less rapidly than wild-type males, probably accounting for a retardation, but not prevention, of hyperglycemia. Thus, AIRA and the B-lymphocyte component of the peri-insulitis in chronic diabetics were not essential either to development of insulin resistance or to eventual pancreatic beta cell failure and loss. A new substrain, designated NZL, was generated by inbreeding Igh-6 wild-type segregants. Currently at the F10 generation, NZL mice exhibit the same juvenile-onset obesity as NZO/HILt males, but develop type 2 diabetes at a higher frequency (>80%). Also, unlike NZO/HILt mice that are difficult to breed, the NZL/Lt strain breeds well and thus offers clear advantages to obesity/diabetes researchers. [ABSTRACT FROM AUTHOR]

Particulate matter exposures have been linked to increased mortality and morbidity that may be associated with immune dysfunction. Therefore, Lupus-prone New Zealand mixed mice (NZM) were intranasally instilled with either 30 μ l saline or 30 μ l saline suspensions of 500 μ g acid-washed PM 1648, PM 1648 or PM2.5 collected in Houston, TX, once a week for 4 weeks. Lung injury, mortality, and various immune dysfuntions were assessed. Accelerated mortality was observed in the PM 1648 and PM2.5 instilled mice compared to the acid-washed PM 1648 and saline-instilled mice. PM 1648 and PM2.5 significantly suppressed the natural development of anti-nuclear antibodies in NZM mice at 16 weeks. IgG serum levels were significantly increased in the acid-washed PM 1648 instilled mice at 8 weeks following PM instillation compared to the saline-instilled group. In contrast, IgG serum levels were significantly decreased in the PM 1648 and PM2.5 instilled mice at 8 weeks post-PM instillation as compared to the acid-washed PM 1648 instilled group. There were increases in the amount of immune cell infiltration, fibrosis and collagen deposition within the lungs of PM 1648 and PM2.5 groups in comparison within the saline- and acid-washed PM 1648 instilled mice. These results demonstrate that PM has an immunosuppressive effect on the development of anti-nuclear autoantibodies and modulates the IgG responses in this model of autoimmune disease. [ABSTRACT FROM AUTHOR]

Interleukin-17A (IL-17A) produced by Th17 cells, contributes to the pathogenesis of various autoimmune diseases by stimulating the release of cytokines and chemokines and its regulation. Anti-IL-17A antibody which blocks the function of IL-17A has been proved to be an effective treatment of autoimmune disease. The aim of our study was to generate a potential humanized anti-IL-17A therapeutic monoclonal antibody (mAb) through a comprehensive panel of in vitro and in vivo biological activity studies, as well as physicochemical characterization. HZD37-5, a humanized monoclonal antibody specifically recognizing N78 loci of IL-17A, binds to human and rhesus monkeys, blocks IL-17 induced signal transduction and the release of IL-6, IL-8, CXCL-1 and G-GSF. In an in vivo efficacy mouse model, HZD37-5 significantly inhibited human IL-17A induced-keratinocyte chemoattractant (KC) secretion in a dose-dependent manner. The pharmacokinetics (PK) study result of HZD37-5 in rhesus monkeys indicated that HZD37-5 had favorable PK characteristics with limited distribution (78.0–78.8 ml/kg), slow elimination (5.00–6.45 ml/day/kg), long half-life (9.1–10.7 days) and high bioavailability (103%) following a single IV or SC dose at 1.5 mg/kg. These findings provided a comprehensive preclinical characterization of HZD37-5 and supported that it may be developed as a potential therapeutic for the treatment of autoimmune diseases, including psoriasis, psoriatic arthritis, axial spondyloarthritis, etc. • Immunization and selection of candidate antibodies in New Zealand white rabbit. • Humanization of 37# rabbit antibody. • Affinity and neutralization activities of humanized antibodies HZD37-1 and HZD37-5. • HZD37-5 inhibited keratinocyte chemoattractant (KC) release induced by human IL-17A in mice. • Epitope mapping for HZD37-5 and pharmacokinetics (PK) of HZD37-5 in rhesus monkeys. [ABSTRACT FROM AUTHOR]

The frequent occurrence of autoimmune diseases in patients with B cell chronic lymphocytic leukemia (B-CLL) or in their family members suggests the involvement of related predisposing genetic factors in the two distinct disorders. Because the majority of B-CLL is of CD5 B cell type, and because the majority of CD5 B cells produces polyreactive autoantibodies, certain regulatory abnormalities in the proliferation and differentiation of CD5 B cells appear to be involved in B-CLL and autoimmune disease, respectively. In studies using MHC(H-2)-congenic New Zealand mouse strains, NZB(H-2d), NZW(H-2z) and NZB x NZW F1(H-2d/z), we found that while H-2d/z heterozygosity acts as one genetic predisposing element for autoimmune disease, by providing the element for abnormal differentiation of CD5 B cells, the H-2z/z homozygosity serves as one predisposition for B-CLL, by promoting the abnormal proliferation of CD5 B cells. Another non-MHC-linked genes were also involved in the aberrant proliferation of CD5 B cells, as determined by microsatellite DNA analysis. Among these, there was a single dominant NZW locus located on chromosome 6, closely linked to the locus for TNF receptor p55. Hence our mouse model provides an appropriate tool for studying the relationship between genetic factors predisposing to B-CLL and autoimmune diseases. [ABSTRACT FROM AUTHOR]

We previously reported that laboratory mice from all global vendors are frequently colonized with Staphylococcus aureus (S. aureus). Genotyping of a snap sample of murine S. aureus isolates from Charles River, US, showed that mice were predominantly colonized with methicillin-sensitive CC88 strains. Here, we expanded our view and investigated whether laboratory mice from other global animal facilities are colonized with similar strains or novel S. aureus lineages, and whether the murine S. aureus isolates show features of host adaptation. In total, we genotyped 230 S. aureus isolates from various vendor facilities of laboratory mice around the globe (Charles River facilities in the USA, Canada, France, and Germany; another US facility) and university- or company-associated breeding facilities in Germany, China and New Zealand. Spa typing was performed to analyse the clonal relationship of the isolates. Moreover, multiplex PCRs were performed for human-specific virulence factors, the immune-evasion cluster (IEC) and superantigen genes (SAg). We found a total of 58 different spa types that clustered into 15 clonal complexes (CCs). Three of these S. aureus lineages had spread globally among laboratory mice and accounted for three quarters of the isolates: CC1 (13.5%), CC15 (14.3%), and CC88 (47.0%). Compared to human colonizing isolates of the same lineages, the murine isolates frequently lacked IEC genes and SAg genes on mobile genetic elements, implying long-term adaptation to the murine host. In conclusion, laboratory mice from various vendors are colonized with host-adapted S. aureus-strains of a few lineages, predominantly the CC88 lineage. S. aureus researchers must be cautioned that S. aureus colonization might be a relevant confounder in infection and vaccination studies and are therefore advised to screen their mice before experimentation., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Introduction: The New Zealand Black (NZB)×New Zealand White (NZW) F1 hybrid female mice (NZB/WF1) develop a disease closely resembling human systemic lupus erythematosus (SLE), characterized by the production of antinuclear antibodies, severe glomerulonephritis and early mortality. Recently, innate immune responses have been reported to play an important role in the development of autoimmune disease. In this study we investigated the role of Myd88 protein (an important regulator of innate immune signaling pathways) in the pathogenesis of lupus-like disease in Myd88 knockout NZB/W F1 mice. Methods: The Myd88-deficient mice were backcrossed separately in the NZB and NZW backgroud. Heterozygous NZB as well as NZW of F10 backcross generation were intercrossed to achieve Myd88 -/- NZB/W F1 mice (KO) and Myd88 +/+ NZB/W F1 mice (WT). WT and Myd88 KO mice were compared for serum concentrations of anti-dsDNAantibody, biochemical markers of active disease (BUN, Cr, Alb, TP, T-CHO, protein urea), histological analysis of kidney pathology and mortality. Results: Compared with WT mice, Myd88 KO mice featured significantly reduced serum concentrations of anti-dsDNAantibody, reduced levels of biochemical markers of active disease, reduced kidney pathology and reduced mortality. Conclusion: Our result indicates that innate immunity participates in the pathogenesis of lupus prone mice and Myd88 is its important regulator. [ABSTRACT FROM AUTHOR]