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At least 721 records · Page 40Linked to original sources
PubMed2005

Induction of immunomodulator transcriptional responses by cholera toxin.

Cholera toxin (CT) is the causative agent of cholera, binds to GM1 glycosphingolipids, induces the production of cellular cAMP and is also a very powerful mucosal adjuvant. Although the mechanism of the CT induction of cAMP production is well understood, molecular mechanisms of the adjuvanticity of cholera toxin are yet to be delineated. Here, we examined the interaction of CT with human lymphocytes and monocytes by analyzing the host transcriptional profiles using cDNA arrays. The time courses of the transcriptional activations and repressions of affected genes in lymphocytes and monocytes in response to cholera toxin were determined. CT induced the expression of IL-8 and MIP-1 early in the CT exposure. VEGF, TIMP1, HIF-1alpha, MMP11, hek 8, MCP1, IL-6, GCP 2, urokinase plasminogen activator, and TNF-alpha receptor were upregulated after 4h CT treatment. These genes showed increased expression for 48 h. MRP-14, MRP-8A increased expression after 16 h CT treatment. RT-PCR and real-time PCR using cDNA specific primers confirmed the CT induction and repression of selected genes. The results suggest that immunomodulatory genes were among the genes that were affected the most by CT, and induction of these genes may contribute to the CT adjuvanticity.

Cells, Cultured↗
PubMed2005

Context matters: the hen or egg problem in Ewing's sarcoma.

Ewing's sarcoma and related tumors (ESFT) are characterized by rearrangements of EWS with ets family genes. While detection of these gene fusions greatly facilitated diagnosis, it has not provided any clues about the tissue of origin. Immunological and gene expression profiling studies favour a neuroectodermal histogenesis. These investigations did not appreciate the impact of EWS-ets proteins on the tumor phenotype. Introduction of EWS-ets into different cellular models resulted in diverse outcomes ranging from the induction of cell cycle arrest or apoptosis to transformation and tumorigenicity, and from blocked differentiation to trans-differentiation. Thus, the molecular signature of EWS-ets proteins depends on the cell type. The hen or egg problem in ESFT, therefore, is whether ESFT reflect the phenotype of the tumor stem cell that is blocked in differentiation by the activity of the EWS-ets gene fusion or if the oncogene imposes an incomplete differentiation program on a pluripotent precursor cell. This article addresses the problem by considering the tissue distribution of FLI1 and ERG expression and by reviewing evidence for combinatorial control of EWS-ets activity.

Animals↗
PubMed1997

Fetal antigen 1 (FA1), a circulating member of the epidermal growth factor (EGF) superfamily: ELISA development, physiology and metabolism in relation to renal function.

We describe an ELISA technique for quantification of fetal antigen 1 (FA1), a glycoprotein belonging to the EGF-superfamily. The ELISA is based on immunospecifically purified polyclonal antibodies and has a dynamic range of 0.7-5.3 ng/ml, intra- and inter-assay C.V.s of less than 3.2% and an average recovery of 105% in serum and 98% in urine. Comparison of FA1 in amniotic fluid, serum and urine revealed parallel titration curves, identical elution volumes following size chromatography, immunological identity and similar profiles when analysed by MALDI-MS. The reference interval for serum FA1 was 12.3-46.6 ng/ml and the levels were 10 times higher in patients with renal failure. FA1 showed no diurnal variation, no variation during the menstrual cycle and was not influenced by the acute phase reaction. In humans (n = 10) the renal clearance of FA1 was 11 ml/min and an identical high renal clearance was found in rats when expressed per 100 g body weight. In rats the initial increase in serum FA1 was 10 ng/ml/h following bilateral nephrectomy, explaining the increased serum concentrations of FA1 observed in patients with renal failure.

Acute-Phase Reaction↗
PubMed1999

Comparative characterisation of Russell's viper (Daboia/Vipera russelli) venoms from different regions of the Indian peninsula.

Russell's viper (Daboia/Vipera russelli) venom from different regions of India was subjected to chromatographic, electrophoretic, biochemical and immunological analysis. The elution profiles from ion-exchange chromatography and protein banding pattern from SDS-PAGE showed a significant variation in the constituents of venoms. The acidic proteins are found to be predominant in the venoms of eastern and western regions while basic proteins are the major contributors of the northern and southern regional venoms. The major variation of phospholipases A(2) in the venom samples of India may be described as: southern regional venom is rich in basic, toxic PLA(2) while this activity showed a dramatic decrease as one moves towards west, north and eastern regions of India. In addition, the caseinolytic, TAME-hydrolytic, anticoagulant, oedema-inducing and haemorrhagic activities of the venoms have also varied from one region to another. The muscle specimens of mice injected with venoms of different regions showed variable change in the muscle fibre damage and cell morphology. The eastern regional venom is most lethal among all the venoms. The lethal potencies for four regional venoms vary as: eastern>western>southern>northern. The polyclonal antibodies prepared against the venom of southern region showed cross-reaction with the venoms of other regions, but the extent of cross-reaction and diffusion patterns are different. However, the polyclonal antibodies prepared against southern regional venom showed no protection against lethal toxicity of other regional venoms.

Animals↗
PubMed2001

During pregnancy, in the context of a Th2-type cytokine profile, serum IL-6 levels might condition the quality of the synthesized antibodies.

PROBLEM: In recent years, the central role of cytokines in the immune response has been widely studied. It is considered that a T helper (Th)1-type cytokine profile is associated with the rejection phenomenon, whereas a Th2-type cytokine profile is associated with immunological tolerance. In pregnancy, the enhanced Th2/Th1 ratio seems to be necessary to fetal protection. Taking into account that a Th2-type response means antibody production by B cells, and that these antibodies could induce degradation of the paternal antigens, we investigated the quality of the antibodies produced during pregnancy and their regulation. METHOD OF STUDY: Review of previous data. RESULTS: The regulation of protective antibodies by IL-6 in a dose-dependent fashion is proposed as a hypothesis. CONCLUSION: Cytokines play a central role in the success (or failure) of pregnancy. However, the quality of the synthesized antibodies is also a regulatory key. The preferential synthesis of asymmetric immunoglobulin G antibodies during pregnancy could be one of the several pathways that lead to a successful pregnancy

Animals↗
PubMed2006

Gene expression profiles of human proximal tubular epithelial cells in proteinuric nephropathies.

In kidney disease renal proximal tubular epithelial cells (RPTEC) actively contribute to the progression of tubulointerstitial fibrosis by mediating both an inflammatory response and via epithelial-to-mesenchymal transition. Using laser capture microdissection we specifically isolated RPTEC from cryosections of the healthy parts of kidneys removed owing to renal cell carcinoma and from kidney biopsies from patients with proteinuric nephropathies. RNA was extracted and hybridized to complementary DNA microarrays after linear RNA amplification. Statistical analysis identified 168 unique genes with known gene ontology association, which separated patients from controls. Besides distinct alterations in signal-transduction pathways (e.g. Wnt signalling), functional annotation revealed a significant upregulation of genes involved in cell proliferation and cell cycle control (like insulin-like growth factor 1 or cell division cycle 34), cell differentiation (e.g. bone morphogenetic protein 7), immune response, intracellular transport and metabolism in RPTEC from patients. On the contrary we found differential expression of a number of genes responsible for cell adhesion (like BH-protocadherin) with a marked downregulation of most of these transcripts. In summary, our results obtained from RPTEC revealed a differential regulation of genes, which are likely to be involved in either pro-fibrotic or tubulo-protective mechanisms in proteinuric patients at an early stage of kidney disease.

Aged↗
PubMedDate not supplied

Understanding autoimmune mechanisms in multiple sclerosis using gene expression microarrays: treatment effect and cytokine-related pathways.

Multiple sclerosis (MS) is a central nervous system disease in which activated autoreactive T-cells invade the blood brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, as well as the mechanisms associated with its unexpected onset, the unpredictable clinical course spanning decades, and the different rates of progression leading to disability over time, remains an enigma. We have applied gene expression microarrays technology in peripheral blood mononuclear cells (PBMC) to better understand MS pathogenesis and better target treatment approaches. A signature of 535 genes were found to distinguish immunomodulatory treatment effects between 13 treated and 13 untreated MS patients. In addition, the expression pattern of 1109 gene transcripts that were previously reported to significantly differentiate between MS patients and healthy subjects were further analyzed to study the effect of cytokine-related pathways on disease pathogenesis. When relative gene expression for 26 MS patients was compared to 18 healthy controls, 30 genes related to various cytokine-associated pathways were identified. These genes belong to a variety of families such as interleukins, small inducible cytokine subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed seven cytokine-associated genes within the immunomodulatory treatment signature, and two cytokine-associated genes SCYA4 (small inducible cytokine A4) and FCAR (Fc fragment of IgA, CD89) that were common to both the MS gene expression signature and the immunomodulatory treatment gene expression signature. Our results indicate that cytokine-associated genes are involved in various pathogenic pathways in MS and also related to immunomodulatory treatment effects.

Apoptosis↗
PubMed2002

Gamma-herpesvirus latency is preferentially maintained in splenic germinal center and memory B cells.

The gamma-herpesviruses are oncogenic B cell lymphotrophic viruses that establish life-long latency in the host. Murine gamma-herpesvirus 68 (MHV-68) infection of mice represents a unique system for analyzing gamma-herpesvirus latency in splenic B cells at different stages of infection. After intranasal infection with MHV-68 we analyzed the establishment of latency 14 days after infection, and the maintenance of latency 3 months after infection in different purified subpopulations of B cells in the spleen. The data show that MHV-68 latency is mainly established in germinal center B cells and that long-term latency is preferentially maintained in two different subsets of isotype-switched B cells, germinal center and memory B cells. Cell cycle analysis indicates that MHV-68 is located in both cycling and resting isotype-switched B cells. Analysis of viral gene expression showed that both lytic and latent viral transcripts were differentially expressed in germinal center and memory B cells during long-term latency. Together, these observations suggested that gamma-herpesviruses exploit the B cell life cycle in the spleen.

Animals↗
PubMed1986

Lymph node interdigitating reticulum cell sarcoma.

A 67-year-old man presented with a malignant tumor involving abdominal lymph nodes, spleen, liver, and lungs, with associated protracted fever and night sweats. The tumor consisted of large pleomorphic cells, often surrounding microabscesses. Intracytoplasmic S100 protein, surface T6, Leu-3a (T4), and HLA-DR antigens were demonstrated. The malignant cells also possessed ATPase activity. Ultrastructurally, the cells exhibited numerous interdigitating cell processes but no Birbeck granules. The anatomic distribution of the tumor, its ultrastructural features, immunologic phenotype, and enzymatic profile are all consistent with a derivation from lymph node interdigitating reticulum cell. The tumor was unresponsive to the chemotherapeutic agents administered, and the patient soon died.

Adenosine Triphosphatases↗
PubMed1996

Clinical development of a combined diphtheria, tetanus, acellular pertussis, and hepatitis B vaccine in Italy.

In Italy, oral polio vaccine and diphtheria and tetanus (DT) and hepatitis B (HB) vaccinations are required by law. At present, infants receive DT and HB by two separate intramuscular injections during one visit, and most receive an additional injection of acellular pertussis vaccine at the same time. Although simultaneous administration of the vaccines has the advantage of only one medical visit, it is time-consuming for staff, very expensive, painful to the infants, and stressful for parents. A much better solution would be to administer a ready-to-use mixture containing all the vaccines, provided that this combination vaccine had good local and systemic safety profiles and clinical and immunologic efficacy. To evaluate such a combination vaccine in healthy infants at 3, 5, and 11 and at 2, 4, and 6 months of age, a multicenter clinical study is underway in Italy.

Adolescent↗
PubMed1990

Quantitative fluorescence image analysis in bladder cancer screening.

Quantitative fluorescence image analysis (QFIA) cytology combines image analysis to measure DNA with visual cytology for bladder cancer detection. QFIA sensitivity is 76% to 81% and 95% to 100% for low- and high-grade tumors respectively, with 94% specificity in asymptomatic controls. QFIA screening of 504 persons within a beta-naphthylamine exposed cohort found DNA hyperploidy correlated with the duration of carcinogenic exposure and smoking history; marker prevalence was 23% for exposed workers who smoked and 2% for nonexposed nonsmokers. In prospective animal studies, QFIA was useful in monitoring carcinogenesis and chemoprevention with retinoids. Current QFIA research focuses on measurements of oncogenes, growth factors and their receptors, cytoskeleton, and tumor-associated antigens to improve sensitivity and specificity to low-grade tumors and to identify premalignant conditions. Profiles of biochemical and immunological markers on single cells may further assist in the study of high-risk cohorts and individual risk assessment.

Biomarkers, Tumor↗
PubMed2005

Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia.

OBJECTIVES: To evaluate simplified protease inhibitor (PI)-sparing antiretroviral treatment versus lipid-lowering therapy for the management of highly active antiretroviral therapy (HAART)-induced hyperlipidaemia. DESIGN: Randomized, open-label clinical trial assessing the efficacy on hyperlipidaemia of a switching therapy from PI to non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine or efavirenz versus a hypolipidaemic treatment (with pravastatin or bezafibrate) added to current, unchanged antiretroviral combination. METHODS: All HIV-infected patients on their first HAART regimen, with stable immuno-virological features, naive to all NNRTIs, and with mixed hyperlipidaemia, were randomized to replace PI with nevirapine (arm A) or efavirenz (arm B), or to receive pravastatin (arm C) or bezafibrate (arm D) with unchanged HAART regimen, and were followed-up for 12 months. RESULTS: One hundred and thirty patients were evaluated: 29 patients were randomized to arm A, 34 to arm B, 36 to arm C, and 31 to arm D. At the end of the 12-month follow-up, a reduction of 25.2, 9.4, 41.2 and 46.6% in mean triglyceridaemia versus respective baseline values was reported in groups A, B, C and D, respectively, with statistically significant difference between arms A-B and C-D (P < 0.01). Similar results were reported for total and low-density lipoprotein cholesterol levels. Viro-immunological efficacy and tolerability profile were comparable in all considered arms. CONCLUSION: Pravastatin and bezafibrate proved significantly more effective in the management of HAART-related hyperlipidaemia than the switching therapy from PI to nevirapine or efavirenz.

Adult↗
PubMed2005

Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling.

Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk is a member of the Tec family of protein tyrosine kinases (PTKs) and plays a vital, but diverse, modulatory role in many cellular processes. Mutations affecting Btk block B-lymphocyte development. Btk is conserved among species, and in this review, we present the sequence of the full-length rat Btk and find it to be analogous to the mouse Btk sequence. We have also analyzed the wealth of information compiled in the mutation database for XLA (BTKbase), representing 554 unique molecular events in 823 families and demonstrate that only selected amino acids are sensitive to replacement (P < 0.001). Although genotype-phenotype correlations have not been established in XLA, based on these findings, we hypothesize that this relationship indeed exists. Using short interfering-RNA technology, we have previously generated active constructs downregulating Btk expression. However, application of recently established guidelines to enhance or decrease the activity was not successful, demonstrating the importance of the primary sequence. We also review the outcome of expression profiling, comparing B lymphocytes from XLA-, Xid-, and Btk-knockout (KO) donors to healthy controls. Finally, in spite of a few genes differing in expression between Xid- and Btk-KO mice, in vivo competition between cells expressing either mutation shows that there is no selective survival advantage of cells carrying one genetic defect over the other. We conclusively demonstrate that for the R28C-missense mutant (Xid), there is no biologically relevant residual activity or any dominant negative effect versus other proteins.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2005

Studies of patients' thymi aid in the discovery and characterization of immunodeficiency in humans.

Studying the molecular and genetic bases of primary immunodeficiency is valuable at several levels. First, such information directly benefits patients in both short- and long-term management. Sophisticated diagnostic tools based on these studies can be used early and lead to appropriate treatment before potentially fatal infections and complications arise. Genotyping is also critical for future development and implementation of gene therapy. Secondly, investigating primary immunodeficiency helps understand the normal immune system in humans. As described in this report, the roles of zeta-associated protein of 70 kDa (Zap-70), CD25, and CD3delta are substantially different in humans when compared with the roles of homologous molecules in other species. Last, information obtained from these studies can be applied to other fields of investigation. Prominent examples for such applications include the intensive effort to design and produce specific inhibitors of Zap-70 and Janus kinase 3 as specific immunosuppressive agents. Most types of primary immunodeficiency in general and severe combined immunodeficiency in particular are rare and therefore cannot be easily studied by using traditional genetic methodology. Instead, biochemical methods were used to explore for candidate genes as was the case in the discovery of Zap-70 deficiency. Critical to the success of these discoveries was the careful analysis of patients' thymus glands. Detection of abnormalities in the thymus in these patients, which preceded identification of the genetic defect, aided in the assessment of the severity and nature of the immune disorder (primary versus secondary). Such assessment is critical before high-risk bone marrow transplantation. Equally important was the contribution of studies of the thymus to the description of novel phenotype of immunodeficiency as clearly demonstrated in defining CD8 lymphocytopenia, Zap-70 deficiency, and CD25 deficiency. Indeed, analysis of the thymus directly pointed to CD25 as candidate gene. Recently, the study of thymocyte-derived transcripts using DNA microarrays was key to discovering CD3delta deficiency. Finally, immunohistochemical analysis of the thymus was critical in pinpointing the roles of Zap-70, CD25, and CD3delta in the development of human T cells.

CD3 Complex↗
PubMed1993

Neurologic abnormalities in two dogs suspected Lyme disease.

A 2-year-old mongrel dog developed neurological signs following tick bite. These included astasia, persistent tonic convulsions and hyper-reflexia. Both serum IgG and IgM antibody titers against Borrelia burgdorferi were positive in enzyme-linked immunosorbent assay (ELISA). The neurological signs subsided after high-dose penicillin and streptomycin treatment. A strain of spirochetes (P427a) was isolated from the midgut of Ixodes persulcatus feeding on the dog. Morphological characteristic, immunological property and protein profile revealed that the isolate was B. burgdorferi. Similarly, a 2-year-old Labrador retriever dog developed neurological signs after tick bite and showed a positive IgG antibody titer against B. burgdorferi. Antibiotic treatment was effective also in this case. These findings suggest that neurological symptoms shown in both dogs were caused by infection with B. burgdorferi.

Animals↗
PubMed1997

Evaluation of different subcellular fractions of Vibrio cholerae O139 in protection to challenge in experimental cholera.

Various cellular fractions of Vibrio cholerae O139 were prepared and evaluated in the rabbit ileal loop model of experimental cholera for identification of the protective antigen(s) relevant for vaccine development. Lipopolysaccharides (LPS) and capsular polysaccharides (CPS) of O139 strains and its cell surface, membrane and cytosolic fractions were assayed for antibacterial immunity, whereas the cholera toxin was examined for antitoxic immunity. The lipopolysaccharides, membrane fraction and cholera toxin induced moderate protection, however there was a significant synergistic effect when cholera toxin was combined with membrane proteins or lipopolysaccharides. The O139 strains strongly resembled O1 strains in the profile of proteins and immunological cross reactivity, yet there was no cross protection. The results warrant further investigation of the pathogenesis of O139 strains and identify the critical somatic antigens relevant to protection.

Animals↗
PubMed2006

Development of neonatal mouse and fetal human testicular tissue as ectopic grafts in immunodeficient mice.

AIM: To investigate the stepwise development and germ cell gene expression in allografted neonatal mouse testes and the differentiation of immature human testicular cells in xenografted human testes. METHODS: Immunodeficient nude mice were used as hosts for allografting of neonatal mouse testes and xenografting of human fetal testicular tissues. Stepwise development and stage-specific gene expression of germ cells in allografts were systematically evaluated and parallel compared with those in intact mice by periodically monitoring the graft status with measurement of graft weight, histological analysis and determination of five stage-specific genes. Human testicular tissues from 20 and 26 weeks fetuses were used for the xenografting study. Histological analysis of xenografts was performed 116 and 135 d after the grafting procedure. RESULTS: In the allografting study, progressive increase in tissue volume and weight as well as in tubule diameter in grafts was observed; the appearance time of various germ cells in seminiferous tubules, including spermatogonia, spermatocytes, round and elongate spermatids and sperm, was comparable with that in intact donors; the initiation of gene transcription in grafts showed a similar trend as in normal mice. Graft weight ceased to increase after 7-8 weeks and degradation of grafts was observed after 5 weeks with progressive damage to seminiferous epithelium. In the xenografting study using immature human testicular tissues, graft survival and development was indicated by increasing graft weight, Sertoli cells differentiation into advanced stage, germ cells migration and location to the basal lamina and formation of a niche-like structure. CONCLUSION: The developmental course and gene expression pattern of germ cells in allografts were similar to those in intact mice. The best time point for retrieval of mouse sperm from grafts was 5-7 weeks after grafting procedure. An accelerated development of immature human testicular cells could be achieved by ectopic xenografting of human testes.

Animals↗