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Results for “clonal modeling”

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At least 613 records · Page 34Linked to original sources

PubMed2003

Clonal expansion of double-positive intraepithelial lymphocytes by MHC class I-related chain A expressed in mouse small intestinal epithelium.

Expression of a distant homologue MHC class I molecule, MHC class I-related chain A (MICA), has been found to be stress inducible and limited to the intestinal epithelium. This nonclassical MHC molecule is associated with various carcinomas in humans. To understand the biological consequences of MICA expression in the gut, we generated transgenic (Tg) mice (T3(b)-MICA Tg) under the control of the T3(b) promoter. The T3(b)-MICA Tg mice expressed MICA selectively in the intestine and had an increased number of TCRalphabeta CD4CD8alphaalpha, double-positive (DP) intraepithelial lymphocytes (IELs) in the small bowel. These MICA-expanded DP IELs exhibited a bias to Vbeta8.2 and overlapped motifs of the complementarity-determining region 3 region among various Tg mice. Hence, the overexpression of MICA resulted in a clonal expansion of DP IELs. Studies in model of inflammatory bowel disease showed that transgenic MICA was able to attenuate the acute colitis induced by dextran sodium sulfate administration. Therefore, this unique in vivo model will enable investigation of possible influences of stress-inducible MICA on the gut immune surveillance.

Animals↗

PubMed1995

Programmed cell death in dystrophic (mdx) muscle is inhibited by IGF-II.

The pathology of Duchenne Muscular Dystrophy (DMD) is characterised by unstable muscle fibres and by increased cell turnover due to the absence of functional dystrophin protein. We have used skeletal muscle, primary muscle stem cell cultures (Smith and Schofield, 1994; Smith et al., paper submitted) and clonal cell lines of the mouse DMD model (mdx) and its congenic control (C57BI) to demonstrate that programmed cell death (PCD) and apoptotic morphology is increased in dystrophic (mdx) muscle and in cultured muscle cells. We also show that the peptide growth factor (IGF-II), which is thought to play a role in mammalian myogenesis, reduces PCD in mammalian skeletal muscle myoblasts both in vivo and in vitro. This is the first time that apoptosis or PCD have been demonstrated in normal mammalian skeletal muscle. We discuss the potential of this system in determining the role of PCD in mammalian myogenesis and skeletal muscle maturation, its significance in dystrophic muscle, and suggest a novel therapeutic route whereby the pathology of DMD may be alleviated using the survival properties of IGF-II.

Journal Article↗

PubMed1986

Cytosolic calcium elevation and cGMP production induced by serotonin in a clonal cell of glial origin.

It has been shown recently that astroglial cells of the mammalian CNS possess receptors for neurotransmitters. In order to analyze what sequences of cellular events occur upon activation of these glial receptors, we utilized a 5-HT receptor in a rat clonal cell of glial origin as a model system. When the C6BU-1 glioma cells were exposed to 5-HT, the cytosolic Ca2+ concentration ([Ca2+]i) was elevated and the cellular content of cGMP was increased in a dose-dependent manner. 5-HT receptor antagonists and a Ca2+ entry blocker suppressed the increases in both [Ca2+]i and cGMP. The magnitude of the cGMP increment depended on the environmental Ca2+ concentration and was totally blocked by Ca2+ depletion. Application of a Ca2+ ionophore increased [Ca2+]i and cGMP. There was a tendency for extremely high [Ca2+]i to suppress the cGMP increment. On the contrary, membrane-permeable cyclic nucleotide analogs failed to increase [Ca2+]i. These results suggest that the following sequence of events occurs in 5-HT-induced C6BU-1 cells: activation of 5-HT receptors, Ca2+ influx, a rise in [Ca2+]i, activation of guanylate cyclase, and, finally, activation of cyclic nucleotide phosphodiesterase.

Animals↗

PubMed1987

Limiting dilution clonal assay of human bone marrow hematopoietic progenitors (granulocytes-macrophages).

We have developed a limiting dilution assay for human bone marrow hematopoietic precursor (granulocytes-macrophages) in microwells. Bone marrow cells were fractionated by discontinuous Percoll gradients and diluted in culture medium containing colony-stimulating factors. They were diluted and cultured in medium containing colony-stimulating factor and 10(-5) M hydrocortisone in microwells over a range of cell densities that allowed calculation of the frequency of growth-inducible precursors. After 10 days, the wells were examined for clonal growth. Clonal proliferation followed the single-hit model of the Poisson distribution. More progenitors were detected in this assay than in simultaneous methylcellulose colony assays or agar cultures. Thymidine suicide experiments led to an increase in the frequency of progenitors detected in this assay, but a decrease in the frequency of methylcellulose colonies. This system may detect additional, less mature progenitors than are detected in semisolid culture systems.

Bone Marrow Cells↗

PubMed1984

Emergence of permanently differentiated cell clones in a human colonic cancer cell line in culture after treatment with sodium butyrate.

The human colonic cancer cell line HT29 is undifferentiated in standard culture conditions (Dulbecco's medium:10% fetal bovine serum). These cells were cultured in 5 mM sodium butyrate for 9 days; then they were trypsinized and subcultured in sodium butyrate for an additional 14 days. Multinucleation occurred during this second phase of the treatment. The cells were then transferred to standard medium and multinucleation disappeared. Morphological changes appeared 10 to 12 days after return to standard culture conditions; some cells flattened and became more adherent to the bottom of the flasks. These altered cells divided actively and formed "flat foci" interspersed among the densely packed undifferentiated HT29 cells. This altered phenotype persists after more than 24 months of culture in standard medium. Clonal cell lines were established from these flat foci-forming cells and characterized. These clonal lines exhibited morphological cell polarity defined by an apical cell surface separated by junctional complexes from the basolateral cell surface. Functional differentiation did also occur since some clonal lines formed domes representing active transepithelial transport, and others exhibited massive mucus secretion. In conclusion, our findings indicate that permanently differentiated cell populations emerged in a colonic cancer cell line after sodium butyrate treatment. These new clonal lines will be useful in future models for the study of differentiation programs of both normal and cancerous colonic cells.

Butyrates↗

PubMed1990

Clonal deletion: a mechanism of tolerance in mixed bone marrow chimeras.

The mechanism of antigen-specific immunologic unresponsiveness which results from lethal irradiation and mixed (syngeneic-allogeneic) bone marrow cell (BMC) reconstitution is unknown. To determine whether clonal deletion is the mechanism of tolerance in this model, monoclonal antibody (Mab) RR-4-4, specific for a T-cell receptor (V beta 6) reactive against the minor alloantigen MLsa, was employed. Six-week-old B10 mice (H-2b, Mlsb, Thyl.2) were tolerized to AKR antigens (H-2k, Mlsa, Thyl.1) by whole body irradiation (950 R) and iv infusion of T-cell-depleted (TCD) B10 BMC + non-TCD AKR BMC. Chimerism and antigen-specific tolerance were documented by flow microfluorometry (FMF), skin grafting, mixed lymphocyte reaction, and cell-mediated lympholysis. When tolerant B10 mice (n = 15) had accepted AKR skin grafts for greater than 100 days, these animals were studied for the presence of host V beta 6+ T cells using Mab RR-4-4. FMF revealed that 0-5% of host (B10) lymph node and spleen cells from chimeras were V beta 6+ while 15-20% of lymph node and spleen cells from control B10 mice expressed V beta 6. These data demonstrate that clonal deletion occurs in the lethal irradiation-mixed reconstitution model as evidenced by the near total elimination of Mlsa-reactive V beta 6+ T cells and suggest that it maybe a mechanism responsible for tolerance in adult mice.

Animals↗

PubMed1991

Mathematical model of antiviral immune response. I. Data analysis, generalized picture construction and parameters evaluation for hepatitis B.

The present approach to the mathematical modelling of infectious diseases is based upon the idea that specific immune mechanisms play a leading role in development, course, and outcome of infectious disease. The model describing the reaction of the immune system to infectious agent invasion is constructed on the bases of Burnet's clonal selection theory and the co-recognition principle. The mathematical model of antiviral immune response is formulated by a system of ten non-linear delay-differential equations. The delayed argument terms in the right-hand part are used for the description of lymphocyte division, multiplication and differentiation processes into effector cells. The analysis of clinical and experimental data allows one to construct the generalized picture of the acute form of viral hepatitis B. The concept of the generalized picture includes a quantitative description of dynamics of the principal immunological, virological and clinical characteristics of the disease. Data of immunological experiments in vitro and experiments on animals are used to obtain estimates of permissible values of model parameters. This analysis forms the bases for the solution of the parameter identification problem for the mathematical model of antiviral immune response which will be the topic of the following paper (Marchuk et al., 1991, J. theor. Biol. 15).

Hepatitis B↗

PubMed2007

Inferring a population structure for Staphylococcus epidermidis from multilocus sequence typing data.

Despite its importance as a human pathogen, information on population structure and global epidemiology of Staphylococcus epidermidis is scarce and the relative importance of the mechanisms contributing to clonal diversification is unknown. In this study, we addressed these issues by analyzing a representative collection of S. epidermidis isolates from diverse geographic and clinical origins using multilocus sequence typing (MLST). Additionally, we characterized the mobile element (SCCmec) carrying the genetic determinant of methicillin resistance. The 217 S. epidermidis isolates from our collection were split by MLST into 74 types, suggesting a high level of genetic diversity. Analysis of MLST data using the eBURST algorithm revealed the existence of nine epidemic clonal lineages that were disseminated worldwide. One single clonal lineage (clonal complex 2) comprised 74% of the isolates, whereas the remaining isolates were clustered into 8 minor clonal lineages and 13 singletons. According to our evolutionary model, SCCmec was acquired at least 56 times by S. epidermidis. Although geographic dissemination of S. epidermidis strains and the value of the index of association between the alleles, 0.2898 (P < 0.05), support the clonality of S. epidermidis species, examination of the sequence changes at MLST loci during clonal diversification showed that recombination gives rise to new alleles approximately twice as frequently as point mutations. We suggest that S. epidermidis has a population with an epidemic structure, in which nine clones have emerged upon a recombining background and evolved quickly through frequent transfer of genetic mobile elements, including SCCmec.

Algorithms↗

PubMed2002

The influence of host dynamics on the clonal composition of Escherichia coli populations.

Species, be they plant or animal, vary in their capacity for population growth or decline. Populations of the same species may also differ in their capacity for population change. A series of mathematical models were developed with the aim of determining if host population dynamics could influence the clonal composition of the Escherichia coli community in that host population. The biological assumptions underlying the models are described in some detail. Analytical and numerical approaches were used to investigate the behaviour of these models. The results demonstrate that host dynamics can have a profound influence on the E. coli clonal composition of the host population. This outcome is largely independent of the nature of the assumptions underlying the models. The ways in which the predictions of these models may be tested empirically are discussed, as are the implications of these models for understanding the nature of host-bacterial pathogen dynamics.

Animals↗

PubMed1999

Dominant regulation: a common mechanism of monoclonal antibody induced tolerance?

Transplantation tolerance can be induced by a range of agents that block T cell/antigen-presenting cell (APC) interactions known to be important for initiation of the adaptive immune response. Tolerance so induced has been shown to have a regulatory phenotype dependent on CD4+ cells. This was first observed with nonlytic anti-CD4 antibodies, and was recently demonstrated following other therapeutic approaches. Dominant tolerance also plays a role in natural regulation of the immune response, functioning to prevent autoaggressive cells mediating self-destruction. The mechanism by which dominant tolerance is established and maintained remains unclear, and the reported characteristics of regulatory cells in different experimental models vary widely. Here we review the evidence for potential mechanisms involved and propose that there is a common pathway by which dominant tolerance is mediated.

Antibodies, Monoclonal↗

PubMed2006

Analysis of epidemiological cohort data on smoking effects and lung cancer with a multi-stage cancer model.

A stochastic two-stage cancer model is used to analyse the relation between lung cancer and cigarette smoking. The model contains the main rate-limiting stages of carcinogenesis, which include initiation, promotion (clonal expansion of initiated cells), malignant transformation and a lag time for tumour formation. Various data sets were used to test the model. These include the data of a large prospective collaborative project carried out in 10 different European countries, the European Prospective Investigation into Cancer and Nutrition (EPIC). This new data set has not been modelled before. The model is also tested on other published data from CPS-II (Cancer Prevention Study II) of the American Cancer Society and the British doctors' study. The analyses indicate that the EPIC data are best described with smoking dependence on the rates of malignant transformation and clonal expansion. With increasing smoking rates, saturation effects in the two exposure rate-dependent model parameters were observed. The results find confirmation in the biological literature, where both mutational effects and promotional effects of cigarette smoke are documented.

Adolescent↗

PubMedDate not supplied

[A mathematical model of pre-epidemic circulation: an analysis of the mechanisms of oriented transformation].

The probable mechanisms of the regulation of the clonal composition of the infective agent in the course of its pre-epidemic circulation are studied. The mathematical model (in the form of two subsystems) describes asymptomatic circulation and the dynamics of the clonal composition: the beginning of the active circulation of faintly virulent variants, the oriented selection of virulent variants and the fixation of the epidemic variant.

Cloning, Molecular↗

PubMed1994

Clonal expansion but lack of subsequent clonal deletion of bacterial superantigen-reactive T cells in murine retroviral infection.

Several studies have suggested that activation-induced apoptosis of Ag-specific CD4+ T cells leads to depletion of this subset during HIV infection. The bacterial superantigen, staphylococcal enterotoxin A (SEA), is known to induce activation-induced apoptosis in the TCR V beta-bearing CD4+ T cells in the periphery after clonal expansion of these cells. The murine retroviral model of AIDS (MAIDS), which is induced by LP-BM5 murine leukemia virus, shares many common features with HIV infection in humans, except that CD4+ T cells increase progressively in susceptible strains. In this study, we challenged SEA to MAIDS mice and examined whether this retrovirus affects the fate of the SEA-reactive CD4+ T cells in vivo. At 4 wk post-infection with LP-BM5 murine leukemia virus, clonal expression and subsequent deletion of SEA-reactive CD4+V beta 3+ T cells occurred normally after SEA administration, whereas in vitro proliferative responses were severely impaired. At 8 wk postinfection, the in vivo expansion of CD4+V beta 3+ T cells was evident, but not followed by clonal deletion, as late as 14 days after SEA administration. This expanding subset in the infected mice expressed the Fas Ag in the same amount as the same subset in uninfected controls. These findings suggest that activation-induced apoptosis of superantigen-reactive CD4+ T cells is interfered with in vivo during the course of MAIDS, which is not attributable to underexpression of the Fas Ag by the CD4+ T cells.

Animals↗

PubMed2005

The kinetics of clonal dominance in myeloproliferative disorders.

To study clonal evolution in myeloproliferative disorders, we used stochastic models of hematopoiesis for mouse and cat, species for which the in vivo kinetics of hematopoietic stem cells (HSCs) have been experimentally defined. We determined the consequence if 1 HSC became able to survive without the support of a microenvironmental niche while the rest of its behavior did not change. Neoplastic cells persisted and dominated hematopoiesis in 14% of mice and 17% of cats, requiring mean times of 2.5 +/- 0.5 and 7.0 +/- 1.2 years, respectively (n=1000 simulations/species). In both species, when the number of neoplastic HSCs exceeded 0.5% of all HSCs, clonal dominance was inevitable. Our results can explain the absence of clonal myeloproliferative disorders in mice (lifetime, 2 years), are consistent with clinical observations in cats, and provide insight into the progression of chronic myelogenous leukemia (CML) in humans. They also demonstrate that competition for microenvironmental support can lead to the suppression of normal hematopoiesis as neoplasia evolves. Toxic or immunologic suppression of normal HSCs is not required.

Animals↗

PubMed2004

Central tolerance to self-antigen expressed by cortical epithelial cells.

The exposure of developing thymocytes to high-affinity self-Ag results in T cell tolerance. A predominant mechanism for this is clonal deletion; though receptor editing, anergy induction, and positive selection of regulatory T cells have also been described. It is unclear what signals are involved in determining different tolerance mechanisms. In particular, OT-I mice displayed receptor editing when the high-affinity self-Ag was expressed in cortical epithelial cells (cEC) using the human keratin 14 promoter. To test the hypothesis that receptor editing is a consequence of a unique instruction given by cEC presenting self-Ag, we created mice expressing the 2C and HY ligands under control of the keratin 14 promoter. Alternatively, we studied the fate of developing T cells in OT-I mice where Ag was presented by all thymic APC. Surprisingly, we found that the tolerance mechanism was not influenced by the APC subset involved in presentation. Clonal deletion was observed in 2C and HY models even when Ag was presented only by cEC; and receptor editing was observed in OT-I mice even when Ag was presented by all thymic APC. These results suggest that different TCRs show intrinsic differences in thymic tolerance mechanism.

Animals↗

PubMed1991

Genetic analysis of germ cell tumors: current progress and future prospects.

Cytogenetic analysis of germ cell tumors (GCTs) has identified i(12p) as a specific cytogenetic abnormality identified in more than 80% of GCTs, present in all histologies, in primary and metastatic lesions, in testicular and extragonadal presentations, and in ovarian and sex cord stromal tumors. Other nonrandom numeric and structural chromosomal abnormalities have also been identified. Oncogene studies suggest a potential role for n-ras mutations in GCT transformation. The role of loss of tumor suppressor genes and increased genomic dosage of growth promoter genes remain areas of great interest. Leukemias and differentiated malignancies that arise in the setting of GCT appear to be clonally derived from GCT cells, with evidence of karyotypic progression and acquisition of other tumor-specific cytogenetic markers. Identification of i(12p) in poorly differentiated midline carcinomas of uncertain histogenesis can assist in the diagnosis of GCT. The presence of three or more copies of 12p may predict resistance to chemotherapy and portend a higher likelihood of treatment failure. Future cytogenetic studies in GCT promise to provide insight into the biology and treatment of all solid tumors, because GCTs are a model of chemotherapeutic responsiveness, cellular differentiation, and tumor clonal evolution.

Cell Differentiation↗

PubMed2000

Contemporary models for peripheral tolerance and the classical 'historical postulate'.

The formulators of Clonal Selection Theory proposed that what distinguishes self from foreign antigens is their early appearance in development, and their continuous presence thereafter. This early presence of a self antigen in an animals life history was envisaged to ensure that lymphocytes specific for the self antigen were silenced rather than activated. I call this idea 'the historical postulate'. Contemporary models for the activation/inactivation of helper T cells implicitly violate this postulate. I argue against such a violation and for a model of T helper cell activation/inactivation that reconciles contemporary observations with the postulate.

Antigen-Presenting Cells↗

PubMed2001

Update on hepatic stem cells.

The liver, like most organs in an adult healthy body, maintains a perfect balance between cell gain and cell loss. Though normally proliferatively quiescent, simple hepatocyte loss such as that caused by partial hepatectomy, uncomplicated by virus infection or inflammation, invokes a rapid regenerative response to restore liver mass. This restoration of moderate cell loss and 'wear and tear' renewal is largely achieved by hepatocyte self-replication. Furthermore, cell transplant models have shown that hepatocytes can undergo significant clonal expansion. Such observations indicate that hepatocytes are the functional stem cells of the liver. More severe liver injury activates a facultative stem cell compartment located within the intrahepatic biliary tree, giving rise to cords of biliary epithelia within the lobules before these cells differentiate into hepatocytes. A third population of stem cells with hepatic potential resides in the bone marrow; these haematopoietic stem cells can contribute to the albeit low renewal rate of hepatocytes, make a more significant contribution to regeneration, and even completely restore normal function in a murine model of hereditary tyrosinaemia. How these three stem cell populations integrate to achieve a homeostatic balance is not understood. This review focuses on three aspects of liver stem cell biology: 1) the hepatic stem cell candidates; 2) models of cell transplantation into the liver; and 3) the therapeutic potential of hepatic stem cells.

Animals↗