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Results for “clonal modeling”

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PubMed1990

An in vitro model for cyclosporin A-induced interference of intrathymic clonal elimination.

The effects of cyclosporin A (CsA) on influencing the intrathymic clonal deletion were investigated by using our established thymic stromal cell clone with capacities to express Ia antigens and to produce a unique T cell growth factor. The following were revealed: (a) T cell clone with a given specificity was killed on the Ia+ stromal cell monolayer in the presence of the relevant antigens, a process depending on T cell receptor (TCR) stimulation; and (b) CsA allowed the T cell clone to continuously proliferate even during TCR stimulation by virtue of the stromal cell-derived T cell growth factor. This paper describes an in vitro model of a mechanism by which CsA is responsible for the generation of normally "forbidden" T cell clones.

Animals↗

PubMed2005

The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade.

Peripheral and central clonal deletion are important tolerance mechanisms in models using bone marrow transplantation (BMT) with costimulation blockade (CB). However, since tolerance can be found before peripheral deletion is complete and since elimination of recipient CD4(+) cells at the time of BMT prevents tolerance induction, we investigated the potential roles of regulation and anergy in such a murine model. We found that transient elimination of CD25(+) cells or neutralization of IL2 immediately after BMT and CB prevented the induction of skin graft tolerance. Cotransfer into SCID mice of CD4(+) cells taken from chimeras early after BMT, together with naive recipient-type CD4(+) cells significantly prolonged donor skin graft survival. In contrast, cotransfer of CD4(+) cells harvested from chimeras late after BMT did not prolong donor skin graft survival. Besides, depletion of CD25(+) cells in established chimeras several months post-BMT did not break tolerance. In vivo administration of recombinant IL2 inhibited chimerism and tolerance neither early nor late post-BMT, arguing against a decisive role for classical anergy. Thus, CD4 cell-mediated regulation contributes significantly to tolerance induction early after BMT, but appears to have no critical role in the maintenance of tolerance.

Animals↗

PubMed1998

Clonality of lymphomas at multiple sites in SJL mice.

SJL mice are an inbred strain of mice with a high incidence of spontaneous lymphomas of B-cell type often involving multiple abdominal organs, and are therefore a useful model for studying the clonal relationship among lymphomas at multiple sites. Thirteen SJL mice with well-developed tumors were killed at a median age of 56 weeks. Autopsy samples were taken from various enlarged lymphoid organs, and the histologic appearance of lymphomas was recorded. Using rearrangements of immunoglobulin genes (heavy and kappa-light chain genes) and integration patterns of murine leukemia virus as clonal markers, 7 of the 13 informative mice showed complete clonal identity among the different sites selected from each mouse; 5 of 13 mice demonstrated at least one shared clonal band with one or more markers being different among the different sites. The histologic appearance of the lymphomas from the various sites was found to be heterogeneous, even when there was clonal identity. These findings suggest that SJL lymphomas in multiple sites within one mouse are usually derived from a single clone but may show development of subclones within a major clonal population, thus supporting the notion that clonal evolution is a common event in the course of development of lymphoid neoplasia.

Animals↗

PubMed1994

Information and clonal concepts in ageing.

A model based on information theory and one based on somatic mutation in an expanding pool of cells are combined to give a theory of ageing. A mathematical formula, based on concepts from information theory, gives a close fit to the age incidence of mortality and disease in middle and old age. The basic concept is that biological systems process information and make decisions to maintain their integrity. But the decision process is fallible and significant errors could lead to disease or death. Decay in the components of the system will lead to a rising error rate with age and the form of the curve will be influenced by redundancy which is a fundamental property of information systems. In addition it is suggested that an important part of the decay in the decision process is due to a subset of mutant stem cells which have a proliferative advantage and slowly expand in number throughout life. This idea is derived from application of a model of somatic mutation in expanding cells to data in cancer and on the increase of dominant mutations with paternal age. This composite view explains why ageing is less subject to the vagaries of the extrauterine environment than suggested by the simple information model and points to a significant role for the intrauterine environment in the ageing process.

Aging↗

PubMed1986

A fetal Syrian hamster lung epithelial cell line as an in vitro model for respiratory carcinogenesis.

A clonal continuous cell line consisting of pre-differentiated lung epithelial cells was established from a Syrian golden hamster fetus on day 15 of gestation. Immunocytological techniques revealed cytoplasmic filaments positive to antikeratin antibody and positive to antivimentin antibody in these cells. Supplementation of the medium with epidermal growth factor, insulin, other types of hormones and vitamin A markedly enhanced cell growth and DNA synthesis. Simultaneously, the cell differentiation characterized by mucus-like glycoprotein production was greatly stimulated. Removal of vitamin A diminished cell growth and this differentiation. The cell system was found to be useful for studying the relationship between in vitro cell transformation and differentiation. Additionally, studies to define general chemical toxicities in this cell system by evaluating several parameters such as cell survival, sialic acid content and enzyme leakage into the medium are in progress.

Animals↗

PubMed1994

A stem cell model for carcinogenesis.

A modification to the well-known two-stage model of carcinogenesis with clonal expansion is proposed. A true stem cell is applied to the production of intermediate cells by incorporating a birth-death process with a reflecting barrier into the model. The distribution of the number of detectable intermediate cell clones is derived, and systems of differential equations are formulated for the cumulative distribution function for the appearance of malignant tumors. The model is applied to data on papilloma formation in a mouse skin painting experiment. Tests for the importance of intermediate cells in tumor incidence can be derived.

Animals↗

PubMed1990

Evidence of clonal proliferation of hepatocytes after carbon-tetrachloride-induced hepatic injury in PGK-1 mosaic mice.

During aging processes, the liver is exposed continuously to both endogenous and exogenous chemicals which result in various degrees of hepatic damage. Hepatocytes maintain mitotic potential so that damaged cells are replaced by proliferation of selected clones of cells. Changes in the clonality after hepatic damage were investigated using carbon tetrachloride (CCl4) as a model hepatotoxin. The changes in clonality were determined by the alteration of the electrophoretic patterns of the allozyme, phosphoglycerate kinase-1A/1B (PGK-1A/1B), the locus of which is on the X-chromosome. In mammalian females random inactivation of one of the two X-chromosomes, of either paternal or maternal origin, are known to result in phenotype mosaicism. Heterozygous female (PGK-1a/1b) mice were obtained by crossing female (PGK-1b/1b) and male (PGK-1a/-) C3H/He mice. Liver samples were collected from these mice 5 days before (by biopsy) and 18 days after dosing with CCl4 (1 ml/kg, i.p.). Quantitative evaluation of the electrophoretic bands showed significant changes (percent change more than 7.2%, P less than 0.01) in the relative PGK-1A activity in 4 out of 10 cases. In one mouse a remarkable change, from 83.0 to 59.2%, was observed. Thus we concluded that selective hepatocyte proliferation occurs after cellular damage. We speculated that this process may play an important role in the aging of the liver.

Aging↗

PubMed2003

Biological parameters for lung cancer in mathematical models of carcinogenesis.

Applications of the two-step model of carcinogenesis with clonal expansion (TSCE) to lung cancer data are reviewed, including those on atomic bomb survivors from Hiroshima and Nagasaki. British doctors, Colorado Plateau miners and Chinese tin miners. Different sets of identifiable model parameters are used in the literature. The parameter set which could be determined with the lowest uncertainty consists of the net proliferation rate gamma of intermediate cells, the hazard h55 at an intermediate age and the hazard h(infinity) at an asymptotically large age. Also, the values of these three parameters obtained in the various studies are more consistent than other identifiable combinations of the biological parameters. Based on representative results for these three parameters, implications for the biological parameters in the TSCE model are derived.

Cell Transformation, Neoplastic↗

PubMed2005

Environmental chemical-induced bone marrow B cell apoptosis: death receptor-independent activation of a caspase-3 to caspase-8 pathway.

Programmed cell death is a critical process in B lymphocyte development. Premature apoptosis in developing B cells could affect the repertoire and number of mature B cells produced. Of particular concern is the ability of environmentally ubiquitous polycyclic aromatic hydrocarbons (PAH) to induce B cell apoptosis within the bone marrow microenvironment in a clonally nonspecific way. Here, models of bone marrow B cell development were used to assess the role of the "extrinsic" apoptosis pathway in PAH-induced apoptosis and to compare PAH-induced apoptosis with that induced during clonal deletion. As demonstrated previously with a nontransformed pro-/pre-B cell line, primary pro-B cells cultured on bone marrow stromal cells underwent apoptosis after exposure to a prototypic PAH, 7,12-dimethylbenz[a]anthracene (DMBA). Apoptosis was preceded by cleavage of caspase-3 (4-6 h) and caspase-8 (6-8 h) and their respective substrates, alpha-fodrin and Bid. Inhibition of caspase-3 blocked caspase-8 activation and apoptosis. Furthermore, a pan-caspase inhibitor blocked apoptosis and activation of both caspases-3 and -8. Cells from mice defective in tumor necrosis factor (TNF)-alpha, TNF-beta, lymphotoxin-beta, or TNFR1, TNFR2, Fas, or death receptor 6 were as susceptible to apoptosis signaling as wild-type cells. These results suggest a complex death receptor-independent B cell apoptosis pathway in which caspase-8 is activated downstream of caspase-3.

Apoptosis↗

PubMed1996

Tolerance in a rat cardiac allograft model after short-term treatment with LF 08-0299. Absence of clonal deletion and evidence of CD4+ suppressor cells.

LF 08-0299 is a new immunosuppressive compound. In a fully mismatched rat cardiac allograft model (Dark Agouti [DA]-->Lewis [LEW]), long-term unresponsiveness was observed after LF 08-0299 short-term treatment (20 days). Survival of additional cardiac and skin DA allografts, and rejection of third-party (Brown Norway [BN]) skin allografts demonstrated induction of a donor-specific tolerance state. The aim of this study was to investigate mechanisms of cardiac acceptance in this model. LEW rats with long-term surviving heart grafts (LTS LEW) were examined for their immune proliferative and cytotoxic responses toward donors (DA) and third-party (BN) antigens. Normal proliferative responses were observed and limiting dilution analysis did not reveal a reduction of T cytotoxic cell precursors. In our model, tolerance exists despite the presence of cells reactive with donor alloantigens. In vivo adoptive transfer of serum from LTS LEW failed to transfer unresponsiveness, indicating that serum factors do not seem to be involved in tolerance maintenance. Transfer of spleen cells, obtained from LTS LEW, showed specific prolongation of DA cardiac allografts in syngeneic hosts. Moreover, these cells were able to induce the rejection of third-party BN grafts. These results suggest that although LTS LEW possessed suppressor cells, they remained immunocompetent in recognizing and responding to third-party alloantigens. Purified CD4+ cells transferred unresponsiveness to secondary hosts, but CD8+ cells did not. Taken together, these results suggest that tolerance to donor alloantigens after treatment with LF 08-0299 in the rat cardiac allograft model is most likely due to induction of specific CD4+ suppressor cell activity, rather than induction of suppressive serum factor and selective elimination of antidonor helper or cytotoxic cell precursors (clonal deletion).

Animals↗

PubMed1989

Clonally derived cell lines with altered DNA methylation as models for error correction and mutation in tumours.

We have investigated the relative importance of DNA methylation-directed repair of replication errors to the production of mutation/gene rearrangements in mammalian cells with hypomethylated genomes. Using a series of sibling (Chinese hamster derived) cell clones with stably altered DNA methylation levels, we found that genomic hypomethylation was frequently associated with an elevated spontaneous mutation rate in the hypoxanthine phosphoribosyl transferase (HPRT) gene and with increased sensitivity to 2-aminopurine, a known inducer of DNA base mismatches. However, while there are some alterations in sites of DNA methylation around the HPRT gene, there was no systematic direction of change to differentiate between cells with normal or with elevated mutation rates. Further, the nature of gene alterations giving rise to the HPRT mutations suggested that methylation-directed mismatch repair is of little if any significance in influencing error avoidance in mammalian cells with hypomethylated genomes and that increased mutation associated with DNA hypomethylation is more likely to be due to increased genomic instability through activation of such factors as transposable elements.

Animals↗

PubMed1999

Models for antigen receptor gene rearrangement. I. Biased receptor editing in B cells: implications for allelic exclusion.

Recent evidence suggests that lymphocyte Ag receptor gene rearrangement does not always stop after the expression of the first productively rearranged receptor. Light chain gene rearrangement in B cells, and alpha-chain rearrangement in T cells can continue, which raises the question: how is allelic exclusion maintained, if at all, in the face of continued rearrangement? In this and the accompanying paper, we present comprehensive models of Ag receptor gene rearrangement and the interaction of this process with clonal selection. Our B cell model enables us to reconcile observations on the kappa:lambda ratio and on kappa allele usage, showing that B cell receptor gene rearrangement must be a highly ordered, rather than a random, process. We show that order is exhibited on three levels: a preference for rearranging kappa rather than lambda light chain genes; a preference to make secondary rearrangements on the allele that has already been rearranged, rather than choosing the location of the next rearrangement at random; and a sequentiality of J segment choice within each kappa allele. This order, combined with the stringency of negative selection, is shown to lead to effective allelic exclusion.

Alleles↗

PubMed1998

Activation of preexisting T cell clones by targeted interleukin 2 therapy.

The induction of an immunological antitumor response capable of eradicating metastatic tumors is the ultimate goal of immunotherapy. We have recently shown that this can be achieved by interleukin 2 (IL-2) therapy directed to the tumor microenvironment by a recombinant antibody-IL-2 fusion protein. It is not known, however, whether this curative treatment is associated with a predominance of T cells carrying specific T cell receptor variable beta regions (TCRBV) or the presence of clonally expanded T cells. To address this question, we have used a quantitative reverse transcriptase-coupled PCR method to analyze the TCRBV region repertoire in tumor-infiltrating lymphocytes of treated and untreated animals. As controls the TCRBV region repertoire was analyzed in blood and skin from disease-free animals. The results indicate an overexpression of TCRBV5 in the tumors of all treated mice and an additional overexpression of individual regions in each tumor. Direct sequencing of these TCRBV regions did not reveal any evidence of clonal expansions. However, since clonal expansions could exist as subpopulations in highly expressed regions, not detectable by direct sequencing, a denaturing gradient gel electrophoresis assay was used for clonal analysis of TCRBV PCR products. Denaturing gradient gel electrophoresis analysis of selected TCRBV regions revealed the presence of clonotypic T cells in tumors from both treated and untreated animals. These data indicate that targeted IL-2 therapy in this model does not induce clonal T cell responses de novo, rather it acts as an activator for an already existing population of clonotypic T cells.

Animals↗

PubMed1990

Human Caki-1 cells are the first model for extraneuronal transport of noradrenaline (uptake2) which is based on a clonal cell line.

The neurotransmitter noradrenaline is inactivated by active transport out of the synaptic cleft--either back into the adrenergic neuron or into extraneuronal cells. Transport studies on isolated cells provide many advantages. However, an experimental model for the extraneuronal uptake of noradrenaline which is based on a clonal cell line was not known until now. The human renal carcinoma cell line Caki-1 is the first clonal cell line known to express the extraneuronal transport system for noradrenaline.

Animals↗

PubMed1992

Inability of IL-2 and IL-10 to counteract B cell clonal deletion.

The B cell antigen receptor (BCR) delivers inhibitory signals in nascent B cells leading to the establishment of tolerance via clonal deletion or clonal anergy depending upon the type of antigen to which the B cells are exposed. In previous work, it has been demonstrated that activated Th2 cells, as well as some recombinant lymphokines, prevent the inhibition of growth and subsequent cell death induced through the BCR in model B cell lymphomas. Herein, we extend this work to another Th2 lymphokine, IL-10, that in contrast to IL-4 does not interfere with the deletion promoted by IgM crosslinking. The effect of individual lymphokines has also begun to be analyzed in a transgenic model of B cell clonal deletion. To this end, we have administered a recombinant vaccinia virus producing human IL-2 to mice expressing an autoreactive H-2Kk,b-specific transgenic IgMk and found that IL-2 does not abrogate B cell deletion in vivo.

Animals↗

PubMed2000

The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion.

Leukocytes extravasate from the blood in response to physiologic or pathologic demands by means of complementary ligand interactions between leukocytes and endothelial cells. The multistep model of leukocyte extravasation involves an initial transient interaction ("rolling" adhesion), followed by secondary (firm) adhesion. We recently showed that binding of CD44 on activated T lymphocytes to endothelial hyaluronan (HA) mediates a primary adhesive interaction under shear stress, permitting extravasation at sites of inflammation. The mechanism for subsequent firm adhesion has not been elucidated. Here we demonstrate that the integrin VLA-4 is used in secondary adhesion after CD44-mediated primary adhesion of human and mouse T cells in vitro, and by mouse T cells in an in vivo model. We show that clonal cell lines and polyclonally activated normal T cells roll under physiologic shear forces on hyaluronate and require VCAM-1, but not ICAM-1, as ligand for subsequent firm adhesion. This firm adhesion is also VLA-4 dependent, as shown by antibody inhibition. Moreover, in vivo short-term homing experiments in a model dependent on CD44 and HA demonstrate that superantigen-activated T cells require VLA-4, but not LFA-1, for entry into an inflamed peritoneal site. Thus, extravasation of activated T cells initiated by CD44 binding to HA depends upon VLA-4-mediated firm adhesion, which may explain the frequent association of these adhesion receptors with diverse chronic inflammatory processes.

Animals↗

PubMed2006

Multifocal urothelial cancers with the mutator phenotype are of monoclonal origin and require panurothelial treatment for tumor clearance.

PURPOSE: UC is a disease of the entire urothelium, characterized by multiplicity and multifocality. The clonal relationship among multiple UCs has implications regarding adjuvant chemotherapy. It has been investigated in studies of chromosomal alteration and single gene mutation. However, these genetic changes can occur in unrelated tumors under similar carcinogenic selection pressures. Tumors with high MSI have numerous DNA mutations, of which many provide no selection benefit. While these tumors represent an ideal model for studying UC clonality, their low frequency has prevented their previous investigation. MATERIALS AND METHODS: We investigated 32 upper and lower urinary tract UCs with high MSI and 4 nonUC primary cancers in 9 patients. We used the high frequency and specificity of individual DNA mutations in these tumors (MSI at 17 loci) and the early timing of epigenetic events (methylation of 7 gene promoters) to investigate tumor clonality. RESULTS: Molecular alterations varied among tumors from different primary organs but they appeared related in the UCs of all 9 patients. While 7 patients had a high degree of concordance among UCs, in 2 the UCs shared only a few similar alterations. Genetic and epigenetic abnormalities were frequently found in normal urothelial samples. CONCLUSIONS: Multiple UCs in each patient appeared to arise from a single clone. The molecular order of tumor development varied from the timing of clinical presentation and suggested that residual malignant cells persist in the urinary tract despite apparent curative surgery. These cells lead to subsequent tumor relapse and new methods are required to detect and eradicate them.

Adult↗

PubMed1997

Role of mutator alleles in adaptive evolution.

Because most newly arising mutations are neutral or deleterious, it has been argued that the mutation rate has evolved to be as low as possible, limited only by the cost of error-avoidance and error-correction mechanisms. But up to one per cent of natural bacterial isolates are 'mutator' clones that have high mutation rates. We consider here whether high mutation rates might play an important role in adaptive evolution. Models of large, asexual, clonal populations adapting to a new environment show that strong mutator genes (such as those that increase mutation rates by 1,000-fold) can accelerate adaptation, even if the mutator gene remains at a very low frequency (for example, 10[-5]). Less potent mutators (10 to 100-fold increase) can become fixed in a fraction of finite populations. The parameters of the model have been set to values typical for Escherichia coli cultures, which behave in a manner similar to the model in long-term adaptation experiments.

Adaptation, Physiological↗