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Results for “Proliferation”

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PubMed1998

CD4+ cells proliferate after peanut-extract-specific and CD8+ cells proliferate after polyclonal stimulation of PBMC of children with atopic dermatitis.

BACKGROUND: Few studies describe in vitro food-allergen induced proliferative responses and cytokine production of PBMC of children with atopic dermatitis. This is especially true for peanut-allergen. OBJECTIVES: To analyse the specificity of the T cell in proliferative responses, in children with atopic dermatitis with or without peanut allergy and healthy age-matched children. METHODS: Proliferative responses were measured by [3H]-thymidine incorporation and by expression of the intracellular Ki67-antigen using flow cytometry after antigen-specific stimulation of PBMC with peanut-extract (day 7) or polyclonal stimulation with Phorbol-12myristate-13acetate and Ca-ionophore (day 3). Cytokine mRNA (Interferon-gamma (IFNgamma), IL-4) was detected by semiquantitative RT-PCR. Cytokine production (IL-4, IFNgamma) was measured by ELISA. RESULTS: Peanut-extract induced proliferative responses of PBMC from children with atopic dermatitis and peanut allergy (AD+PA+) were significantly higher as compared with the other groups studied. Ki67-antigen double staining revealed that 80-100% of the proliferating cells were CD4+. These proliferative responses correlated significantly with the increase in IL-4 mRNA expression after peanut-extract specific stimulation. After polyclonal stimulation, however, CD8+ cells preferentially proliferated. The degree of proliferation after polyclonal stimulation correlated inversely with the ratio of IL-4/IFNgamma production. CONCLUSIONS: The principal responding population of T cells in proliferative responses is different after peanut-extract specific and polyclonal stimulation of PBMC from AD+PA+ patients. Furthermore, we found indirect evidence that the PBMC fraction of AD+PA+ children contains increased frequencies of peanut-specific T helper-2 cells.

Antibodies, Monoclonal↗

PubMed2003

Peroxisome proliferator-activated receptor-beta signaling contributes to enhanced proliferation of hepatic stellate cells.

BACKGROUND & AIMS: The peroxisome proliferator-activated nuclear receptors (PPAR-alpha, PPAR-beta, and PPAR-gamma), which modulate the expression of genes involved in energy homeostasis, cell cycle, and immune function, may play a role in hepatic stellate cell activation. Previous studies focused on the decreased expression of PPAR-gamma in hepatic stellate cell activation but did not investigate the expression and role of the PPAR-alpha and -beta isotypes. The aim of this study was to evaluate the expression of the different PPARs during hepatic stellate cell activation in vitro and in situ and to analyze possible factors that might contribute to their expression. In a second part of the study, the effect of a PPAR-beta agonist on acute liver injury was evaluated. METHODS: The effects of PPAR isotype-specific ligands on hepatic stellate cell transition were evaluated by bromodeoxyuridine incorporation, gel shifts, immunoprecipitation, and use of antisense PPAR-beta RNA-expressing adenoviruses. Tumor necrosis factor alpha-induced PPAR-beta phosphorylation and expression was evaluated by metabolic labeling and by using specific P38 inhibitors. RESULTS: Hepatic stellate cells constitutively express high levels of PPAR-beta, which become further induced during culture activation and in vivo fibrogenesis. No significant expression of PPAR-alpha or -gamma was found. Stimulation of the P38 mitogen-activated protein kinase pathway modulated the expression of PPAR-beta. Transcriptional activation of PPAR-beta by L165041 enhanced hepatic stellate cell proliferation. Treatment of rats with a single bolus of CCl(4) in combination with L165041 further enhanced the expression of fibrotic markers. CONCLUSIONS: PPAR-beta is an important signal-transducing factor contributing to hepatic stellate cell proliferation during acute and chronic liver inflammation.

Acute Disease↗

PubMed2002

PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival.

Growth factors are known to favor both proliferation and survival of hepatocytes. In this work, we investigated the role of 2 main signaling pathways, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), in these processes. First, evidence was provided that the PI3K cascade as well as the MEK/ERK cascade is a key transduction pathway controlling hepatocyte proliferation, as ascertained by arrest of DNA synthesis in the presence of LY294002, a specific PI3K inhibitor. Inhibition of FRAP/mTOR by rapamycin also abrogated DNA replication and protein synthesis induced by growth factor. We showed that expression of cyclin D1 at messenger RNA (mRNA) and protein levels was regulated by this pathway. We highlighted that 4E-BP1 phosphorylation was not activated by epidermal growth factor (EGF) but was under an insulin-regulation mechanism through a PI3K-FRAP/mTOR activation that could account for the permissive role of insulin on hepatocyte proliferation. No interference between the MEK/ERK pathway and 4E-BP1 phosphorylation was detected, whereas p70S6K phosphorylation induced by EGF was under a U0126-sensitive regulation. Last, we established that the antiapoptotic function of EGF was dependent on MEK, whereas LY294002 and rapamycin had no direct effect on cell survival. Taken together, these data highlight the regulation and the role of 2 pathways that mediate growth-related response by acting onto distinct steps. In conclusion, hepatocyte progression in late G1 phase induced by EGF generates survival signals depending on MEK activation, whereas PI3K and MEK/ERK cascades are both necessary for hepatocyte replication.

Animals↗

PubMed1984

Schwann cell proliferation and localized proteolysis: expression of plasminogen-activator activity predominates in the proliferating cell populations.

The role of the serum proteolytic system plasminogen/plasminogen activator as a biochemical tool used by the glia or neurons, or both, for maintaining their temporary and flexible cellular interactions during histogenesis of the nervous system is under study. The present report identifies a glia cell type, the Schwann cell, as one of the cellular components of the nervous system that uses extracellular proteolysis at the time of the tissue construction. Purified dividing mouse Schwann cells in culture produce extracellular plasminogen activator. The levels of extracellular plasminogen-activator activity, as measured by the biochemical fibrinolytic assay, were directly related to the proliferation rates of the Schwann cells. The cellular plasminogen-activator specific activity at the maximal rate of cell proliferation was 3-4 times higher than that of the cells at low rate of mitosis. It is concluded that plasminogen-activator activity is expressed predominantly by the proliferating Schwann cell populations, suggesting that the extracellular proteolysis is used by the tissue at those stages when the cells divide.

Animals↗

PubMed1996

The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling.

The yeast two-hybrid system was used to isolate novel cellular factors that interact with the mouse peroxisome proliferator-activated receptor alpha (PPARalpha). One of the interacting clones isolated encoded LXRalpha, a recently described human orphan nuclear hormone receptor. LXRalpha bound directly to PPARalpha, as well as to the common heterodimerization partner 9-cis-retinoic acid receptor (RXRalpha). LXRalpha did not form a DNA binding complex with PPARalpha on synthetic hormone response elements composed of direct repeats of the TGACCT consensus half-site or on naturally occurring peroxisome proliferator response elements (PPREs) or LXRalpha response elements. However, LXRalpha inhibited binding of PPARalpha/RXRalpha heterodimers to PPREs, and coexpression of LXRalpha in mammalian cells antagonized peroxisome proliferator signaling mediated by PPARalpha/RXRalpha in vivo. These findings identify a novel partner for PPARalpha and suggest that LXRalpha plays a role in modulating PPAR-signaling pathways in the cell.

Animals↗

PubMed2002

Peroxisome proliferator-activated receptor delta is up-regulated during vascular lesion formation and promotes post-confluent cell proliferation in vascular smooth muscle cells.

Although peroxisome proliferator-activated receptor (PPAR) delta is widely expressed in many tissues, the role of PPARdelta is poorly understood. In this study, we report that PPARdelta was up-regulated in vascular smooth muscle cells (VSMC) during vascular lesion formation. By using Northern blot analysis, we demonstrated that PPARdelta was increased by 3-4-fold in VSMC treated with platelet-derived growth factor (PDGF) (20 ng/ml). In addition, PDGF-induced PPARdelta mRNA expression neither needs de novo protein synthesis nor affects the stability of PPARdelta mRNA in VSMC. Preincubation of VSMC with phosphatidylinositol 3-kinase inhibitor (LY294002, 50 micromol/liter) or infection of VSMC with an adenovirus carrying the gene for a dominant negative form of Akt abrogated PDGF-induced PPARdelta mRNA expression, suggesting that phosphatidylinositol 3-kinase/Akt signaling pathway is involved in the regulation of PDGF-induced PPARdelta mRNA expression in VSMC. To explore the role of PPARdelta in VSMC, we generated rat vascular smooth muscle cells (A7r5) stably overexpressing PPARdelta and the control green fluorescent protein. Overexpression of PPARdelta in VSMC increased post-confluent cell proliferation by increasing the cyclin A and CDK2 as well as decreasing p57(kip2). Taken together, the results suggest that PPARdelta plays an important role in the pathology of diseases associated with VSMC proliferation, such as primary atherosclerosis and restenosis.

Animals↗

PubMed1967

Primary immune response in grafted cells. Dissociation between the proliferation of activity and the proliferation of cells.

The primary immune response elicited by host antigens in a grafted population of immunologically competent cells has been compared in conditions where the same dose of parental cells were grafted simultaneously to F(1) hybrid embryos of 13 or 17 days of age. The enlarged chimeric spleens harvested 4 days later were analyzed for donor cell proliferation by using the sex chromosomes as karyological markers, and for proliferation of immunological activity by means of transfer to secondary hosts of the same genotype. Whereas the total number of dividing donor cells were on the average 16 times higher in 17-day than in 13-day hosts, the recovery of immunological reactivity showed a 6- to 7-fold difference in the opposite direction. The experiments cast doubt on the proposition that cellular proliferation is necessary for development of a primary immune response. They suggest that there exists an alternative way in which a primary immune response may unfold from involving a few to involving a much larger number of cells.

Animals↗

PubMed1985

Anticlonotypic monoclonal antibodies induce proliferation of clonotype-positive T cells in peripheral blood human T lymphocytes. Evidence for a phenotypic (T4/T8) heterogeneity of the clonotype-positive proliferating cells.

Three previously selected monoclonal antibodies (mAb) directed against the clonotypic structure of a variant (termed JA3) of the interleukin 2 (IL-2)-producing Jurkat leukemia cell line (anti-JTi1-3 mAb) were found to induce an adherent cell-dependent proliferation of peripheral blood T cells in 20 different donors. Unlike the early cell proliferation induced by anti-T3 mAb, anti-JTi mAb-induced proliferation was detectable at day 5-6 of culture and reached peak levels at day 7-9. Less than 1% JTi+ cells were consistently detected in the starting peripheral blood lymphocytes or in control cultures in which cells were stimulated with anti-T3, phytohemagglutinin, or allogeneic cells. However, JTi+ cells were found in increasing proportions after culture with anti-JTi mAb and they were mostly represented by large blast cells expressing either the T4 or the T8 antigen, together with typical activation antigens including HLA-DR, IL-2 receptor, and 4F2. Immunoprecipitation experiments and sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that anti-JTi-reactive molecules present on antibody-stimulated lymphocytes or on JA3 cells were similar, disulphide-linked heterodimeric structures.

Animals↗

PubMed1997

The product of proliferation disrupter is concentrated at centromeres and required for mitotic chromosome condensation and cell proliferation in Drosophila.

Homozygosity for a null mutation in the proliferation disrupter (prod) gene of Drosophila causes decreased mitotic index, defects of anaphase chromatid separation, and imperfect chromosome condensation in larval neuroblasts and other proliferating cell populations. The defective condensation is especially obvious near the centromeres. Mutant larvae show slow growth and massive cell death in proliferating cell populations, followed by late larval lethality. Loss of prod function in mitotic clones leads to the arrest of oogenesis in the ovary and defective cuticle formation in imaginal disc derivatives. The prod gene encodes a novel 301-amino-acid protein that is ubiquitously expressed and highly concentrated at the centric heterochromatin of the second and third mitotic chromosomes, as well as at > 400 euchromatic loci on polytene chromosomes. We propose that Prod is a nonhistone protein essential for chromosome condensation and that the chromosomal and developmental defects are caused by incomplete centromere condensation in prod mutants.

Amino Acid Sequence↗

PubMed1989

Differential induction of peroxisomal and microsomal fatty-acid-oxidising enzymes by peroxisome proliferators in rat liver and kidney. Characterisation of a renal cytochrome P-450 and implications for peroxisome proliferation.

The induction of renal fatty-acid-oxidising enzymes has been investigated following short-term exposure to a group of structurally diverse peroxisome proliferators and compared to the more extensively documented hepatic responses in the rat. There was a marked compound dependence on induction of both cytochrome P-450-IVA1-dependent omega-hydroxylation of lauric acid and enzymes of the peroxisomal fatty acid beta-oxidation pathway (measured as cyanide-insensitive palmitoyl-CoA oxidation and enoyl-CoA hydratase). Cytochrome P-450 IVA1 (or a very closely related isoenzyme in the same gene family) was a major constitutive haemoprotein in rat kidney microsomes and actively supported the omega-hydroxylation of lauric acid. This activity was induced 2-3-fold by peroxisome proliferators such as clofibrate, di-(2-ethylhexyl)phthalate, bezafibrate and nafenopin. By using a cDNA probe to the cytochrome P-450 IVA1 gene in Northern blot analysis, we have shown that increased renal and hepatic omega-hydroxylation of lauric acid, after treatment with peroxisome proliferators is a consequences of a substantial increase in the mRNA coding for this haemoprotein. In addition, programming of an in vitro rabbit reticulocyte translation system with both renal and hepatic RNA resulted in the synthesis of similar (if not identical) cytochrome-P-450-IVA1-related polypeptides. Furthermore, we have provided Western blot evidence that both rat liver and kidney microsomes contain two closely related cytochrome P-450 IVA1 polypeptides, the major one characterised by a monomeric molecular mass of 51.5 kDa (identical to authentic, purified hepatic cytochrome P-450 IVA1) and a minor one of 52 kDa. The kidney-supported fatty acid omega-hydroxylase activity was refractory to inhibition by a polyclonal antibody to liver cytochrome P-450 IVA1, which may be related to the existence of two closely related (but immunochemically distinct) fatty acid hydroxylases in this tissue. Our studies have also demonstrated that certain of the compounds tested (including clofibrate, bezafibrate and nafenopin) induced renal fatty acid beta-oxidation, mirroring the increased omega-hydroxylase activity in the endoplasmic reticulum. Our studies have also indicated that the kidney was more refractory to induction of the endoplasmic reticulum and peroxisomal fatty-acid-oxidising enzymes than the liver. Taken collectively, our data is strongly suggestive of a possible linkage of the renal fatty acid oxidative enzymes in these two organelles, a situation that also occurs in the liver. In addition, our studies have provided a possible conceptual framework that may rationalise the decreased susceptibility of the k

Amino Acid Sequence↗

PubMed1979

T-antigen expression in proliferating and non-proliferating simian virus 40-transformed mouse cells.

Previous studies with simian virus 40-transformed mouse 3T3 cells which are temperature sensitive for the expression of the transformed phenotype (ts SV3T3 cells) have shown that T-antigen expression and viral DNA transcription are under cell cycle control. Using these ts SV3T3 cells, we studied the expression of the viral genome under proliferating and non-proliferating conditions, in the presence and absence of inhibitors of macromolecular synthesis and of the tumor promoter phorbol myristate acetate. ts SV3TE cells which are growth arrested at 39 degrees C by low serum concentration or saturation density accumulated in G1 and did not express T-antigen. When these cells were induced to proliferate, at either 32 or 39 degrees C, T-antigen synthesis preceded the entry of the cells into the S-phase and was not coupled to DNA replication. G1-arrested ts SV3T3 cells were induced to synthesize T-antigen by phorbol myristate acetate treatment, but T-antigen alone was not sufficient to induce cellular DNA synthesis. Isoleucine deprivation arrested growth of ts SV3T3 cells, but these cells, as well as normal 3T3, did not accumulate in G1 and continued to express T-antigen. The temperature-sensitive expression of the transformed phenotype in the ts SV3T3 cells does not appear to be due to a lack of transcription of specific regions of the integrated simian virus 40 genome at 39 degrees C.

Animals↗

PubMed2000

Differential regulation of macrophage peroxisome proliferator-activated receptor expression by glucose : role of peroxisome proliferator-activated receptors in lipoprotein lipase gene expression.

Peroxisome proliferator-activated receptors (PPARs) are implicated in several metabolic disorders with altered glucose and lipid metabolism, including atherosclerosis and diabetes. In the present study, we evaluated the in vitro and ex vivo effects of high glucose concentrations on macrophage PPAR mRNA expression. Exposition of monocyte-derived macrophages isolated from healthy donors to a high glucose environment led to an increase in PPARalpha and PPARbeta mRNA expression. In contrast, this treatment significantly decreased human macrophage PPARgamma mRNA expression. Overexpression of PPARalpha and PPARbeta mRNA and inhibition of PPARgamma mRNA expression were also observed in monocyte-derived macrophages isolated from patients with type 2 diabetes. Because high glucose and PPARalpha agonists increase lipoprotein lipase (LPL) gene expression, the role of PPARalpha in the glucose-mediated upregulation of macrophage LPL gene expression was next evaluated. Incubation of murine J774 macrophages with high glucose concentrations increased the expression of PPARalpha at the mRNA and protein levels and enhanced nuclear protein binding to the peroxisome proliferator responsive element of the LPL promoter. Incubation of nuclear extracts in the presence of anti-PPARalpha and anti-PPARbeta antibodies decreased glucose-stimulated nuclear protein binding to the peroxisome proliferator responsive element. These results demonstrate that glucose is an important regulator of macrophage PPAR expression and suggest a role of PPARalpha and PPARbeta in the upregulation of macrophage LPL by glucose. Dysregulation of macrophage PPAR expression in type 2 diabetes may contribute, by altering arterial lipid metabolism and inflammatory response, to the accelerated atherosclerosis associated with diabetes.

Animals↗

PubMed2004

Effects of peroxisome proliferator activated receptors-alpha and -gamma agonists on estradiol-induced proliferation and hyperplasia formation in the mouse uterus.

It is suggested that the action of peroxisome proliferator-activated receptors (PPARs) cross-talks with estrogen signaling in the uterus. However, it is not known how PPAR agonists affect estrogen-dependent processes in the uterus, especially proliferation and morphogenetic changes. The effects of agonists of PPAR-alpha and -gamma on proliferative and morphogenetic reactions in the uterus under short- and long-term estrogen treatments were therefore examined. Ovariectomized mice were treated with estradiol dipropionate (4 micro g/100 g, s.c., once a week) or vehicle and rosiglitazone (PPAR-gamma agonist) or fenofibrate (PPAR-alpha agonist) or with no additional treatment for 2 days or for 30 days. Treatment with estradiol and PPAR agonists for 2 days did not affect uterine mass. In mice treated with estradiol and rosiglitazone for 2 days, proliferation was enhanced and levels of estrogen receptors-alpha and beta-catenin were decreased in all uterine tissues. Treatment with estradiol and fenofibrate for 2 days had the opposite effects on the parameters tested. In animals treated with estradiol and rosiglitazone for 30 days, uterine mass was increased, abnormal uterine glands and atypical endometrial hyperplasia were found more often and levels of estrogen receptors-alpha and beta-catenin were decreased. In animals treated with estradiol and fenofibrate for 30 days, uterine mass was decreased, most of the uterine glands had a normal structure, no cases of atypical hyperplasia were diagnosed, proliferative activity was declined and the levels of estrogen receptors-alpha and beta-catenin were markedly higher. Treatment with rosiglitazone or fenofibrate did not affect the serum estradiol level in the mice which received estradiol together with PPAR agonists for 30 days. Thus, rosiglitazone exerted the proliferative and morphogenetic effects of estradiol, but fenofibrate had the opposite effect. The actions of rosiglitazone and fenofibrate are associated with changes in the expression of estrogen receptors-alpha and beta-catenin in the uterus.

Animals↗

PubMed2003

Inhibition of proliferation and estrogen receptor signaling by peroxisome proliferator-activated receptor gamma ligands in uterine leiomyoma.

Peroxisome proliferator-activated receptor (PPAR) gamma is an important signaling molecule in cells of mesenchymal origin, inducing differentiation and regulating cell proliferation in several cell types such as vascular smooth muscle cells. Leiomyomas arise from smooth muscle cells of the uterine myometrium with an incidence rate as high as 70% in women of reproductive age. PPAR signaling has not been characterized in these tumors, although prostaglandins, natural PPAR ligands, are known effectors of key biological functions in the normal myometrium. Leiomyomas and tumor-derived cells isolated from a rat model for this disease were characterized by Western analysis and found to express all three PPAR isoforms, suggesting that signaling pathways mediated by these receptors were intact in this tumor type. In vitro experiments with a leiomyoma-derived cell line demonstrated that the pan-PPAR ligand cis-4,7,10,13,16,19-docosahexaenoic acid and PPARgamma-specific ligands 15-deoxy-delta(12,14)-prostaglandin J(2), troglitazone, and ciglitazone inhibited 17beta-estradiol-stimulated cell proliferation. This inhibitory effect was not observed with PPARalpha- or PPARbeta-specific ligands. Although both PPAR and estrogen receptor (ER) signaling pathways were intact in leiomyoma cells, in addition to growth inhibition, stimulation of PPARgamma signaling also inhibited ER-mediated gene expression. Human leiomyomas were also found to express all three PPAR isoforms, and primary cultures of these cells were sensitive to the inhibitory effects of PPARgamma ligands. These results suggest that in uterine leiomyomas PPARgamma activation is growth inhibitory and that this inhibition is mediated at least in part by negative cross-talk between ER and PPAR signaling pathways.

Animals↗

PubMed1990

Functional control of hepatocyte proliferation. Comparison with the temporal control of cardiomyocyte proliferation.

A 4.1-fold difference in liver weight, a 2.5 fold difference in hepatocyte number, and a 1.5-fold difference in mean ploidy were seen in mice on the day of weaning (day 21) reared four (fast-growing group) or sixteen (slow-growing group) to a litter. These differences in proliferation parameters were eliminated in adult mice that had similar liver weights. The kinetics of the changes were not time dependent, i.e. under temporal control, but corresponded to liver-weight kinetics. The definitive number of hepatocytes was established by 3 weeks of age in the fast-growing mice and by 3 months in the slow-growing ones. In contrast to the hepatocytes, multiplication of heart myocytes of the same mice was inhibited by 3-4 days after birth and polyploidization ceased about 3 weeks after birth in mice from both fast- and slow-growing litters, and a stable (approximately 40%) difference in cardiac myocyte number and ploidy persisted throughout the entire period of ontogenesis. It is concluded that hepatocyte proliferation is under functional control whereas cardiac myocyte proliferation is time dependent. Postmitotic hypertrophy of the cell cytoplasm is functionally dependent in both heart and liver. In slow-growing mice, an increase in heart weight occurs only as a result of cytoplasmic hypertrophy, whereas in the liver, cell number and ploidy are both involved.

Age Factors↗

PubMed1972

Cell proliferation in rat kidney induced by lead acetate and effects of uninephrectomy on the proliferation.

Effects of a single dose of lead (0.04 mg lead g body weight) on the proliferation of proximal tubular epithelium in rat kidneys were investigated by autoradiography over a period of 72 hours, using (3)H-thymidine as a label. The results demonstrate that cell proliferation was greatly stimulated within 2 days after lead was injected. The increase in DNA synthesis began about 20 hours after intraperitoneal injection of lead, reached a sharp peak at 30 hours, and declined rapidly thereafter. At the peak, the mean labeling activity was 40 times that observed in control rats. Cumulatively, an average of 14.5% of the proximal tubular epithelial cells were labeled 72 hours after lead was injected. When uninephrectomy was followed immediately by injection of lead, the stimulation of DNA synthesis in the remaining kidney was, on the average, greater than the sum of the separate effects of the two treatments. This indicates that the stimulatory effects of uninephrectomy and injection of lead on renal cell proliferation were additive.

Animals↗

PubMed1981

Lymphoid cell proliferation in non-lymphoid organs during graft-versus-host reactions (GVHR): I. Lack of correlation between mortality and grafted cell proliferation.

The course of development of graft-versus-host reactions (GVHR) following lethal irradiation was compared in two mouse donor-host combinations disparate at non H-2 loci alone or associated to H-2 complex. The pathogenesis of these reactions was very different (mortality rates faster in the second situation for example). The donor cell proliferation kinetics was followed in lymphoid (pooled lymph nodes, spleen, thymus) and in non-lymphoid organs (kidney and liver) from day 0 to day 28 post-transplantation, and showed the same profile in both GVH reactions. Our data emphasize the discordance between the clinical evolution of the GVH disease on one hand, and the stimulation of the grafted cell proliferation on the other hand, induced by a same H-2 disparity. In addition, we have demonstrated the relatively high level of the lymphocyte proliferation in non-lymphoid organs during the course of a GVHR, even in the case of minor histoincompatibility.

Animals↗

PubMed1995

Cell proliferation kinetics in human tumor xenografts measured with iododeoxyuridine labeling and flow cytometry: a study of heterogeneity and a comparison between different methods of calculation and other proliferation measurements.

The influence of overall treatment time in the results of fractionated radiation treatment was initially established in experimental tumors and, subsequently, in the clinic. The availability of techniques (antibodies against halogenated thymidine analogues and flow cytometry) which permit determinations of the duration of the synthesis phase, the labeling index, and the tumor potential doubling time (Tpot) in a short period of time and requiring only a small biopsy of tumor tissue, has expanded interest in the relationship between tumor cell proliferation and response to irradiation. A valuable tool in the study of this relationship are human tumor xenografts. Previous studies have shown a substantial intratumoral heterogeneity in the determinations of Tpot. Different methods of calculation of the kinetic parameters have been published. We have conducted a heterogeneity analysis and an evaluation of the different calculation methods in order to define the validity of Tpot as a proliferation rate measurement in human tumor xenografts. Results show the intertumoral variability in Tpot [between different types of human tumor xenografts systems (coefficient of variation = 88.2%)] to be greater than mean intratumoral variation (coefficient of variation = 30.8%); this suggests that this variation is potentially adequate to serve as a predictor of response. The diverse calculation methods provided significantly different absolute values but not different tumor ranking, probably because the time interval between labeling and sampling was maintained, for all the samples, between 6 and 8 h. Our study has found significant differences between the labeling index and the S-phase fraction determined with the DNA profile in 9 out of 10 tumor types. No correlation was found between the DNA index of the tumors in this series and their proliferation rate.

Animals↗