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M Dardenne

Publications and source records attributed to M Dardenne.

At least 37 records · Page 2Linked to original sources
PubMed1998

Growth hormone receptors and immunocompetent cells.

Growth hormone plays a significant role in regulation of the humoral and cellular immune responses in physiological as well as pathological situations. This role is exerted via the existence of specific receptors on cells of the immune system. Using flow cytofluorometry and biotinylated bovine GH, we have recently analyzed the expression of GH receptors (GHRs) in murine lymphoid organs. GHRs are widely expressed in all murine hematopoietic tissues and in fetuses, newborns, and 3- and 7-week-old animals. In the bone marrow, all hematopoietic lineages express variables levels of GH receptors, whereas in the thymus, this expression is mainly seen in CD4-, CD8-, CD4+CD8+, and CD8+ subpopulations. At the periphery, 50% of splenocytes and peripheral blood lymphocytes and 20% of lymph node cells are GHR positive, with a wider receptor expression on B cells and macrophages (approximately 50%) than on T cells (approximately 20%), where the labeling is seen on both CD4+ and CD8+ cell subsets. Interestingly, the proportion of GHRs bearing CD4+ and CD8+ splenocytes is increased after T-cell activation with Con A or anti-CD3. Finally, all peripheral T cells expressing GHRs also express prolactin receptors. These data provide a molecular basis to study the factors controlling GHR expression and regulation of immune function.

Animals↗
PubMed1998

The influence of HLA-matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA. European Organization for Research and Treatment of Cancer. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto.

To determine whether patients with a HLA-identical sibling donor have a better outcome than patients without a donor, an analysis on the basis of intention-to-treat principles was performed within the framework of the EORTC-GIMEMA randomized phase III AML 8A trial. Patients in complete remission (CR) received one intensive consolidation course. Patients with a histocompatible sibling donor were then allocated allogeneic bone marrow transplantation (alloBMT), the patients without a donor were randomized between autologous BMT (ABMT) and a second intensive consolidation (IC2). 831 patients <46 years old and alive >8 weeks from diagnosis were included. HLA typing was performed in 672 patients. AlloBMT was performed during CR1 in 180 (61%) out of 295 patients with a donor. Another 38 patients were allografted: five in resistant disease, 14 during relapse and 19 in CR2. ABMT was performed in 130 (34%) out of 377 patients without a donor in CR1, in six (2%) patients during relapse and in 38 (10%) patients during CR2. The disease-free survival (DFS) from CR for patients with a donor was significantly longer than for patients without a donor (46% v 33% at 6 years; P=0.01, RR 0.78, 95% confidence interval 0.63-0.96). The overall survival from diagnosis for patients with a donor was longer, but not statistically significant, than for patients without a donor (48% v 40% at 6 years; logrank P=0.24). When patients were stratified according to prognostic risk groups, the same trend in favour of patients with a donor was seen for survival duration and the DFS remained significantly longer for this group of patients.

Adolescent↗
PubMed1998

Role of prolactin and growth hormone on thymus physiology.

Intrathymic T-cell differentiation is under the control of the thymic microenvironment, which acts on maturing thymocytes via membrane as well as soluble products. Increasing data show that this process can be modulated by classical hormones, as exemplified herein by prolactin (PRL) and growth hormone (GH), largely secreted by the pituitary gland. Both PRL and GH stimulate the secretion of thymulin, a thymic hormone produced by thymic epithelial cells. Conversely, low levels of circulating thymulin parallel hypopituitary states. Interestingly, the enhancing effects of GH on thymulin seem to be mediated by insulinlike growth factor 1 (IGF-1) since they can be abrogated with anti-IGF-1 or anti-IGF-1-receptor antibodies. The influence of PRL and GH on the thymic epithelium is pleiotropic: PRL enhances in vivo the expression of high-molecular-weight cytokeratins and stimulates in vitro TEC proliferation, an effect that is shared by GH and IGF-1. Differentiating T cells are also targets for the intrathymic action of PRL and GH. In vivo inoculation of a rat pituitary cell line into old rats results in restoration of the thymus, including differentiation of CD4- CD8- thymocytes into CD4+ CD8+ cells. Furthermore, PRL may regulate the maintenance of thymocyte viability during the double-positive stage of thymocyte differentiation. Injections of GH into aging mice increase total thymocyte numbers and the percentage of CD3-bearing cells, as well as the Concanavalin-A mitogenic response and IL-6 production by thymocytes. Interestingly, similar findings are observed in animals treated with IGF-1. Lastly, the thymic hypoplasia observed in dwarf mice can be reversed with GH treatment. In keeping with the data summarized earlier is the detection of receptors for PRL and GH on both thymocytes and thymic epithelial cells. Importantly, recent studies indicate that both cell types can produce PRL and GH intrathymically. Similarly, production of IGF-1 and expression of a corresponding receptor has also been demonstrated. In conclusion, these data strongly indicate that the thymus is physiologically under control of pituitary hormones PRL and GH. In addition to the classical endocrine pathway, paracrine and autocrine circuits are probably implicated in such control.

Animals↗
PubMed1998

Glucose homeostasis in the nonobese diabetic mouse at the prediabetic stage.

Because few data were available on glucose homeostasis at the early prediabetic stage in the nonobese diabetic (NOD) mouse, we investigated glycemia, insulinemia, and pancreatic insulin content under basal conditions in both sexes of 4-, 6-, and 8-week-old fed NOD mice, compared with sex- and age-matched fed C57BL/6 mice. We also investigated glucose tolerance in both sexes of fasting 8-week-old NOD and C57BL/6 mice. The main results obtained under basal fed conditions, when comparing both strains, were lower glycemia and higher insulinemia in NOD females at all ages investigated and in NOD males (particularly at 6 weeks of age). Glucose tolerance tests showed that: 1) the blood glucose response to 1 g/kg i.p. glucose was less sustained in both sexes of 8-week-old NOD mice than in their control counterparts; 2) the blood insulin response to glucose (1 g/kg i.p.) appeared earlier in both sexes of NOD mice than in sex-matched C57BL/6 mice; 3) an unusual sexual dimorphism existed in NOD mice, compared with controls, with females secreting, in response to glucose, twice as much insulin as males; 4) dose-response studies (1-6 g/kg glucose) confirmed the lower increase in blood glucose levels in both sexes of NOD mice and their unusual sexual dimorphism in insulin secretion; and 5) glucose tolerance tests in 4- to 8-week-old NOD mice showed that although the sexual dimorphism in insulin secretion was not observed in 4-week-old mice, it was particularly striking at 6 weeks of age. Taken together, these results suggest that beta-cell hyperactivity exists in the NOD mouse at the early prediabetic stage, especially in NOD females.

Age Factors↗
PubMed1998

Pancreatic hormone expression in the murine thymus: localization in dendritic cells and macrophages.

The expression of preproinsulin (ppIns), proglucagon, prosomatostatin, and propancreatic polypeptide was investigated in thymic extracts, thymic cells, and thymic cell lines from C57BL/6 mice by RT-PCR. The expression of pancreatic hormones was similar in thymic extracts taken from neonatal and 2-, 4-, and 8-week-old animals, but was decreased in 20-week-old animals. Pancreatic hormone expression was not observed in mouse liver, salivary gland, or spleen. Analysis of thymic cell populations revealed a 10- to 20-fold enrichment in expression of all hormones in low buoyant density cells. No expression was detected in high buoyant density cells (predominantly thymocytes) or in thymic epithelial cell lines, primary cultures of epithelial cells, or peripheral macrophages. In addition, immunoreactive insulin, measured by specific RIA, was detectable in the low buoyant density population, but not in high buoyant density cells. The enriched cell population was depleted of contaminating lymphocytes and sorted based on reactivity to the cell surface markers F4/80 (macrophage) or N418 (dendritic cells). Cells gated for N418 demonstrated expression for ppIns, but not the other pancreatic hormones. Conversely, expression for proglucagon, prosomatostatin, and propancreatic polypeptide, but not ppIns, was detected in F4/80-gated cells. Our data indicate that pancreatic endocrine hormones are differentially expressed by dendritic cells and macrophages in a normal mice.

Animals↗
PubMed1998

Growth hormone and its receptor are expressed in human thymic cells.

GH has been shown to modulate various functions of the thymus. We now demonstrate the production of human GH (hGH) by human thymic cells, and the expression of GH receptors in thymic epithelial cells (TEC) and in thymocytes at different stages of differentiation. The presence of hGH messenger RNA was shown by RT-PCR in both human thymocytes and in primary cultures of TEC. Moreover, immunoreactive hGH material was detected in culture media of thymocytes and TEC with the use of a sensitive immunoradiometric assay. GH receptor gene expression was shown in TEC in primary cultures and in fetal and postnatal TEC lines as well as in thymocytes. By immunocytochemistry, the presence of GH receptors in the various TEC preparations was confirmed. In cytofluorometric studies with the use of a biotinylated anti-GH receptor monoclonal antibody, we could show that GH receptors are predominantly expressed by immature thymocytes: over 90% of CD3- CD4- CD8- CD19- CD34+ CD2- cells (a phenotype characterizing the most immature T cell progenitors in the thymus) were GH receptor positive. Our results provide a molecular basis for an autocrine/paracrine mode of action of GH in the human thymus.

Cells, Cultured↗
PubMed1998

Basal concentrations of various steroids in the nonobese diabetic (NOD) mouse and effect of immobilization stress.

The progression of type I diabetes in the NOD mouse is modulated by, among other things, stressful events and steroids. We measured in 2-month-old prediabetic NOD mice various circulating steroids (progesterone, corticosterone, dehydroepiandrosterone, delta4-androstenedione, testosterone, estrone and estradiol) under basal and stressful conditions (1.5h immobilization). Basal progesterone concentrations were low but measurable in randomized cycling NOD females and under the detection limit in NOD males. Immobilization increased progesterone concentrations in both sexes. Serum corticosterone concentrations also increased after immobilization but with the sexual dimorphism normally observed in rodents. Dehydroepiandrosterone concentrations were similar in both sexes and remained unaffected by stress. Testosterone and delta4-androstenedione were drastically reduced after immobilization in NOD males. Serum estrone and estradiol were not found to be statistically different in NOD females and males, but slightly higher to that described in the literature, and immobilization increased estrone concentrations in NOD males. In conclusion, while nonspecific to the NOD mouse, the modulation of circulating corticosteroids, estrogens and androgens induced by environmental factors may be part of the mechanism(s) by which these factors modulate the progression of type I diabetes. The hormonal changes may act in a complex manner at different levels: the immune system, the islet of Langerhans and the other structures involved in glucose homeostasis.

Adrenalectomy↗
PubMed1997

Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group.

We conducted a prospective randomized multicenter clinical trial comparing the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to intensive chemotherapy in patients of 61 years and older with untreated newly diagnosed acute myeloid leukemia (AML). Patients were randomized to either receive daunomycin-cytosine arabinoside with GM-CSF or daunomycin-cytosine arabinoside (control arm). Based on the rationale that GM-CSF might sensitize the leukemic cells to the cytotoxicity of chemotherapy as well as enhance white blood cell regeneration, GM-CSF was given during chemotherapy as well as after chemotherapy. Patients were treated with one, and in case of a partial response, with two remission induction cycles. When a complete remission was attained they received one additional cycle of consolidation therapy. Of 318 evaluable patients with a median age of 68 years, 157 were randomized to receive GM-CSF and 161 were assigned to control therapy. The effect of GM-CSF on treatment was evaluated according to intention-to-treat. Complete remission was achieved in 56% of the patients in the GM-CSF group and 55% of the control patients (P = .98). Recovery of neutrophils was significantly faster in GM-CSF-treated patients. The median time of recovery of neutrophils towards 0.5 x 10(9)/L was 23 days in the GM-CSF group versus 25 days in the control group (P = .0002) with the percentages of patients who recovered being 81% and 71%, respectively. With a median follow-up of 36 months, the probabilities of survival at 2 years after randomization were estimated at 22% for individuals assigned to the GM-CSF treatment as well as for control patients (P = .55). Disease-free survival at 2 years compared 15% and 19% for the two treatment groups (P = .69). The number of nights spent in the hospital, number of transfusions, and frequencies and types of hemorrhages and infections did not differ either. The cytogenetic results at diagnosis of this study in elderly AML shows that there is a relatively high numerical representation of patients with abnormal cytogenetics (55% of documented cases), who showed significantly inferior response rates and survival duration. We conclude that, except for a faster neutrophil recovery, GM-CSF during and after induction chemotherapy does not improve the clinical outcome of elderly patients with AML.

Acute Disease↗
PubMed1997

Involvement of laminin and its receptor in abrogation of heart graft rejection by autoreactive T cells from Trypanosoma cruzi-infected mice.

Extracellular matrix ligands and receptors have been identified as determining in vivo lymphocyte positioning and activation, including effector functions in alloreactive responses. Herein we evaluated the involvement of laminin and its receptor, the very late antigen 6 (VLA-6) integrin, in CD4+ T cell-dependent autoreactivity, using a transplantation model for the autoimmune myocarditis occurring in mice chronically infected with Trypanosoma cruzi. Previous work showed that syngeneic mouse hearts grafted in the ears of chronic chagasic recipients were rejected through a CD4+ T cell-dependent mechanism. Rejection also occurred when cells from chagasic animals were transferred adjacent to hearts transplanted into naive recipients. Here, we observed the formation of a thick laminin network during rejection, with donor-derived CD4+ T cells concentrated in the laminin-rich areas. Most importantly, anti-laminin as well as anti-laminin receptor Ab inhibited the rejection of syngeneic hearts by T cells from chagasic animals. Our results suggest that interaction of the VLA-6 molecule with laminin is involved in triggering the antimyocardial autoreactive process by driving the influx of CD4+ T cells to the heart. They also support the concept that an Ag-specific T cell response, even an autoreactive one, can be modulated by in vivo interactions involving extracellular matrix ligands and receptors. In this regard, our study represents, to our knowledge, the first in vivo evidence for laminin-mediated T cell echotaxis, with simultaneous experimental demonstration of ligand and receptor involvement. Lastly, our findings indicate that treatment with anti-VLA-6 Abs can be effective in suppressing autoimmune disease activity.

Animals↗
PubMed1997

Ontogeny of glutamic acid decarboxylase gene expression in the mouse pancreas.

Using two RT-PCR quantitative assays, we measured the pancreatic expression of the two isoforms of glutamic acid decarboxylase in the foetus, newborn and 14-, 21- and 35-day-old male and female NOD and C57BL/6 mice. In the C57BL/6 mouse, GAD 67 pancreatic expression is stable; in NOD mice, GAD 67 expression is similar to that found in control mice, except at 5 weeks of age, when pancreatic GAD 67 expression is about 2.5 times higher than in C57BL/6 mice. The pancreatic expression of GAD 65 is under the detection limit of the assay until 5 weeks of age. The overexpression of GAD 67 characterized in pancreas from 5-week-old NOD mice could be the result of beta cell hyperactivity, previously reported in this mouse strain.

Animals↗
PubMed1997

Pituitary hormones modulate cell-cell interactions between thymocytes and thymic epithelial cells.

The thymic microenvironment plays a key role in the intrathymic T-cell differentiation. It is composed of a tridimensional network of epithelial cells whose physiology is controlled by extrinsic circuits such as neuroendocrine axes. Herein we show that the expression of extracellular matrix ligands and receptor by cultured thymic epithelial cells is upregulated by prolactin (PRL) and growth hormone (GH), the latter apparently occurring via insulin-like growth factor I (IGF-I). Thymocyte release from the lymphoepithelial complexes, thymic nurse cells, as well as the reconstitution of these complexes are enhanced by PRL, GH or IGF-I. Treatment of a mouse thymic epithelial cell line with these hormones induced an increase in thymocyte adhesion, an effect significantly prevented in the presence of antibodies to fibronectin, laminin or respective receptors VLA-5 and VLA-6. Our data suggest that the in vitro changes in thymocyte/thymic epithelial cell interactions induced by pituitary hormones are partially mediated by the enhancement of extracellular matrix ligands and receptors.

Animals↗
PubMed1997

Quality of life in patients with acute myelogenous leukemia in prolonged first complete remission after bone marrow transplantation (allogeneic or autologous) or chemotherapy: a cross-sectional study of the EORTC-GIMEMA AML 8A trial.

A cross-sectional study of quality of life (QOL) was performed in 98 patients in continued first complete remission (CR) for 1-7.4 years, after inclusion in the AML 8A trial which prospectively compared allogeneic bone marrow transplantation (AlloBMT), autologous BMT (ABMT) and intensive consolidation chemotherapy. Several significant differences between the three treatment groups were observed, on the basis of patient self-reports, with regard to somatic symptoms (mouth sores, cough, hair loss, headache), repeated acute medical problems, physical functioning, role functioning, leisure activities and, above all, sexual functioning. There were also significant differences for overall physical condition, and overall quality of life. For all these parameters, the ranking was uniformly AlloBMT lower than ABMT lower than chemotherapy. These differences remain significant after adjustment for time interval between CR and QOL evaluation, sex or age. These results, confirming a higher risk of permanent impairment of QOL after BMT, may have an impact on medical decisions and warrant further studies.

Adult↗
PubMed1997

Growth hormone stimulates the proliferation of activated mouse T lymphocytes.

A modulatory role for GH on immune function has been suggested, but hormonal effects have been difficult to demonstrate with isolated cells. We have recently shown that GH receptors are present in murine hematopoietic tissues, with a lower receptor number in T lymphocytes than in B cells or macrophages. The binding of bovine GH (bGH) to murine splenocytes is increased after T cell activation with either concanavalin A or anti-CD3 antibody. In the present study, we show that bGH is able to stimulate the proliferation of activated murine T cells. Splenocytes were stimulated with either Con A or anti-CD3 antibody; addition of the mitogen resulted in increased [3H]thymidine uptake. When added together with the mitogen to the culture medium, bGH was able to further stimulate thymidine uptake. A bell-shaped dose-response curve was observed. bGH was able to increase cell proliferation by 2.5-fold over the effect of anti-CD3 alone. The amplitude of the bGH response was greater in unfractionated splenocytes than in purified T lymphocytes or thymocytes. Splenocytes were also stimulated by lipopolysaccharide, a B cell-specific mitogen; no change in the level of bGH binding was observed during activation of B cells, and no effect of bGH on the proliferative response of splenocytes to lipopolysaccharide was detected. The GH proliferative effect on T lymphocytes is probably direct and not through locally produced insulin-like growth factor I, because insulin-like growth factor I did not affect the cell proliferation when added at concentrations ranging from 10(-9)-10(-7) M. Ovine PRL was also able to stimulate [3H]thymidine uptake in splenocytes and thymocytes, and a synergistic effect was observed when bGH and ovine PRL were added together at 10(-8) M. Our findings support the biological significance of the GH receptors identified in murine T lymphocytes and confirm the role of GH in the regulation of immune functions.

Animals↗
PubMed1997

A randomized phase II study on the effects of 5-Aza-2'-deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group phase II study (06893).

5-Aza-2'-deoxycytidine combined with either amsacrine or idarubicin has been applied in a treatment protocol for patients with a relapse of acute myeloid or lymphocytic leukemia. Sixty-three patients received 5-Aza-2'-deoxycytidine 125 mg/m2 as a 6 h infusion every 12 h for 6 days in combination with either amsacrine 120 mg/m2 as a 1 h infusion on days 6 and 7 (n=30) or idarubicin 12 mg/m2 as a 15 min infusion on days 5, 6 and 7 (n = 33). Twenty-three patients (36.5%) obtained a complete remission (CR); eight of 30 patients treated with amsacrine and 15 of 33 treated with idarubicin. Patients with an interval of more than 1 year between initial diagnosis and start of the protocol achieved CR in 51.4%, compared to 15.4% for patients with an interval of less than 1 year. Patients with normal cytogenetics had a higher CR rate (61%) than those with abnormal cytogenetic findings (15.8%). Digestive tract and hematologic toxicity was prolonged, compared to standard induction schedules. Median disease-free survival was approximately 8 months, with only 20% of patients staying in remission for more than 1 year. 5-Aza-2'-deoxycytidine is a good antileukemic agent with considerable toxicity. Current results merit further investigations in previously untreated leukemia.

Adolescent↗
PubMed1996

Glutamic acid decarboxylase (GAD 67) gene expression in the pancreas and brain of the nonobese diabetic mouse.

A quantitative PCR was developed to measure GAD 67 mRNA levels in pancreas from NOD mice. Two nonautoimmune mouse strains were used as controls. An internal standard, rat GAD 67 mRNA, was prepared to quantify the reaction. In NOD mice GAD 67 expression in the pancreas was in the order of 2 x 10(6) molecules/microgram of total RNA; this expression was five times less in the two control mouse strains, whatever the age. The overexpression of GAD 67 characterized in the NOD mouse could be restricted to the pancreas since similar analysis performed in mouse brain did not reveal a large difference between the three mouse strains studied.

Aging↗
PubMed1996

Gene expression of pancreatic glutamic acid decarboxylase in the nonobese diabetic mouse.

The 65 kDa isoform of glutamic acid decarboxylase (GAD 65) is an autoantigen implicated in type I diabetes. We have developed a quantitative PCR method to measure GAD 65 mRNA in the pancreas of nonobese diabetic (NOD) mice. Two other nonautoimmune mouse strains were used as controls. In all mice, pancreatic GAD 65 expression declined with age. In 5-week-old NOD mice, a clear difference was detected between males and females. This sexual dimorphism may explain the absence of tolerance to GAD 65 in the NOD female which could contribute to autoimmune destruction of beta cells in the pancreas and subsequent development of diabetes.

Animals↗
PubMed1996

Effect of prophylactic insulin treatment on the number of ER-MP23+ macrophages in the pancreas of NOD mice. Is the prevention of diabetes based on beta-cell rest?

Prophylactic insulin treatment has been shown to have beneficial effects in type 1 diabetes, both in humans and in various animal models of the disease. In experimental models, the protective effect of prophylactic insulin treatment was observed in two parameters: (1) progression of insulitis and (2) diabetes incidence. The mechanism of protection still remains to be investigated. We therefore analysed by immunohistochemistry the effect of prophylactic insulin treatment vs placebo treatment (from 4 to 13 weeks of age) on ER-MP23+ macrophage infiltration in and around pancreatic islets in the non-obese diabetic (NOD) mouse, a spontaneous model for type 1 diabetes. BALB/c mice were used as diabetes-free controls. Using conventional haematoxylin-eosin staining, we detected a protective effect of prophylactic insulin treatment in NOD females on the lymphocytic insulitis, significant at 13 weeks, but not at 9 weeks of age. However, when assessed by immunostaining for early infiltration of ER-MP23+ macrophages around islets, the reduction in severity of insulitis could already be detected as early as 9 weeks of age. With regard to the early accumulation of ER-MP23+ cells, we observed that their numbers per mm2 surface area of the exocrine pancreas and per micron at the circumference of the islet were higher in placebo-treated NODs (197 +/- 13.8 and 14 +/- 0.9, respectively) as compared to age-matched BALB/c mice (123.1 +/- 7.1 and 3.5 +/- 0.9, respectively). Prophylactic insulin treatment of NODs lowered the attraction of ER-MP23+ macrophages to the exocrine pancreas and to the circumference of the islets (156.3 +/- 8.5 and 7.9 +/- 1, respectively). Interestingly also, the islet size was found to be larger in placebo-treated NODs (51% was larger than 10 microns2) than in age-matched BALB/c mice (9% larger than 10 microns2). Prophylactic insulin treatment of NODs reduced their islet size to sizes found in the control BALB/c strain. In conclusion, the decrease in islet size by early insulin administration, and the lower attraction of ER-MP23+ macrophages to the islets are morphological indications that prevention of diabetes development by prophylactic insulin treatment results from a down-regulation of islet metabolism and growth, with a concomitant decline in the release of islet factors attracting macrophages.

Animals↗