Search PubMed⌕ Search

Biomedical subjects

M Dardenne

Publications and source records attributed to M Dardenne.

At least 91 records · Page 5Linked to original sources
PubMed1994

Immunohistochemical characterization of monocytes-macrophages and dendritic cells involved in the initiation of the insulitis and beta-cell destruction in NOD mice.

This immunohistochemical study describes the infiltration pattern of monocytes-macrophages and dendritic cells during the development of insulitis and diabetes in the NOD mouse. A panel of monoclonal antibodies (MoAbs) was used to analyze pancreases of nondiabetic (glucosuria negative) male and female NOD mice at 3, 7, 10, and 17 weeks of age. BALB/c female mice 17-weeks-old, diabetic NOD female mice 20- to 30-weeks-old, and nondiabetic NOD male mice 22-weeks-old were used as controls. Three MoAbs (viz., ER-MP23, MOMA1, and BM8) were special and appeared to identify macrophage/dendritic cell subsets that either had a characteristic infiltration pattern in the initial phases of the autoimmune reaction before T-cell infiltration or were typical for the later beta-cell destructive insulitis process. 1) Raised numbers of ER-MP23+ and MOMA-1+ dendritic cells/macrophages were characteristic for the initial phases of the NOD insulitis in 3-week-old mice. The cells were found in and near swollen para-insular vessels. In 7-week-old mice, these ER-MP23+ and MOMA-1+ cells had accumulated around the islets and were the first hematopoietic cells detectable at these spots. 2) From 7 weeks of age onward, BM8+ macrophages could be found in the para- and peri-insulitis processes. However, only in females were these BM8+ macrophages found to infiltrate into the islets. In lymphoid tissues, ER-MP23 predominantly reacts with macrophages/dendritic cells present in the subcapsular and interfollicular sinuses of lymph nodes and the T-cell zones of these lymph nodes. ER-MP23 also reacts with tissue macrophages/dendritic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Treatment of patients with acute promyelocytic leukemia. The EORTC-LCG experience. EORTC Leukemia Cooperative Group.

Acute promyelocytic leukemia (M3) is, as one of the FAB subtypes of AML, included in the EORTC/GIMEMA AML-8A and 8B randomized trials. In these trials 1519 patients were included, 477 of them in non-Italian EORTC-LCG centers and 1042 in GIMEMA centers. A total of 80 patients were classified as M3 including 18 patients with M3-variant. Thirty-nine were male and 41 female. Ages ranged from 15 to 59 years; 25 (31.3%) of them were younger than 30, 34 (42.5%) between 30 and 45, and 21 (26.3%) older than 45 years of age. 56.3% of the patients had leukocytes less than 5 x 10(9)/l at the time of diagnosis vs. 24.9% of the patients belonging to the other FAB subtypes. Remission induction consisted of a standard protocol with 3 days daunorubicin and 7 days of cytosine arabinoside. Forty-three patients (53.8%) achieved a complete remission compared to 64.6% of the remaining AML patients. After salvage treatment this percentage increased to 70%, which is the same as for the other AML subtypes. Thirteen (16.3%) patients died during remission induction, mainly due to hemorrhagic complications. This percentage is significantly higher than the death rate (9.1%) in the other FAB subtypes of AML. All patients received one course of consolidation treatment. Post consolidation treatment could be either standard maintenance, intensive consolidation courses, autologous or allogeneic transplantation, according to the guidelines of the treatment protocols. At present, relapses almost all in the bone marrow, are seen in only 34.9% of the M3 patients, compared to 48.4% in the remaining AML patients. Disease-free survival for patients less than 45 years of age with the M2 and M3 subtypes was approximately 50% at 3 years compared to 30-40% for the other FAB subtypes. Despite the higher death rate during induction, the long-term survival results were better for M3 patients in comparison with the remaining AML patients. The projected survival at 3 years was 50% for M3 patients vs. 38% for remaining patients.

Adolescent↗
PubMed1994

A randomized phase II study of low-dose cytosine arabinoside (LD-AraC) plus granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in myelodysplastic syndromes (MDS) with a high risk of developing leukemia. EORTC Leukemia Cooperative Group.

In a randomized phase II study, patients with myelodysplastic syndromes (MDS) with 10-30% blasts in the bone marrow and hematopoietic failure were treated with low-dose Ara C (2 x 10 mg/m2 subcutaneously (s.c.) days 1-14) and rhGM-CSF (fully glycosylated, Sandoz/Schering-Plough, 2 x 150 micrograms protein/day s.c.) given either following Ara C (days 15-21) or simultaneously (days 8-14) for 1-5 cycles. 108 patients with a median age of 65 years, range 17-80 years and refractory anemia with an excess of blasts (RAEB, n = 54), RAEB with transformation (RAEBt, n = 50) or with chronic myelomonocytic leukemia (CMML, n = 4) were evaluable. Complete remission was achieved in 15 cases (14%), 11 had a partial response (10%), and 16 a minor response (15%). Stable disease was reached in 35 cases (32%). There were 16 cases of toxic death (15%), progression occurred in 15 patients (14%). No differences existed between the two treatment arms with respect to response and duration of response. Prognostic factors for poor response included the presence of cytogenetic abnormalities and a history of previous blood transfusions. Major adverse events during treatment were hemorrhage (55%), infections (54%), and fever associated with GM-CSF administration (40%). The overall response rate ws 39%, median duration was 12.5 months from start of treatment which allowed responding patients to lead good quality life without further therapy. The question whether the combination is indeed superior to LD-Ara C alone is not settled but will be evaluated in an ongoing clinical trial.

Acute Disease↗
PubMed1993

Expression of prolactin receptors in murine lymphoid cells in normal and autoimmune situations.

We have analyzed the expression of prolactin receptors (PRL-R) on murine lymphoid cells by using flow cytofluorometry analysis with biotinylated anti-PRL-R mAb raised against several epitopes of the extracellular domain of the PRL-R and by using polymerase chain reaction amplification. We demonstrated that PRL-R were universally expressed in normal rat and mouse hematopoietic tissues. In both primary lymphoid organs, namely, thymus and bone marrow, > 90% of cells were labeled by the anti-PRL-R mAb, but the density of PRL-R (assessed by fluorescence intensity) was lower on thymocytes than on bone marrow cells. In peripheral lymphoid organs there were smaller proportions of cells bearing PRL-R and we could clearly distinguish cell subsets of various fluorescence intensities. By using classical markers for lymphoid cell populations, we noted that all B cells and macrophages from spleen, lymph nodes, and blood strongly expressed the PRL-R. Regarding T cell populations, large proportions (> 85%) of PRL-R+ cells were detected in the four thymocyte subsets, thus contrasting with the smaller proportions (50 to 65%) of T cells labeled in the periphery. Similar percentages of PRL-R+ cells were observed in CD4+ and CD8+ peripheral lymphocyte subsets. Importantly, the stimulation of thymocytes and spleen cells with the T cell mitogen Con A promoted an enhancement of the density of PRL-R molecules on the cell membranes. Because hyperprolactinemia is associated with some autoimmune diseases, we also investigated PRL-R expression in the NZB autoimmune mouse. In contrast to the pattern observed in normal animals, the frequencies of PRL-R-bearing T cells as well as the density of PRL-R per cell increased with age in NZB mice, suggesting that some imbalances of PRL/PRL-R interaction might occur in autoimmune situations. In conclusion, our data provide a molecular basis for a better understanding on the mode of action of PRL within the immune system in physiologic and pathologic situations.

Animals↗
PubMed1993

Restoration of the thymus in aging mice by in vivo zinc supplementation.

A multiparametric study of the thymus was performed in normal aging mice (12-15 months old) submitted to a mild oral zinc supplementation during 3-6 months as compared to age-matched control mice. First, this study demonstrated that in rodents, zinc levels are significantly reduced with aging and can be restored to values close to those observed in young animals after 6 months of zinc supplementation. Second, our data showed that oral zinc administration stimulates thymus growth and partially restores the microenvironmental as well as lymphoid compartments of the organ. Regarding thymic endocrine function, a significant increase in thymulin levels and a concomitant decrease in plasma thymulin inhibitors were observed, suggesting that the age-related decline of thymic function might at least partially be due to extrinsic factors, such as zinc deficiency. The total number of thymic lymphocytes was consistently increased, without significant changes in CD4/CD8 defined thymocyte subsets. Finally, structural changes of the thymus epithelium were also detected, including the disappearance of epithelial cysts frequently observed in old animals, reappearance of a normal pattern of the thymic epithelial cell network, and a decrease in the extracellular matrix network. Taken together, these data suggest that aging-related physiological zinc deficiency induces some relevant changes in thymus structure and function which can be partially corrected by a mild oral zinc supplementation.

Administration, Oral↗
PubMed1993

Effects of various environmental stress paradigms and adrenalectomy on the expression of autoimmune type 1 diabetes in the non-obese diabetic (NOD) mouse.

The effects of long-term chronic stress (induced by repeated restraint, overcrowding or both), short-term chronic stress (induced by a triad of stressors over a short period of time early in life) and adrenalectomy were investigated on the prevalence, on the degree of insulitis and various physiological and immunological parameters in the NOD mouse, a spontaneous model of type I-insulin-dependent diabetes mellitus (IDDM). Long-term chronic stress, obtained by restraint once a week or overcrowding, significantly protected NOD females, while both applied concomitantly had only a tendency to protect against diabetes. In contrast, short-term chronic stress had no significant effect on diabetes expression, whereas adrenalectomy resulted in a trend toward accelerated diabetes onset. The various long-term chronic stress paradigms exerted different effects on the progression of insulitis: repeated restraint tended to protect against insulitis, overcrowding had no effect but, when associated with restraint, significantly counteracted the beneficial effect of restraint alone. Adrenalectomy and short-term chronic stress had no significant effect on the development of insulitis. Various parameters, such as body, thymus and spleen weights, thymus and spleen cellularities, mitogen-induced spleen cell proliferation and serum corticosterone levels were also studied under the various experimental conditions. Taken together, the observations suggest that stressors modulate the expression of spontaneous autoimmune diabetes by exerting pleiotropic effects on immune and/or inflammatory components at the pancreas level and on peripheral glucose metabolism.

Adrenal Glands↗
PubMed1993

The neuroendocrine-immune axis.

The three different systems that contribute to development and maintenance of homeostasis, the nervous, endocrine and immune systems are closely interrelated. First, it was established that the neuroendocrine system was able to modulate the immune response. More recently, it has been shown that the immune system is able to function as a neuroendocrine organ, since it can synthesize not only hormones and neuropeptides, but also cytokines that have an impact on the neuroendocrine system. This has led to the demonstration of the existence of cytokine receptors within the nervous system. At the same time, various cytokine effects on the nervous system have been described including growth-promoting activity, neuromodulatory action, fever induction, sleep and decreased food intake. The latest element in this network of intricate interrelationships has been the demonstration of cytokine production by cells of the nervous system. Moreover, it appears that the brain is no longer the immunologically deprived site it was once thought to be, and that all phases of an immune response can potentially occur within the confines of the BBB.

Animals↗
PubMed1993

A trial of zinc supplementation in young rural Gambian children.

The present study tested the hypothesis that inadequate Zn intake might be responsible for failure to thrive and impaired catch-up growth in young rural Gambian children, and that Zn supplements might be beneficial. Gambian children might be deprived of Zn because of its poor availability from their predominantly plant-based diet. Rural Gambian children (110; fifty boys, sixty girls) aged between 0.57 and 2.30 years were divided into two matched groups, one to receive 70 mg Zn twice weekly for 1.25 years, and the other a placebo. Growth and mid-upper-arm circumference were measured at weekly intervals throughout the study and illnesses were monitored. Capillary blood and urine samples were collected at 0, 2 and 8 weeks. Body weights and arm circumferences showed a linear increase, plus a seasonal effect (rainy season faltering). For body weight there was no significant overall effect of the supplement. For arm circumference, a very small (2%) but significant (P < 0.01) difference favoured the supplemented group. Plasma thymulin was much lower at the first clinic than at the second and third clinics, and in vitro Zn stimulation was greater at the first clinic. There was, however, no effect of Zn in vivo. Likewise, Zn did not significantly benefit T-cell numbers or ratios, secretory IgA in urine, circulating hormone levels or biochemical indices of Zn status. One index of intestinal permeability, i.e. lactulose: creatinine, was improved (P < 0.02) by the supplement, but the lactulose: mannitol value was not; this requires further investigation. Dietary Zn deficiency is, thus, unlikely to be of major overall importance for rural Gambian children's ability to thrive, and blanket Zn supplementation is not justified. There may, however, be vulnerable sub-groups who would benefit from Zn supplements.

Anthropometry↗
PubMed1993

A physiological amount of zinc supplementation: effects on nutritional, lipid, and thymic status in an elderly population.

Forty-four institutionalized elderly subjects with body mass indexes (BMI) of either > or = 24 or < or = 21 participated in a 16-wk crossover study designed to determine the effects of low-dose zinc supplementation [306 mumol (20 mg)/d] on food intake, anthropometry, and biochemical and immunological indexes. Initial serum zinc concentrations were low in both groups and increased by approximately 20% after zinc supplementation. Zinc supplementation allowed a partial but significant restoration of serum thymulin activity and improved nutritional status (food intake and serum albumin and transthyretin concentrations) but had no effect on anthropometric indexes or serum apolipoproteins, except apolipoprotein CII and apolipoprotein CIII. After zinc supplementation, serum copper concentration decreased but there was no change in the ratio of low-density-lipoprotein cholesterol to high-density-lipoprotein cholesterol. Low-dose zinc supplementation allows restoration, at least partially, of nutritional and thymic status without the known disadvantages of high doses of zinc.

Aged↗
PubMed1993

Effects of growth hormone and thyroxine on thymulin secretion in aging rats.

It is well-established that the activity of the endocrine thymus is under neuroendocrine control. In particular, growth hormone (GH) and thyroxine (T4) have been shown to be capable of reconstituting thymus function in hormone-deficient animals. It was therefore of interest to assess the effect of combined administration of ovine GH (0.1 mg/100 g BW/day) and T4 (10 micrograms/100 g BW/day) on serum thymulin levels in young (5 months), old (21 months) and senescent (29-30 months) male Sprague-Dawley rats. Age-matched controls received 0.1 mg bovine serum albumin/100 g BW daily during the same period (14 days). Prolactin (Prl), GH, T4 and triiodothyronine (T3) were measured in serum by radioimmunoassay, whereas serum thymulin was determined by rosette bioassay. As expected, GH and T4 were lower in the old and senescent controls whereas serum Prl displayed a slight age-related increase. No age changes were detected in serum T3. Hormone-treated animals showed supraphysiologic levels of both T4 and T3, but serum levels were comparable among the three treated age groups for each thyroid hormone. Endogenous GH levels were moderately elevated in the treated rats. In the control rats serum thymulin showed a marked reduction from 5 to 21 months of age but no further reduction was observed between 21 and 29-30 months. Hormone treatment induced a mean relative increase (% increase relative to age-matched controls) in serum thymulin of 44, 38 and 48% in young, old and senescent rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1993

Pleiotropic influence of triiodothyronine on thymus physiology.

It is well demonstrated that the thymus gland is under neuroendocrine control. Thymic endocrine function can be modulated by a variety of hormones including those secreted by the thyroid gland. This prompted us to investigate putative influences of T3 in further aspects of thymus physiology. We showed that T3-treated animals exhibited an increase in thymus weight, cellularity and cycling cells. Moreover, Thy1+ thymocytes as well as CD4-CD8 defined subsets were augmented in absolute numbers, whereas PgP.1+ cells increased in both absolute and percentage values. In parallel, the total numbers of thymic nurse cells were also increased. Regarding the expression of extracellular matrix components (ECM) by microenvironmental cells, we observed an enhancement in the intrathymic ECM upon T3 in vivo treatment. Similar effects were found in vitro by treating a thymic epithelial cell line or thymic nurse cell-derived epithelial cultures with T3. This treatment also increased the expression of ECM receptors by thymic epithelial cultures. Interestingly, an enhancement in thymocyte/thymic epithelial cell adhesion ratio was observed after T3 treatment of epithelial cells. Our data suggest that T3 exerts a pleiotropic effect upon thymus physiology, stimulating thymocyte differentiation, not only by modulating epithelial cell hormonal secretion but also their production of ECM proteins and respective receptors.

Animals↗
PubMed1993

Characterization of the extracellular matrix-containing giant perivascular spaces in the NOD mouse thymus.

It is well established that the NOD mouse develops T-cell-dependent autoimmune type I diabetes that is abolished by neonatal Tx and enhanced by Tx at weaning. In a previous study, we demonstrated that the NOD thymus displays various abnormalities in the microenvironmental compartment, including abnormal distribution of epithelial cell subsets, precocious decline in thymic hormone production and formation of giant PVS. These latter structures present an internal ECM-containing network filled with T-cells and to a lesser extent B-cells. Herein we have investigated further the giant PVS and particularly the origin of the T-cells that colonize these structures. The thymic origin of intra-PVS T-cells was ascertained by distinct protocols. First, sublethal X-ray irradiation or HC treatment leading to cortical thymocyte depletion showed that intra-PVS lymphocytes were resistant, similar to medullary thymocytes. Second, adoptive transfer experiments that used newborn or adult irradiated Thy-1 congenic recipients demonstrated that intra-PVS accumulation of T-cells did not result from the reentry of peripheral mature T-cells into the thymus. Third, kinetic studies that used BrdUrd pulse chase revealed that labeled intra-PVS cells appear late, simultaneously with medullary thymocytes, and remain only transiently within the PVS. Thus, the kinetics of T-cell reconstitution of PVS was compatible with the progressive differentiation of T-cell precursors originating from the thymic cortex. In this respect, the giant PVS of the NOD mouse thymus may represent a useful model to study the relationships between trafficking thymocytes and ECM proteins.

Animals↗
PubMed1992

Hematopoietic stem cells and myeloid precursor cells in nonobese diabetic (NOD) mice.

Expression of diabetes susceptibility genes at the hemopoietic stem cell level is sufficient for the development of the disease in nonobese diabetic (NOD) mice. This work investigated whether the defects that reside within the stem cells have consequences on the homeostasis of the stem and progenitor cell compartments. The fraction of cyclically active stem cells, or spleen colony-forming units (CFU-s), is enlarged, and their differentiation toward megakaryocytopoiesis seems to be enhanced in NOD mice at 3 and 10 weeks of age as compared to C57BL/6 mice. Whereas colony-forming unit assay (CFU-A) numbers are normal in the bone marrow, they are significantly increased in the spleen of NOD mice. A strain-dependent difference in granulocyte-macrophage colony-forming cell (GM-CFC) numbers was observed; they were higher in NOD mice than in B6 mice of three and ten weeks of age. These results suggest that autoimmune type 1 diabetes mellitus of the NOD mouse is accompanied by disorders of myelopoiesis and megakaryopoiesis. This observation is in keeping with the role of macrophages in the development of diabetes and with the hyperactivity of diabetic platelets.

Animals↗
PubMed1992

Glucocorticoids in the nonobese diabetic (NOD) mouse: basal serum levels, effect of endocrine manipulation and immobilization stress.

The NOD mouse is a recognized model for studying immunologically mediated insulin-dependent diabetes mellitus (IDDM). In most colonies, the disease appears with a greater preponderance in females than in males and castration alters the expression of the disease. The prevalence of diabetes may also vary depending upon environmental factors such as stress. Therefore, we measured in the NOD mouse serum glucocorticoid concentrations in basal and stress conditions. We observed in NOD as well as in C57BL/6 mice, taken as controls, a circadian rhythm of corticosterone, with females having higher values than males. After a single restraint stress, female and male NOD mice exhibit a comparable response, whereas after repeated stress, males respond significantly less than females, suggesting an adaptation phenomenon. In contrast, there is no difference in the pattern of corticosterone response of C57BL/6 females and males to both types of stress, but females always respond better than males. Moreover, whatever the stress considered, NOD mice generally exhibit a higher corticosterone response than C57BL/6 mice. The sexual dimorphism in diabetes expression in NOD mice may be related to the levels of corticosterone, a hyperglycemic hormone, in both basal and stress conditions. However, the understanding of corticosteroid effects in this model of type I IDDM is rather complex given their well known anti-inflammatory and immunosuppressive effects in other models of autoimmune diseases.

Adrenalectomy↗
PubMed1992

Enhanced metabolism of arachidonic acid by macrophages from nonobese diabetic (NOD) mice.

The inbred nonobese diabetic (NOD) mouse spontaneously develops an autoimmune diabetes, which is now recognized as an experimental model for human type I insulin-dependent diabetes mellitus (IDDM). The autoimmune reaction, specifically directed against pancreatic beta cells (insulitis), involves both macrophages and T lymphocytes. The study of the production of cyclooxygenase and lipoxygenase derivatives of arachidonic acid metabolism shows that in some conditions, and in particular in the presence of zymosan A, macrophages from NOD mice produced significantly more 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene C4 (LTC4) than macrophages from age- and sex-matched C57BL/6 mice. Moreover, zymosan A-stimulated macrophages from NOD females produced significantly more LTC4 than did macrophages from NOD males. These results may be of interest, given the bidirectional relationship between the various cytokines involved in the destruction of beta cells of the islets of Langerhans and different eicosanoids.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

In vivo effects of growth hormone on thymus function in aging mice.

It is well demonstrated that the normal functioning of the thymus gland is under neuroendocrine control. Thus, steroid, thyroid, and pituitary hormones can affect distinct structural and/or functional thymic parameters. Particularly growth hormone (GH) was shown to be capable of restoring some thymus functions in old individuals. This prompted us to carry out a multiparametric analysis of the thymus in young, middle-aged, and old mice, subjected to GH treatment lasting 3 or 6 weeks. For that, we treated animals with daily injections of ovine GH (2 micrograms/g BW). Although the general microarchitecture of the thymus remained unchanged following in vivo GH treatment, there was a clearcut increase in thymulin production, independent of the age group analyzed. Regarding the lymphoid compartment, we could not find evidence of changes in total thymocyte numbers nor in the subsets phenotypically defined by the expression of CD3, CD4, and CD8 antigens. Nonetheless, in GH-treated middle-aged and old mice, the concanavalin A-dependent proliferative response of thymocytes, as well as IL-6 production were enhanced compared to age-matched controls. These findings support the notion that GH has a pleiotropic effect upon the thymus, functionally affecting both microenvironmental and lymphoid compartments of the organ.

Aging↗